bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024‒06‒23
89 papers selected by
Viktor Korolchuk, Newcastle University
  1. Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.
  2. Novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease.
  3. SPRED2 Is a Novel Regulator of Autophagy in Hepatocellular Carcinoma Cells and Normal Hepatocytes.
  4. Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration.
  5. An initial HOPS-mediated fusion event is critical for autophagosome transport initiation from the axon terminal.
  6. Calorie restriction and calorie-restriction mimetics activate chaperone-mediated autophagy.
  7. Dissecting the multifaceted roles of autophagy in cancer initiation, growth, and metastasis: from molecular mechanisms to therapeutic applications.
  8. Secretory autophagy - a new paradigm regulating synaptic plasticity.
  9. mTOR: Its Critical Role in Metabolic Diseases, Cancer, and the Aging Process.
  10. NCOA4 initiates ferritinophagy by binding GATE16 using two highly avid short linear interaction motifs.
  11. The role of autophagy regulated by the PI3K/AKT/mTOR pathway and innate lymphoid cells in eosinophilic chronic sinusitis with nasal polyps.
  12. Hijacking autophagy for infection by flaviviruses.
  13. Sequestosome-1 (SQSTM1/p62) as a target in dopamine catabolite-mediated cellular dyshomeostasis.
  14. A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1.
  15. RCHY1 and OPTN: an E3-ligase and an autophagy receptor required for melanophagy, respectively.
  16. RIT2 regulates autophagy lysosomal pathway induction and protects against α-synuclein pathology in a cellular model of Parkinson's disease.
  17. Crosstalk between degradation and bioenergetics: how autophagy and endolysosomal processes regulate energy production.
  18. Rbpms2 promotes female fate upstream of the nutrient sensing Gator2 complex component Mios.
  19. Exploring Importance and Regulation of Autophagy in Cancer Stem Cells and Stem Cell-Based Therapies.
  20. IL-37d suppresses Rheb-mTORC1 axis independently of TCS2 to alleviate alcoholic liver disease.
  21. Copper Chelation Therapy Attenuates Periodontitis Inflammation through the Cuproptosis/Autophagy/Lysosome Axis.
  22. The autophagic regulation of rosiglitazone-promoted adipocyte browning.
  23. Regulation of Autophagy Signaling Pathways by Ginseng Saponins: A Review.
  24. TSC2 loss in neural progenitor cells suppresses translation of ASD/NDD-associated transcripts in an mTORC1- and MNK1/2-reversible fashion.
  25. Inflammasomes Are Influenced by Epigenetic and Autophagy Mechanisms in Colorectal Cancer Signaling.
  26. PLA2G15 is a Lysosomal BMP Hydrolase with Ester Position Specificity and its Targeting Ameliorates Lysosomal Disease.
  27. Transcription factor EB (TFEB) interaction with RagC is disrupted during enterovirus D68 infection.
  28. Inhibition of PIKfyve Leads to Lysosomal Disorders via Dysregulation of mTOR Signaling.
  29. Research progress of autophagy in heart failure.
  30. CRISPRa Analysis of Phosphoinositide Phosphatases Shows That TMEM55A Is a Positive Regulator of Autophagy.
  31. HLH-30/TFEB rewires the chaperone network to promote proteostasis under conditions of Coenzyme A and Iron-Sulfur Cluster Deficiency.
  32. Ulk1 Phosphorylation at S555 is Not Required in Exercise Training-mediated Improvements in Endurance and Metabolic Capacity in Healthy Mice.
  33. Progress in the study of autophagy-related proteins affecting resistance to chemotherapeutic drugs in leukemia.
  34. Expression of Wild-Type and Mutant Human TDP-43 in Yeast Inhibits TOROID (TORC1 Organized in Inhibited Domain) Formation and Autophagy Proportionally to the Levels of TDP-43 Toxicity.
  35. The role of glucagon-like peptide-1/GLP-1R and autophagy in diabetic cardiovascular disease.
  36. Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes.
  37. Opposing actions of JIP4 and RILPL1 provide antagonistic motor force to dynamically regulate membrane reformation during lysosomal tubulation/sorting driven by LRRK2.
  38. Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease.
  39. Inhibition of CSPG-PTPσ Activates Autophagy Flux and Lysosome Fusion, Aids Axon and Synaptic Reorganization in Spinal Cord Injury.
  40. Autophagy Promotes Enrichment of Raft Components within Extracellular Vesicles Secreted by Human 2FTGH Cells.
  41. Hesperidin Alleviates Hepatic Injury Caused by Deoxynivalenol Exposure through Activation of mTOR and AKT/GSK3β/TFEB Pathways.
  42. SNX14 inhibits autophagy via the PI3K/AKT/mTOR signaling cascade in breast cancer cells.
  43. Trophoblast-specific overexpression of the LAT1 increases transplacental transport of essential amino acids and fetal growth in mice.
  44. Human TSC2 Mutant Cells Exhibit Aberrations in Early Neurodevelopment Accompanied by Changes in the DNA Methylome.
  45. Mitigation of experimental ER stress and diabetes mellitus induced peripheral neuropathy by autophagy promoter, 6-BIO.
  46. Mitophagy as a link between ECM stiffness and chondrocyte senescence.
  47. Targeting a mTOR/autophagy axis: a double-edged sword of rapamycin in spontaneous miscarriage.
  48. Immunohistochemistry analysis of autophagy-related proteins Beclin-1, p62/SQSTM1, and LC3B in breast carcinoma progression to bone metastasis.
  49. UFMylation: An integral post-translational modification for the regulation of proteostasis and cellular functions.
  50. Induction of DEPP1 by HIF Mediates Multiple Hallmarks of Ischemic Cardiomyopathy.
  51. Erastin promotes random-pattern skin flaps survival by inducing mTORC1-TFEB mediated autophagy.
  52. Olfaction regulates peripheral mitophagy and mitochondrial function.
  53. Therapeutic Relevance of Inducing Autophagy in β-Thalassemia.
  54. Lysosome damage triggers acute formation of ER to lysosomes membrane tethers mediated by the bridge-like lipid transport protein VPS13C.
  55. Interlinked destinies: How ubiquitin-proteasome and autophagy systems underpin neurocognitive outcomes.
  56. FABP5-binding lipids regulate autophagy in differentiated SH-SY5Y cells.
  57. Disruptions in axonal lysosome transport and its contribution to neurological disease.
  58. Autophagy and inflammation an intricate affair in the management of obesity and metabolic disorders: evidence for novel pharmacological strategies?
  59. Lysosome Targeting Chimaeras for Glut1-Facilitated Targeted Protein Degradation.
  60. Extracellular Matrix Remodeling Alleviates Memory Deficits in Alzheimer's Disease by Enhancing the Astrocytic Autophagy-Lysosome Pathway.
  61. β-Synuclein Intermediates α-Synuclein Neurotoxicity in Parkinson's Disease.
  62. Endosome mediated nucleocytoplasmic trafficking and endomembrane allocation is crucial to polyglutamine toxicity.
  63. A genetically-encoded fluorescence-based reporter to spatiotemporally investigate mannose-6-phosphate pathway.
  64. The hexosamine biosynthetic pathway rescues lysosomal dysfunction in Parkinson's disease patient iPSC derived midbrain neurons.
  65. The neuroprotective effect of Chinese herbal medicine for cerebral ischemia reperfusion injury through regulating mitophagy.
  66. The emerging role and clinicopathological significance of MFSD12 in cancer and lysosomal storage diseases.
  67. The Role of Plant Ubiquitin-like Modifiers in the Formation of Salt Stress Tolerance.
  68. In situ stoichiometry amounts of p62 and poly-ubiquitin exceed the increase of alpha-synuclein during degeneration of catecholamine cells induced by autophagy inhibition in vitro.
  69. CCDC50 mediates the clearance of protein aggregates to prevent cellular proteotoxicity.
  70. A multimodal exercise countermeasure prevents the negative impact of head-down tilt bed rest on muscle volume and mitochondrial health in older adults.
  71. Claudin-4 modulates autophagy via SLC1A5/LAT1 as a mechanism to regulate micronuclei.
  72. Hippocampal mitophagy contributes to spatial memory via maintaining neurogenesis during the development of mice.
  73. Quantitative control of subcellular protein localization with a photochromic dimerizer.
  74. Natural autophagy activators: A promising strategy for combating photoaging.
  75. Paeoniflorin alleviates depression by inhibiting the activation of NLRP3 inflammasome via promoting mitochondrial autophagy.
  76. Autophagy markers LC3 and p62 in aging lumbar motor neurons.
  77. Metallothionein 3 Potentiates Pulmonary Artery Smooth Muscle Cell Proliferation by Promoting Zinc-MTF1-ATG5 Axis-mediated Autophagosome Formation.
  78. Mitochondrial Dysfunction in Systemic Lupus Erythematosus with a Focus on Lupus Nephritis.
  79. M133S mutation possibly involve in the ER stress and mitophagy pathway in maintenance hemodialysis patients with occult hepatitis B infection.
  80. Ovarian Cancer Cell-Conditioning Medium Induces Cancer-Associated Fibroblast Phenoconversion through Glucose-Dependent Inhibition of Autophagy.
  81. Arabidopsis CaLB1 undergoes phase separation with the ESCRT protein ALIX and modulates autophagosome maturation.
  82. Mild heat shock at 40ºC increases levels of autophagy: role of Nrf2.
  83. CTRP9 alleviates diet induced obesity through increasing lipolysis mediated by enhancing autophagy-initiation complex formation.
  84. Tumor suppressor Par-4 activates autophagy-dependent ferroptosis.
  85. Astragaloside IV Protects Against Podocyte Injury by Upregulating Mitophagy via the Mfn2/Pink1/Parkin Axis.
  86. Autophagic degradation of DHCR7 activates AKT3 and promotes sevoflurane-induced hippocampal neuroinflammation in neonatal mice.
  87. Autophagy: A potential target for natural products in the treatment of ulcerative colitis.
  88. Atg7 autophagy-independent role on governing neural stem cell fate could be potentially applied for regenerative medicine.
  89. Cytarabine prevents neuronal damage by enhancing AMPK to stimulate PINK1 / Parkin-involved mitophagy in Parkinson's disease model.
  1. Dev Cell. 2024 May 20. pii: S1534-5807(24)00295-8. [Epub ahead of print]
    Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.
    George Kelly, Tetsushi Kataura, Johan Panek, Gailing Ma, Hanna Salmonowicz, Ashley Davis, Hannah Kendall, Charlotte Brookes, Daniel Moscoh Ayine-Tora, Peter Banks, Glyn Nelson, Laura Dobby, Patricia R Pitrez, Laura Booth, Lydia Costello, Gavin D Richardson, Penny Lovat, Stefan Przyborski, Lino Ferreira, Laura Greaves, Karolina Szczepanowska, Thomas von Zglinicki, Satomi Miwa, Max Brown, Michael Flagler, John E Oblong, Charles C Bascom, Bernadette Carroll, Jóhannes Reynisson, Viktor I Korolchuk.
      Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor (SAR). Importantly, this pathway was suppressed upon the induction of cellular senescence and in naturally aged cells, leading to a robust shutdown of mitophagy. Inhibition of mitophagy in proliferating cells was sufficient to trigger the senescence program, while reactivation of mitophagy was necessary for the anti-senescence effects of NAD precursors or rapamycin. Furthermore, reactivation of mitophagy by a p62-targeting small molecule rescued markers of cellular aging, which establishes mitochondrial quality control as a promising target for anti-aging interventions.
    Keywords:  PINK1; Parkin; aging; autophagy; mitophagy; nicotinamide; nicotinamide riboside; p62; rapamycin; redox; senescence
    DOI:  https://doi.org/10.1016/j.devcel.2024.04.020
  2. Elife. 2024 Jun 20. pii: e98649. [Epub ahead of print]13
    Novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease.
    Yuki Date, Yukiko Sasazawa, Mitsuhiro Kitagawa, Kentaro Gejima, Ayami Suzuki, Hideyuki Saya, Yasuyuki Kida, Masaya Imoto, Eisuke Itakura, Nobutaka Hattori, Shinji Saiki.
      The autophagy-lysosome pathway plays an indispensable role in the protein quality control by degrading abnormal organelles and proteins including a-synuclein (aSyn) associated with the pathogenesis of Parkinson's disease (PD). However, the activation of this pathway is mainly by targeting lysosomal enzymic activity. Here, we focused on the autophagosome-lysosome fusion process around the microtubule-organizing center (MTOC) regulated by lysosomal positioning. Through high-throughput chemical screening, we identified 6 out of 1,200 clinically approved drugs enabling the lysosomes to accumulate around the MTOC with autophagy flux enhancement. We further demonstrated that these compounds induce the lysosomal clustering through a JIP4-TRPML1-dependent mechanism. Among them, the lysosomal-clustering compound albendazole promoted the autophagy-dependent degradation of Triton-X-insoluble, proteasome inhibitor-induced aggregates. In a cellular PD model, albendazole boosted insoluble aSyn degradation. Our results revealed that lysosomal clustering can facilitate the breakdown of protein aggregates, suggesting that lysosome-clustering compounds may offer a promising therapeutic strategy against neurodegenerative diseases characterized by the presence of aggregate-prone proteins.
    Keywords:  cell biology
    DOI:  https://doi.org/10.7554/eLife.98649
  3. Int J Mol Sci. 2024 Jun 06. pii: 6269. [Epub ahead of print]25(11):
    SPRED2 Is a Novel Regulator of Autophagy in Hepatocellular Carcinoma Cells and Normal Hepatocytes.
    Tianyi Wang, Tong Gao, Masayoshi Fujisawa, Toshiaki Ohara, Masakiyo Sakaguchi, Teizo Yoshimura, Akihiro Matsukawa.
      Sprouty-related enabled/vasodilator-stimulated phosphoprotein homology 1 domain containing 2 (SPRED2) is an inhibitor of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and has been shown to promote autophagy in several cancers. Here, we aimed to determine whether SPRED2 plays a role in autophagy in hepatocellular carcinoma (HCC) cells. The Cancer Genome Atlas (TCGA) Liver Cancer Database showed a negative association between the level of SPRED2 and p62, a ubiquitin-binding scaffold protein that accumulates when autophagy is inhibited. Immunohistochemically, accumulation of p62 was detected in human HCC tissues with low SPRED2 expression. Overexpression of SPRED2 in HCC cells increased the number of autophagosomes and autophagic vacuoles containing damaged mitochondria, decreased p62 levels, and increased levels of light-chain-3 (LC3)-II, an autophagy marker. In contrast, SPRED2 deficiency increased p62 levels and decreased LC3-II levels. SPRED2 expression levels were negatively correlated with translocase of outer mitochondrial membrane 20 (TOM20) expression levels, suggesting its role in mitophagy. Mechanistically, SPRED2 overexpression reduced ERK activation followed by the mechanistic or mammalian target of rapamycin complex 1 (mTORC1)-mediated signaling pathway, and SPRED2 deficiency showed the opposite pattern. Finally, hepatic autophagy was impaired in the liver of SPRED2-deficient mice with hepatic lipid droplet accumulation in response to starvation. These results indicate that SPRED2 is a critical regulator of autophagy not only in HCC cells, but also in hepatocytes, and thus the manipulation of this process may provide new insights into liver pathology.
    Keywords:  MAPK/ERK; SPRED proteins; autophagy; hepatocellular carcinoma; mTOR; mitophagy
    DOI:  https://doi.org/10.3390/ijms25116269
  4. Mol Neurodegener. 2024 Jun 18. 19(1): 49
    Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration.
    Juan Ignacio Jiménez-Loygorri, Álvaro Viedma-Poyatos, Raquel Gómez-Sintes, Patricia Boya.
      BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the developed world, and the number of people affected is expected to almost double by 2040. The retina presents one of the highest metabolic demands in our bodies that is partially or fully fulfilled by mitochondria in the neuroretina and retinal pigment epithelium (RPE), respectively. Together with its post-mitotic status and constant photooxidative damage from incoming light, the retina requires a tightly-regulated housekeeping system that involves autophagy. The natural polyphenol Urolithin A (UA) has shown neuroprotective benefits in several models of aging and age-associated disorders, mostly attributed to its ability to induce mitophagy and mitochondrial biogenesis. Sodium iodate (SI) administration recapitulates the late stages of AMD, including geographic atrophy and photoreceptor cell death.METHODS: A combination of in vitro, ex vivo and in vivo models were used to test the neuroprotective potential of UA in the SI model. Functional assays (OCT, ERGs), cellular analysis (flow cytometry, qPCR) and fine confocal microscopy (immunohistochemistry, tandem selective autophagy reporters) helped address this question.
    RESULTS: UA alleviated neurodegeneration and preserved visual function in SI-treated mice. Simultaneously, we observed severe proteostasis defects upon SI damage induction, including autophagosome accumulation, that were resolved in animals that received UA. Treatment with UA restored autophagic flux and triggered PINK1/Parkin-dependent mitophagy, as previously reported in the literature. Autophagy blockage caused by SI was caused by severe lysosomal membrane permeabilization. While UA did not induce lysosomal biogenesis, it did restore upcycling of permeabilized lysosomes through lysophagy. Knockdown of the lysophagy adaptor SQSTM1/p62 abrogated viability rescue by UA in SI-treated cells, exacerbated lysosomal defects and inhibited lysophagy.
    CONCLUSIONS: Collectively, these data highlight a novel putative application of UA in the treatment of AMD whereby it bypasses lysosomal defects by promoting p62-dependent lysophagy to sustain proteostasis.
    Keywords:  Age-related macular degeneration; Autophagy; Lysophagy; Lysosomal membrane permeabilization; SQSTM1/p62; Sodium iodate; Urolithin A
    DOI:  https://doi.org/10.1186/s13024-024-00739-3
  5. Autophagy. 2024 Jun 20. 1-22
    An initial HOPS-mediated fusion event is critical for autophagosome transport initiation from the axon terminal.
    Serena R Wisner, Madison Chlebowski, Amrita Mandal, Don Mai, Chris Stein, Ronald S Petralia, Ya-Xian Wang, Catherine M Drerup.
      In neurons, macroautophagy/autophagy is a frequent and critical process. In the axon, autophagy begins in the axon terminal, where most nascent autophagosomes form. After formation, autophagosomes must initiate transport to exit the axon terminal and move toward the cell body via retrograde transport. During retrograde transport these autophagosomes mature through repetitive fusion events. Complete lysosomal cargo degradation occurs largely in the cell body. The precipitating events to stimulate retrograde autophagosome transport have been debated but their importance is clear: disrupting neuronal autophagy or autophagosome transport is detrimental to neuronal health and function. We have identified the HOPS complex as essential for early autophagosome maturation and consequent initiation of retrograde transport from the axon terminal. In yeast and mammalian cells, HOPS controls fusion between autophagosomes and late endosomes with lysosomes. Using zebrafish strains with loss-of-function mutations in vps18 and vps41, core components of the HOPS complex, we found that disruption of HOPS eliminates autophagosome maturation and disrupts retrograde autophagosome transport initiation from the axon terminal. We confirmed this phenotype was due to loss of HOPS complex formation using an endogenous deletion of the HOPS binding domain in Vps18. Finally, using pharmacological inhibition of lysosomal proteases, we show that initiation of autophagosome retrograde transport requires autophagosome maturation. Together, our data demonstrate that HOPS-mediated fusion events are critical for retrograde autophagosome transport initiation through promoting autophagosome maturation. This reveals critical roles for the HOPS complex in neuronal autophagy which deepens our understanding of the cellular pathology of HOPS-complex linked neurodegenerative diseases.Abbreviations: CORVET: Class C core vacuole/endosome tethering; gRNA: guide RNA; HOPS: homotypic fusion and protein sorting; pLL: posterior lateral line; Vps18: VPS18 core subunit of CORVET and HOPS complexes; Vps41: VPS41 subunit of HOPS complex.
    Keywords:  Axon terminal; Vps18; autophagy; axonal transport; lysosome; neuron
    DOI:  https://doi.org/10.1080/15548627.2024.2366122
  6. Proc Natl Acad Sci U S A. 2024 Jun 25. 121(26): e2317945121
    Calorie restriction and calorie-restriction mimetics activate chaperone-mediated autophagy.
    Maryam Jafari, Adrián Macho-González, Antonio Diaz, Kristen Lindenau, Olaya Santiago-Fernández, Mei Zeng, Ashish C Massey, Rafael de Cabo, Susmita Kaushik, Ana Maria Cuervo.
      Chaperone-mediated autophagy (CMA) is part of the mammalian cellular proteostasis network that ensures protein quality control, maintenance of proteome homeostasis, and proteome changes required for the adaptation to stress. Loss of proteostasis is one of the hallmarks of aging. CMA decreases with age in multiple rodent tissues and human cell types. A decrease in lysosomal levels of the lysosome-associated membrane protein type 2A (LAMP2A), the CMA receptor, has been identified as a main reason for declined CMA in aging. Here, we report constitutive activation of CMA with calorie restriction (CR), an intervention that extends healthspan, in old rodent livers and in an in vitro model of CR with cultured fibroblasts. We found that CR-mediated upregulation of CMA is due to improved stability of LAMP2A at the lysosome membrane. We also explore the translational value of our observations using calorie-restriction mimetics (CRMs), pharmacologically active substances that reproduce the biochemical and functional effects of CR. We show that acute treatment of old mice with CRMs also robustly activates CMA in several tissues and that this activation is required for the higher resistance to lipid dietary challenges conferred by treatment with CRMs. We conclude that part of the beneficial effects associated with CR/CRMs could be a consequence of the constitutive activation of CMA mediated by these interventions.
    Keywords:  aging; autophagy; dietary restriction; gerotherapeutics; lysosomes
    DOI:  https://doi.org/10.1073/pnas.2317945121
  7. Med Oncol. 2024 Jun 20. 41(7): 183
    Dissecting the multifaceted roles of autophagy in cancer initiation, growth, and metastasis: from molecular mechanisms to therapeutic applications.
    Afia Ayub, Md Kamrul Hasan, Zimam Mahmud, Md Sabbir Hossain, Yearul Kabir.
      Autophagy is a cytoplasmic defense mechanism that cells use to break and reprocess their intracellular components. This utilization of autophagy is regarded as a savior in nutrient-deficient and other stressful conditions. Hence, autophagy keeps contact with and responds to miscellaneous cellular tensions and diverse pathways of signal transductions, such as growth signaling and cellular death. Importantly, autophagy is regarded as an effective tumor suppressor because regular autophagic breakdown is essential for cellular maintenance and minimizing cellular damage. However, paradoxically, autophagy has also been observed to promote the events of malignancies. This review discussed the dual role of autophagy in cancer, emphasizing its influence on tumor survival and progression. Possessing such a dual contribution to the malignant establishment, the prevention of autophagy can potentially advocate for the advancement of malignant transformation. In contrast, for the context of the instituted tumor, the agents of preventing autophagy potently inhibit the advancement of the tumor. Key regulators, including calpain 1, mTORC1, and AMPK, modulate autophagy in response to nutritional conditions and stress. Oncogenic mutations like RAS and B-RAF underscore autophagy's pivotal role in cancer development. The review also delves into autophagy's context-dependent roles in tumorigenesis, metastasis, and the tumor microenvironment (TME). It also discusses the therapeutic effectiveness of autophagy for several cancers. The recent implication of autophagy in the control of both innate and antibody-mediated immune systems made it a center of attention to evaluating its role concerning tumor antigens and treatments of cancer.
    Keywords:  Autophagosome; Autophagy; Cancer immunotherapy; Epithelial to mesenchymal transition; Metastatic-cascade; Tumor antigens; Tumor microenvironment; Tumorigenesis
    DOI:  https://doi.org/10.1007/s12032-024-02417-2
  8. Autophagy. 2024 Jun 20.
    Secretory autophagy - a new paradigm regulating synaptic plasticity.
    Yen-Ching Chang, Karen T Chang.
      When exposed to new experiences or changes in the environment, neurons rapidly remodel their synaptic structure and function in a process called activity-induced synaptic remodeling. This process is necessary for transforming transient experiences into stable, lasting memories. The molecular mechanisms underlying acute, activity-dependent synaptic changes are not well understood, partly because processes regulating synaptic plasticity and neurodevelopment are intricately linked. By using an RNAi screen in Drosophila targeting genes associated with human nervous system function, we found that while macroautophagy (referred to as autophagy) is fundamental for both synapse development and synaptic plasticity, activity-induced synaptic remodeling does not rely on genes associated with lysosomal degradation. These findings suggest a requirement for the unconventional secretory autophagy pathway in regulating synaptic plasticity, wherein autophagosomes, instead of fusing with lysosomes for degradation, fuse with the plasma membrane to release their contents extracellularly. To test this hypothesis, we knocked down Sec22, Snap29, and Rab8, molecular components required for secretory autophagy, all of which disrupted structural and functional plasticity. Additionally, by monitoring autophagy, we demonstrated that neuronal activity suppresses degradative autophagy to shift the pathway toward secretory autophagy release. Our work unveils secretory autophagy as a novel trans-synaptic signaling mechanism crucial for activity-induced synaptic remodeling.
    Keywords:  Activity-induced synaptic remodeling; Drosophila; secretory autophagy; synaptic plasticity
    DOI:  https://doi.org/10.1080/15548627.2024.2370179
  9. Int J Mol Sci. 2024 Jun 02. pii: 6141. [Epub ahead of print]25(11):
    mTOR: Its Critical Role in Metabolic Diseases, Cancer, and the Aging Process.
    Sulaiman K Marafie, Fahd Al-Mulla, Jehad Abubaker.
      The mammalian target of rapamycin (mTOR) is a pivotal regulator, integrating diverse environmental signals to control fundamental cellular functions, such as protein synthesis, cell growth, survival, and apoptosis. Embedded in a complex network of signaling pathways, mTOR dysregulation is implicated in the onset and progression of a range of human diseases, including metabolic disorders such as diabetes and cardiovascular diseases, as well as various cancers. mTOR also has a notable role in aging. Given its extensive biological impact, mTOR signaling is a prime therapeutic target for addressing these complex conditions. The development of mTOR inhibitors has proven advantageous in numerous research domains. This review delves into the significance of mTOR signaling, highlighting the critical components of this intricate network that contribute to disease. Additionally, it addresses the latest findings on mTOR inhibitors and their clinical implications. The review also emphasizes the importance of developing more effective next-generation mTOR inhibitors with dual functions to efficiently target the mTOR pathways. A comprehensive understanding of mTOR signaling will enable the development of effective therapeutic strategies for managing diseases associated with mTOR dysregulation.
    Keywords:  aging; cancer; mTOR; mTOR inhibitors; mTORC1; mTORC2; metabolic disease
    DOI:  https://doi.org/10.3390/ijms25116141
  10. bioRxiv. 2024 Jun 09. pii: 2024.06.09.597909. [Epub ahead of print]
    NCOA4 initiates ferritinophagy by binding GATE16 using two highly avid short linear interaction motifs.
    April Lee, Joseph H Davis.
      Cells carefully regulate cytosolic iron, which is a vital enzymatic cofactor, yet is toxic in excess. In mammalian cells, surplus iron is sequestered in ferritin cages that, in iron limiting conditions, are degraded through the selective autophagy pathway ferritinophagy to liberate free iron. Prior work identified the ferritinophagy receptor protein NCOA4, which links ferritin and LC3/GABARAP-family member GATE16, effectively tethering ferritin to the autophagic machinery. Here, we elucidate the molecular mechanism underlying this interaction, discovering two short linear motifs in NCOA4 that each bind GATE16 with weak affinity. These binding motifs are highly avid and, in concert, support high-affinity NCOA4•GATE16 complex formation. We further find the minimal NCOA4 383-522 fragment bearing these motifs is sufficient for ferritinophagy and that both motifs are necessary for this activity. This work suggests a general mechanism wherein selective autophagy receptors can distinguish between the inactive soluble pools of LC3/GABARAPs and the active membrane-conjugated forms that drive autophagy. Finally, we find that iron decreases NCOA4 383-522 's affinity for GATE16, providing a plausible mechanism for iron-dependent regulation of ferritinophagy.
    DOI:  https://doi.org/10.1101/2024.06.09.597909
  11. Immun Inflamm Dis. 2024 Jun;12(6): e1310
    The role of autophagy regulated by the PI3K/AKT/mTOR pathway and innate lymphoid cells in eosinophilic chronic sinusitis with nasal polyps.
    Jin-Jing Zhuo, Chen Wang, Yi-Long Kai, Ying-Ying Xu, Ke-Jia Cheng.
      BACKGROUND: The PI3K/Akt/mTOR pathway and autophagy are important physiological processes. But their roles in eCRSwNP remains controversial.METHODS: In this study, we used the eCRSwNP mouse model, PI3K/Akt/mTOR pathway inhibitors, and autophagy inhibitors and activators to investigate the regulatory effects of the PI3K/Akt/mTOR pathway on autophagy, and their effects on eosinophilic inflammation, and tissue remodeling. The role of ILC2s in eCRSwNP was also studied, and the relationship between ILC2s and autophagy was preliminarily determined.
    RESULTS: Our results show that eosinophilic inflammation in eCRSwNP mice could be inhibited by promoting the autophagy; otherwise, eosinophilic inflammation could be promoted. Meanwhile, inhibition of the PI3K/Akt/mTOR pathway can further promote autophagy and inhibit eosinophilic inflammation. Meanwhile, inhibiting the PI3K/Akt/mTOR pathway and promoting autophagy can reduce the number of ILC2s and the severity of tissue remodeling in the nasal polyps of eCRSwNP mice.
    CONCLUSIONS: We conclude that the PI3K/Akt/mTOR pathway plays roles in eosinophilic inflammation and tissue remodeling of eCRSwNP, in part by regulating the level of autophagy. The downregulation of autophagy is a pathogenesis of eCRSwNP; therefore, the recovery of normal autophagy levels might be a new target for eCRSwNP therapy. Furthermore, autophagy might inhibit eosinophilic inflammation and tissue remodeling, in part by reducing the number of ILC2s.
    Keywords:  autophagy; chronic sinusitis; eosinophil; phosphoinositide 3‐kinase; type 2 innate lymphoid cells
    DOI:  https://doi.org/10.1002/iid3.1310
  12. Virus Res. 2024 Jun 20. pii: S0168-1702(24)00115-1. [Epub ahead of print]347 199422
    Hijacking autophagy for infection by flaviviruses.
    Ming-Hui Song, Yan Sun, Xiao-Bo Qiu.
      Autophagy is a lysosomal degradative pathway, which regulates the homeostasis of eukaryotic cells. This pathway can degrade misfolded or aggregated proteins, clear damaged organelles, and eliminate intracellular pathogens, including viruses, bacteria, and parasites. But, not all types of viruses are eliminated by autophagy. Flaviviruses (e.g., Yellow fever, Japanese encephalitis, Hepatitis C, Dengue, Zika, and West Nile viruses) are single-stranded and enveloped RNA viruses, and transmitted to humans primarily through the bites of arthropods, leading to severe and widespread illnesses. Like the coronavirus SARS-CoV-II, flaviviruses hijack autophagy for their infection and escape from host immune clearance. Thus, it is possible to control these viral infections by inhibiting autophagy. In this review, we summarize recent research progresses on hijacking of autophagy by flaviviruses and discuss the feasibility of antiviral therapies using autophagy inhibitors.
    Keywords:  Antiviral therapy; Autophagy; Flavivirus; Hijacking
    DOI:  https://doi.org/10.1016/j.virusres.2024.199422
  13. Cell Death Dis. 2024 Jun 18. 15(6): 424
    Sequestosome-1 (SQSTM1/p62) as a target in dopamine catabolite-mediated cellular dyshomeostasis.
    Anna Masato, Annapaola Andolfo, Giulia Favetta, Edoardo Niccolò Bellini, Susanna Cogo, Luisa Dalla Valle, Daniela Boassa, Elisa Greggio, Nicoletta Plotegher, Luigi Bubacco.
      Alterations in the dopamine catabolic pathway are known to contribute to the degeneration of nigrostriatal neurons in Parkinson's disease (PD). The progressive cellular buildup of the highly reactive intermediate 3,4-dihydroxyphenylacetaldehye (DOPAL) generates protein cross-linking, oligomerization of the PD-linked αSynuclein (αSyn) and imbalance in protein quality control. In this scenario, the autophagic cargo sequestome-1 (SQSTM1/p62) emerges as a target of DOPAL-dependent oligomerization and accumulation in cytosolic clusters. Although DOPAL-induced oxidative stress and activation of the Nrf2 pathway promote p62 expression, p62 oligomerization rather seems to be a consequence of direct DOPAL modification. DOPAL-induced p62 clusters are positive for ubiquitin and accumulate within lysosomal-related structures, likely affecting the autophagy-lysosomal functionality. Finally, p62 oligomerization and clustering is synergistically augmented by DOPAL-induced αSyn buildup. Hence, the substantial impact on p62 proteostasis caused by DOPAL appears of relevance for dopaminergic neurodegeneration, in which the progressive failure of degradative pathways and the deposition of proteins like αSyn, ubiquitin and p62 in inclusion bodies represent a major trait of PD pathology.
    DOI:  https://doi.org/10.1038/s41419-024-06763-x
  14. bioRxiv. 2024 Jun 03. pii: 2024.06.03.597144. [Epub ahead of print]
    A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1.
    Joanna Koszela, Anne Rintala-Dempsey, Giulia Salzano, Viveka Pimenta, Outi Kamarainen, Mads Gabrielsen, Aasna L Parui, Gary S Shaw, Helen Walden.
      Mutations in the gene encoding for the E3 ubiquitin ligase Parkin have been linked to early-onset Parkinson's disease. Besides many other cellular roles, Parkin is involved in clearance of damaged mitochondria via mitophagy - a process of particular importance in dopaminergic neurons. Upon mitochondrial damage, Parkin accumulates at the outer mitochondrial membrane and is activated, leading to ubiquitination of many mitochondrial substrates and recruitment of mitophagy effectors. While the activation mechanisms of autoinhibited Parkin have been extensively studied, it remains unknown how Parkin recognises its substrates for ubiquitination, and no substrate interaction site in Parkin has been reported. Here, we identify a conserved region in the flexible linker between the Ubl and RING0 domains of Parkin, which is indispensable for Parkin interaction with the mitochondrial GTPase Miro1. Our results explain the preferential targeting and ubiquitination of Miro1 by Parkin and provide a biochemical explanation for the presence of Parkin at the mitochondrial membrane prior to activation induced by mitochondrial damage. Our findings are important for understanding mitochondrial homeostasis and may inspire new therapeutic avenues for Parkinson's disease.
    DOI:  https://doi.org/10.1101/2024.06.03.597144
  15. Autophagy. 2024 Jun 20.
    RCHY1 and OPTN: an E3-ligase and an autophagy receptor required for melanophagy, respectively.
    Ki Won Lee, Yong-Yeon Cho, Kwang Dong Kim.
      Dysregulation of melanin homeostasis is implicated in causing skin pigmentation disorders, such as melasma due to hyperpigmentation and vitiligo due to hypopigmentation. Although the synthesis of melanin has been well studied, the removal of the formed skin pigment requires more research. We determined that β-mangostin, a plant-derived metabolite, induces the degradation of already-formed melanin in the mouse B16F10 cell line. The whitening effect of β-mangostin is mediated by macroautophagy/autophagy, as it was abolished by the knockdown of ATG5 or RB1CC1/FIP200, and by treatment with 3-methyladenine, a phosphatidylinositol 3-kinase complex inhibitor. However, the exact autophagy mechanism of melanosome degradation remains unknown. Selective autophagy for a specific cellular organelle requires specific E3-ligases and autophagic receptors for the target organelle. In this study, an E3-ligase, RCHY1, and an autophagy receptor, OPTN (optineurin), were identified as being essential for melanophagy in the β-mangostin-treated B16F10 cell line. As per our knowledge, this is the first report of a specific mechanism for the degradation of melanosomes, the target organelle of melanophagy. These findings are expected to broaden the scope of melanin homeostasis research and can be exploited for the development of therapeutics for skin pigmentation disorders.
    Keywords:  Melanin homeostasis; RCHY1; melanophagy; melanosome; optineurin; β-mangostin
    DOI:  https://doi.org/10.1080/15548627.2024.2370058
  16. Neurobiol Dis. 2024 Jun 15. pii: S0969-9961(24)00168-2. [Epub ahead of print]199 106568
    RIT2 regulates autophagy lysosomal pathway induction and protects against α-synuclein pathology in a cellular model of Parkinson's disease.
    Andy Y L Gao, Daniel R Montagna, Warren D Hirst, Paul A Temkin.
      Substantial work has been devoted to better understand the contribution of the myriad of genes that may underly the development of Parkinson's disease (PD) and their role in disease etiology. The small GTPase Ras-like without CAAX2 (RIT2) is one such genetic risk factor, with one single nucleotide polymorphism in the RIT2 locus, rs12456492, having been associated with PD risk in multiple populations. While RIT2 has previously been shown to influence signaling pathways, dopamine transporter trafficking, and LRRK2 activity, its cellular function remains unclear. In the current study, we have situated RIT2 to be upstream of various diverse processes associated with PD. In cellular models, we have shown that RIT2 is necessary for activity-dependent changes in the expression of genes related to the autophagy-lysosomal pathway (ALP) by regulating the nuclear translocation of MiT/TFE3-family transcription factors. RIT2 is also associated with lysosomes and can regulate autophagic flux and clearance by regulating lysosomal hydrolase expression and activity. Interestingly, upregulation of RIT2 can augment ALP flux and protect against α-synuclein aggregation in cortical neurons. Taken together, the present study suggests that RIT2 can regulates gene expression upstream of ALP function and that enhancing RIT2 activity may provide therapeutic benefit in PD.
    Keywords:  Autophagy-lysosomal pathway; CLEAR genes; Lysosomal hydrolase; Parkinson's disease; Proteostasis; Ras-like without CAAX 2; TFEB/TFE3; p38 MAPK; α-Synuclein
    DOI:  https://doi.org/10.1016/j.nbd.2024.106568
  17. Neural Regen Res. 2025 Mar 01. 20(3): 671-681
    Crosstalk between degradation and bioenergetics: how autophagy and endolysosomal processes regulate energy production.
    Angelid Pabon, Jagannatham Naidu Bhupana, Ching-On Wong.
      Cells undergo metabolic reprogramming to adapt to changes in nutrient availability, cellular activity, and transitions in cell states. The balance between glycolysis and mitochondrial respiration is crucial for energy production, and metabolic reprogramming stipulates a shift in such balance to optimize both bioenergetic efficiency and anabolic requirements. Failure in switching bioenergetic dependence can lead to maladaptation and pathogenesis. While cellular degradation is known to recycle precursor molecules for anabolism, its potential role in regulating energy production remains less explored. The bioenergetic switch between glycolysis and mitochondrial respiration involves transcription factors and organelle homeostasis, which are both regulated by the cellular degradation pathways. A growing body of studies has demonstrated that both stem cells and differentiated cells exhibit bioenergetic switch upon perturbations of autophagic activity or endolysosomal processes. Here, we highlighted the current understanding of the interplay between degradation processes, specifically autophagy and endolysosomes, transcription factors, endolysosomal signaling, and mitochondrial homeostasis in shaping cellular bioenergetics. This review aims to summarize the relationship between degradation processes and bioenergetics, providing a foundation for future research to unveil deeper mechanistic insights into bioenergetic regulation.
    DOI:  https://doi.org/10.4103/NRR.NRR-D-23-02095
  18. Nat Commun. 2024 Jun 19. 15(1): 5248
    Rbpms2 promotes female fate upstream of the nutrient sensing Gator2 complex component Mios.
    Miranda L Wilson, Shannon N Romano, Nitya Khatri, Devora Aharon, Yulong Liu, Odelya H Kaufman, Bruce W Draper, Florence L Marlow.
      Reproductive success relies on proper establishment and maintenance of biological sex. In many animals, including mammals, the primary gonad is initially ovary biased. We previously showed the RNA binding protein (RNAbp), Rbpms2, is required for ovary fate in zebrafish. Here, we identified Rbpms2 targets in oocytes (Rbpms2-bound oocyte RNAs; rboRNAs). We identify Rbpms2 as a translational regulator of rboRNAs, which include testis factors and ribosome biogenesis factors. Further, genetic analyses indicate that Rbpms2 promotes nucleolar amplification via the mTorc1 signaling pathway, specifically through the mTorc1-activating Gap activity towards Rags 2 (Gator2) component, Missing oocyte (Mios). Cumulatively, our findings indicate that early gonocytes are in a dual poised, bipotential state in which Rbpms2 acts as a binary fate-switch. Specifically, Rbpms2 represses testis factors and promotes oocyte factors to promote oocyte progression through an essential Gator2-mediated checkpoint, thereby integrating regulation of sexual differentiation factors and nutritional availability pathways in zebrafish oogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-49613-2
  19. Cells. 2024 Jun 01. pii: 958. [Epub ahead of print]13(11):
    Exploring Importance and Regulation of Autophagy in Cancer Stem Cells and Stem Cell-Based Therapies.
    Md Ataur Rahman, Ehsanul Hoque Apu, S M Rakib-Uz-Zaman, Somdeepa Chakraborti, Sujay Kumar Bhajan, Shakila Afroz Taleb, Mushfiq H Shaikh, Maroua Jalouli, Abdel Halim Harrath, Bonglee Kim.
      Autophagy is a globally conserved cellular activity that plays a critical role in maintaining cellular homeostasis through the breakdown and recycling of cellular constituents. In recent years, there has been much emphasis given to its complex role in cancer stem cells (CSCs) and stem cell treatment. This study examines the molecular processes that support autophagy and how it is regulated in the context of CSCs and stem cell treatment. Although autophagy plays a dual role in the management of CSCs, affecting their removal as well as their maintenance, the intricate interaction between the several signaling channels that control cellular survival and death as part of the molecular mechanism of autophagy has not been well elucidated. Given that CSCs have a role in the development, progression, and resistance to treatment of tumors, it is imperative to comprehend their biological activities. CSCs are important for cancer biology because they also show a tissue regeneration model that helps with organoid regeneration. In other words, the manipulation of autophagy is a viable therapeutic approach in the treatment of cancer and stem cell therapy. Both synthetic and natural substances that target autophagy pathways have demonstrated promise in improving stem cell-based therapies and eliminating CSCs. Nevertheless, there are difficulties associated with the limitations of autophagy in CSC regulation, including resistance mechanisms and off-target effects. Thus, the regulation of autophagy offers a versatile strategy for focusing on CSCs and enhancing the results of stem cell therapy. Therefore, understanding the complex interactions between autophagy and CSC biology would be essential for creating therapeutic treatments that work in both regenerative medicine and cancer treatment.
    Keywords:  autophagy; cancer cell; cancer stem cells; organoid and tissue regeneration; stem cell therapy; therapeutic target
    DOI:  https://doi.org/10.3390/cells13110958
  20. Commun Biol. 2024 Jun 21. 7(1): 756
    IL-37d suppresses Rheb-mTORC1 axis independently of TCS2 to alleviate alcoholic liver disease.
    Nuo Chen, Xiaoyu Wang, Yaxin Guo, Ming Zhao, Baihui Cao, Bing Zhan, Yubin Li, Tian Zhou, Faliang Zhu, Chun Guo, Yongyu Shi, Qun Wang, Lining Zhang, Yan Li.
      Tuberous sclerosis complex 2 (TSC2) crucially suppresses Rheb activity to prevent mTORC1 activation. However, mutations in TSC genes lead to mTORC1 overactivation, thereby causing various developmental disorders and cancer. Therefore, the discovery of novel Rheb inhibitors is vital to prevent mTOR overactivation. Here, we reveals that the anti-inflammatory cytokine IL-37d can bind to lysosomal Rheb and suppress its activity independent of TSC2, thereby preventing mTORC1 activation. The binding of IL-37d to Rheb switch-II subregion destabilizes the Rheb-mTOR and mTOR-S6K interactions, further halting mTORC1 signaling. Unlike TSC2, IL-37d is reduced under ethanol stimulation, which results in mitigating the suppression of lysosomal Rheb-mTORC1 activity. Consequently, the recombinant human IL-37d protein (rh-IL-37d) with a TAT peptide greatly improves alcohol-induced liver disorders by hindering Rheb-mTORC1 axis overactivation in a TSC2- independent manner. Together, IL-37d emerges as a novel Rheb suppressor independent of TSC2 to terminate mTORC1 activation and improve abnormal lipid metabolism in the liver.
    DOI:  https://doi.org/10.1038/s42003-024-06427-8
  21. Int J Mol Sci. 2024 May 28. pii: 5890. [Epub ahead of print]25(11):
    Copper Chelation Therapy Attenuates Periodontitis Inflammation through the Cuproptosis/Autophagy/Lysosome Axis.
    Lujin Zhang, I-Chen Tsai, Zihan Ni, Beichen Chen, Shuaiyuan Zhang, Luhui Cai, Qiong Xu.
      Periodontitis development arises from the intricate interplay between bacterial biofilms and the host's immune response, where macrophages serve pivotal roles in defense and tissue homeostasis. Here, we uncover the mitigative effect of copper chelator Tetrathiomolybdate (TTM) on periodontitis through inhibiting cuproptosis, a newly identified form of cell death which is dependent on copper. Our study reveals concurrent cuproptosis and a macrophage marker within murine models. In response to lipopolysaccharide (LPS) stimulation, macrophages exhibit elevated cuproptosis-associated markers, which are mitigated by the administration of TTM. TTM treatment enhances autophagosome expression and mitophagy-related gene expression, countering the LPS-induced inhibition of autophagy flux. TTM also attenuates the LPS-induced fusion of autophagosomes and lysosomes, the degradation of lysosomal acidic environments, lysosomal membrane permeability increase, and cathepsin B secretion. In mice with periodontitis, TTM reduces cuproptosis, enhances autophagy flux, and decreases Ctsb levels. Our findings underscore the crucial role of copper-chelating agent TTM in regulating the cuproptosis/mitophagy/lysosome pathway during periodontitis inflammation, suggesting TTM as a promising approach to alleviate macrophage dysfunction. Modulating cuproptosis through TTM treatment holds potential for periodontitis intervention.
    Keywords:  copper chelation; cuproptosis; lysosomes; macrophages; mitophagy; periodontitis
    DOI:  https://doi.org/10.3390/ijms25115890
  22. Front Pharmacol. 2024 ;15 1412520
    The autophagic regulation of rosiglitazone-promoted adipocyte browning.
    Yue Li, Wanqing Zheng, Xinhang Li, Zhengwei Lue, Yun Liu, Jiaying Wu, Xiangnan Zhang.
      Objective: Browning of white adipocytes is considered an efficient approach to combat obesity. Rosiglitazone induces the thermogenetic program of white adipocytes, but the underlying mechanisms remain elusive. Methods: Expression levels of browning and autophagy flux markers were detected by real-time PCR and immunoblotting. H&E and Oil Red O staining were performed to evaluate the lipid droplets area. Nuclear protein extraction and immunoprecipitation were used to detect the proteins interaction. Results: In this study, we reported that rosiglitazone promoted adipocyte browning and inhibited autophagy. Rapamycin, an autophagy inducer, reversed adipocyte browning induced by rosiglitazone. Autophagy inhibition by rosiglitazone does not prevent mitochondrial clearance, which was considered to promote adipose whitening. Instead, autophagy inhibition increased p62 nuclear translocation and stabilized the PPARγ-RXRα heterodimer, which is an essential transcription factor for adipocyte browning. We found that rosiglitazone activated NRF2 in mature adipocytes. Inhibition of NRF2 by ML385 reversed autophagy inhibition and the pro-browning effect of rosiglitazone. Conclusion: Our study linked autophagy inhibition with rosiglitazone-promoted browning of adipocytes and provided a mechanistic insight into the pharmacological effects of rosiglitazone.
    Keywords:  PPARγ agonist; adipocyte browning; autophagy; mitophagy; obesity; rosiglitazone
    DOI:  https://doi.org/10.3389/fphar.2024.1412520
  23. Chem Biodivers. 2024 Jun 19. e202400934
    Regulation of Autophagy Signaling Pathways by Ginseng Saponins: A Review.
    Zhu-Jun Zhuang, Fa-Jing Li, Di Lv, Heng-Qian Duan, Lin-Yi Chen, Peng Chen, Zhi-Qiang Shen, B O He.
      Ginseng saponins ( ginsenosides), bioactive compounds derived from ginseng, are widely used natural products with potent therapeutic properties in the management of various ailments, particularly tumors, cardiovascular and cerebrovascular diseases, and immune system disorders. Autophagy, a highly regulated and multistep process involving the breakdown of impaired organelles and macromolecules by autophagolysosomes and autophagy-related genes (ATGs), has gained increasing attention as a potential target for ginsenoside-mediated disease treatment. This review aims to provide a comprehensive overview of recent research advances in the understanding of autophagy-related signaling pathways and the role of ginsenoside-mediated autophagy regulation. By delving into the intricate autophagy signaling pathways underpinning the pharmacological properties of ginsenosides, we highlight their therapeutic potential in addressing various conditions. Our findings serve as a comprehensive reference for further investigation into the medicinal properties of ginseng or ginseng-related products.
    Keywords:  Keywords: Ginsenoside * Autophagy * mTOR-dependent signaling pathways * mTOR-independent signaling pathways
    DOI:  https://doi.org/10.1002/cbdv.202400934
  24. bioRxiv. 2024 Jun 04. pii: 2024.06.04.597393. [Epub ahead of print]
    TSC2 loss in neural progenitor cells suppresses translation of ASD/NDD-associated transcripts in an mTORC1- and MNK1/2-reversible fashion.
    Pauline Martin, Krzysztof J Szkop, Francis Robert, Srirupa Bhattacharyya, Roberta L Beauchamp, Jacob Brenner, Nicholas E Redmond, Sidong Huang, Serkan Erdin, Ola Larsson, Vijaya Ramesh.
      Tuberous sclerosis complex (TSC), an inherited neurodevelopmental (ND) disorder with frequent manifestations of epilepsy and autism spectrum disorder (ASD). TSC is caused by mutations in TSC1 or TSC2 tumor suppressor genes, with encoded proteins hamartin/TSC1 and tuberin/TSC2 forming a functional complex inhibiting mechanistic target of rapamycin complex-1 (mTORC1) signaling, leading to FDA-approved allosteric mTORC1-selective rapamycin analogs for TSC tumors. Rapalogs are effective for TSC-associated hamartomas, however, they are not effective for treating ND manifestations. mTORC1 signaling plays an essential role in protein synthesis through mTORC1-eIF4F and MNK-eIF4E-mediated mRNA translation. Further, the effects on mRNA translation by specific mTORC1 and MNK inhibitors such as RMC-6272 and eFT-508 in TSC have never been explored. Here, employing CRISPR-modified, isogenic TSC2 patient-derived neural progenitor cells (NPCs), we have examined mRNA translation upon loss of TSC2 . Our results reveal dysregulated translation in TSC2 -Null NPCs, which significantly overlap with the translatome from TSC1 -Null NPCs, which we reported recently. Most notably, numerous non-monogenic ASD-NDD- and epilepsy-associated genes identified in patients harboring putative loss-of-function mutations, including protein truncating, or damaging missense variants, were translationally suppressed in TSC2 -Null NPCs, and their translation were reversed upon RMC-6272 or eFT-508 treatment. Our study here establishes the importance of mTORC1-eIF4F and MNK-eIF4E-mediated mRNA translation in TSC, ASD and other neurodevelopmental disorders and lay the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for TSC as well as ASD/NDD.
    DOI:  https://doi.org/10.1101/2024.06.04.597393
  25. Int J Mol Sci. 2024 Jun 03. pii: 6167. [Epub ahead of print]25(11):
    Inflammasomes Are Influenced by Epigenetic and Autophagy Mechanisms in Colorectal Cancer Signaling.
    Györgyi Műzes, Ferenc Sipos.
      Inflammasomes contribute to colorectal cancer signaling by primarily inducing inflammation in the surrounding tumor microenvironment. Its role in inflammation is receiving increasing attention, as inflammation has a protumor effect in addition to inducing tissue damage. The inflammasome's function is complex and controlled by several layers of regulation. Epigenetic processes impact the functioning or manifestation of genes that are involved in the control of inflammasomes or the subsequent signaling cascades. Researchers have intensively studied the significance of epigenetic mechanisms in regulation, as they encompass several potential therapeutic targets. The regulatory interactions between the inflammasome and autophagy are intricate, exhibiting both advantageous and harmful consequences. The regulatory aspects between the two entities also encompass several therapeutic targets. The relationship between the activation of the inflammasome, autophagy, and epigenetic alterations in CRC is complex and involves several interrelated pathways. This article provides a brief summary of the newest studies on how epigenetics and autophagy control the inflammasome, with a special focus on their role in colorectal cancer. Based on the latest findings, we also provide an overview of the latest therapeutic ideas for this complex network.
    Keywords:  autophagy; colitis; colorectal cancer; epigenetics; inflammasome; regulation; therapeutic target; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms25116167
  26. bioRxiv. 2024 Jun 08. pii: 2024.06.07.597919. [Epub ahead of print]
    PLA2G15 is a Lysosomal BMP Hydrolase with Ester Position Specificity and its Targeting Ameliorates Lysosomal Disease.
    Kwamina Nyame, Jian Xiong, Arthur Ph de Jong, Hisham N Alsohybe, Matthijs Raaben, Guido Hartmann, Judith A Simcox, Vincent A Blomen, Monther Abu-Remaileh.
      Lysosomes catabolize lipids and other biological molecules, a function essential for cellular and organismal homeostasis. Key to lipid catabolism in the lysosome is bis(monoacylglycero)phosphate (BMP), a major lipid constituent of intralysosomal vesicles (ILVs) and a stimulator of lipid-degrading enzymes. BMP levels are altered in a broad spectrum of human conditions, including neurodegenerative diseases. Although BMP synthase was recently discovered, it has long been thought that BMP's unique stereochemistry confers resistance to acid phospholipases, a requirement for its role in the lysosome. Here, we demonstrate that PLA2G15, a major lysosomal phospholipase, efficiently hydrolyzes BMP with primary esters regardless of stereochemistry. Interestingly, we discover that BMP's unique esterification position is what confers resistance to hydrolysis. Purified PLA2G15 catabolizes most BMP species derived from cell and tissue lysosomes under acidic conditions. Furthermore, PLA2G15 catalytic activity against synthesized BMP stereoisomers with primary esters was comparable to its canonical substrates. Conversely, BMP with secondary esters is intrinsically stable in vitro and requires acyl migration for hydrolysis in lysosomes. Consistent with our biochemical data, PLA2G15-deficient tissues and cells accumulate multiple BMP species, a phenotype reversible by supplementing wildtype PLA2G15 but not its catalytically dead mutant. Increasing BMP levels by targeting PLA2G15 reverses the cholesterol accumulation phenotype in Niemann Pick Disease Type C (NPC1) patient fibroblasts and significantly ameliorate disease pathologies in NPC1-deficient mice leading to extended lifespan. Our findings establish the rules that govern the stability of BMP in the lysosome and identify PLA2G15 as a lysosomal BMP hydrolase and as a potential target for modulating BMP levels for therapeutic intervention.
    DOI:  https://doi.org/10.1101/2024.06.07.597919
  27. J Virol. 2024 Jun 18. e0055624
    Transcription factor EB (TFEB) interaction with RagC is disrupted during enterovirus D68 infection.
    Alagie Jassey, Noah Pollack, Michael A Wagner, Jiapeng Wu, Ashley Benton, William T Jackson.
      Enterovirus D68 (EV-D68) is a picornavirus associated with severe respiratory illness and a paralytic disease called acute flaccid myelitis in infants. Currently, no protective vaccines or antivirals are available to combat this virus. Like other enteroviruses, EV-D68 uses components of the cellular autophagy pathway to rewire membranes for its replication. Here, we show that transcription factor EB (TFEB), the master transcriptional regulator of autophagy and lysosomal biogenesis, is crucial for EV-D68 infection. Knockdown of TFEB attenuated EV-D68 genomic RNA replication but did not impact viral binding or entry into host cells. The 3C protease of EV-D68 cleaves TFEB at the N-terminus at glutamine 60 (Q60) immediately post-peak viral RNA replication, disrupting TFEB-RagC interaction and restricting TFEB transport to the surface of the lysosome. Despite this, TFEB remained mostly cytosolic during EV-D68 infection. Overexpression of a TFEB mutant construct lacking the RagC-binding domain, but not the wild-type construct, blocks autophagy and increases EV-D68 nonlytic release in H1HeLa cells but not in autophagy-defective ATG7 KO H1HeLa cells. Our results identify TFEB as a vital host factor regulating multiple stages of the EV-D68 lifecycle and suggest that TFEB could be a promising target for antiviral development against EV-D68.IMPORTANCE: Enteroviruses are among the most significant causes of human disease. Some enteroviruses are responsible for severe paralytic diseases such as poliomyelitis or acute flaccid myelitis. The latter disease is associated with multiple non-polio enterovirus species, including enterovirus D68 (EV-D68), enterovirus 71, and coxsackievirus B3 (CVB3). Here, we demonstrate that EV-D68 interacts with a host transcription factor, transcription factor EB (TFEB), to promote viral RNA(vRNA) replication and regulate the egress of virions from cells. TFEB was previously implicated in the viral egress of CVB3, and the viral protease 3C cleaves TFEB during infection. Here, we show that EV-D68 3C protease also cleaves TFEB after the peak of vRNA replication. This cleavage disrupts TFEB interaction with the host protein RagC, which changes the localization and regulation of TFEB. TFEB lacking a RagC-binding domain inhibits autophagic flux and promotes virus egress. These mechanistic insights highlight how common host factors affect closely related, medically important viruses differently.
    Keywords:  3C; RagC; TFEB; autophagy; enterovirus; picornavirus
    DOI:  https://doi.org/10.1128/jvi.00556-24
  28. Cells. 2024 May 30. pii: 953. [Epub ahead of print]13(11):
    Inhibition of PIKfyve Leads to Lysosomal Disorders via Dysregulation of mTOR Signaling.
    Jianhong Xia, Haiyun Wang, Zhihang Zhong, Jun Jiang.
      PIKfyve is an endosomal lipid kinase that synthesizes phosphatidylinositol 3,5-biphosphate from phosphatidylinositol 3-phsphate. Inhibition of PIKfyve activity leads to lysosomal enlargement and cytoplasmic vacuolation, attributed to impaired lysosomal fission processes and homeostasis. However, the precise molecular mechanisms underlying these effects remain a topic of debate. In this study, we present findings from PIKfyve-deficient zebrafish embryos, revealing enlarged macrophages with giant vacuoles reminiscent of lysosomal storage disorders. Treatment with mTOR inhibitors or effective knockout of mTOR partially reverses these abnormalities and extend the lifespan of mutant larvae. Further in vivo and in vitro mechanistic investigations provide evidence that PIKfyve activity is essential for mTOR shutdown during early zebrafish development and in cells cultured under serum-deprived conditions. These findings underscore the critical role of PIKfyve activity in regulating mTOR signaling and suggest potential therapeutic applications of PIKfyve inhibitors for the treatment of lysosomal storage disorders.
    Keywords:  PIKfyve; lysosome; mTOR; macrophage; vacuolation
    DOI:  https://doi.org/10.3390/cells13110953
  29. Am J Transl Res. 2024 ;16(5): 1991-2000
    Research progress of autophagy in heart failure.
    Lingji Li, Ranran Xi, Bing Gao, Yonglei Zeng, Qiang Ma, Tiantian Gong, Jing Wang.
      Heart failure poses a significant threat to global public health within the realm of cardiovascular diseases. Its pathological progression involves various alterations in cardiomyocytes, among which autophagy, a crucial intracellular degradation mechanism, plays a pivotal role. Autophagy facilitates the breakdown of damaged organelles and proteins, thereby maintaining cellular homeostasis. In the context of heart failure, autophagy coexists with apoptosis and necrosis, influencing myocardial hypertrophy and ventricular remodeling. However, its impact on heart failure manifests a dual nature: moderate autophagy aids in cardiac repair, whereas excessive autophagy may exacerbate ventricular remodeling and cell demise. This review delves into the fundamental biology of autophagy, elucidating its involvement in the pathological cascade of heart failure and its correlation with cardiac hypertrophy and ventricular remodeling. Furthermore, an analysis of the interplay between autophagy regulatory factors and heart failure sheds light on the potential therapeutic implications of autophagy in the prevention and management of heart failure. This exploration provides a theoretical foundation for novel treatment strategies in combating heart failure.
    Keywords:  Heart failure; autophagy; cardiomyocyte
    DOI:  https://doi.org/10.62347/OBXQ9477
  30. Biol Pharm Bull. 2024 ;47(6): 1148-1153
    CRISPRa Analysis of Phosphoinositide Phosphatases Shows That TMEM55A Is a Positive Regulator of Autophagy.
    Kiyomi Nigorikawa, Yu Fukushima, Chinatsu Shimada, Daisuke Matsumoto, Wataru Nomura.
      Transcriptional activation, based on Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) and known as CRISPR activation (CRISPRa), is a specific and safe tool to upregulate endogenous genes. Therefore, CRISPRa is valuable not only for analysis of molecular mechanisms of cellular events, but also for treatment of various diseases. Regulating autophagy has been proposed to enhance effects of some therapies. In this study, we upregulated genes for phosphoinositide phosphatases, SACM1L, PIP4P1, and PIP4P2, using CRISPRa, and their effects on autophagy were examined. Our results suggested that TMEM55A/PIP4P2, a phosphatidylinositol-4,5-bisphosphate 4-phosphatase, positively regulates basal autophagy in 293A cells. Furthermore, it was also suggested that SAC1, a phosphatidylinositol 4-phosphatase, negatively regulates basal autophagic degradation.
    Keywords:  PIP4P2; TMEM55A; autophagy; clustered regularly interspaced short palindromic repeats activation (CRISPRa); phosphoinositide phosphatase
    DOI:  https://doi.org/10.1248/bpb.b23-00865
  31. bioRxiv. 2024 Jun 06. pii: 2024.06.05.597553. [Epub ahead of print]
    HLH-30/TFEB rewires the chaperone network to promote proteostasis under conditions of Coenzyme A and Iron-Sulfur Cluster Deficiency.
    Rewayd Shalash, Mor Levi-Ferber, Henrik von Chrzanowski, Mohammad Khaled Atrash, Yaron Shav-Tal, Sivan Henis-Korenblit.
      The maintenance of a properly folded proteome is critical for cellular function and organismal health, and its age-dependent collapse is associated with a wide range of diseases. Here, we find that despite the central role of Coenzyme A as a molecular cofactor in hundreds of cellular reactions, limiting Coenzyme A levels in C. elegans and in human cells, by inhibiting the conserved pantothenate kinase, promotes proteostasis. Impairment of the cytosolic iron-sulfur clusters formation pathway, which depends on Coenzyme A, similarly promotes proteostasis and acts in the same pathway. Proteostasis improvement by Coenzyme A/iron-sulfur cluster deficiencies are dependent on the conserved HLH-30/TFEB transcription factor. Strikingly, under these conditions, HLH-30 promotes proteostasis by potentiating the expression of select chaperone genes providing a chaperone-mediated proteostasis shield, rather than by its established role as an autophagy and lysosome biogenesis promoting factor. This reflects the versatile nature of this conserved transcription factor, that can transcriptionally activate a wide range of protein quality control mechanisms, including chaperones and stress response genes alongside autophagy and lysosome biogenesis genes. These results highlight TFEB as a key proteostasis-promoting transcription factor and underscore it and its upstream regulators as potential therapeutic targets in proteostasis-related diseases.
    DOI:  https://doi.org/10.1101/2024.06.05.597553
  32. J Appl Physiol (1985). 2024 Jun 20.
    Ulk1 Phosphorylation at S555 is Not Required in Exercise Training-mediated Improvements in Endurance and Metabolic Capacity in Healthy Mice.
    Yuntian Guan, Hannah Spaulding, Yu Qing, Mei Zhang, Orion Willoughby, Joshua C Drake, Zhen Yan.
      Endurance exercise training improves exercise capacity as well as skeletal muscle and whole-body metabolism, which are hallmarks of high quality-of-life and healthy aging. However, its mechanisms are not yet fully understood. Exercise-induced mitophagy has merged as an important step in mitochondrial remodeling. ULK1, specifically its activation by phosphorylation at serine 555, was discovered as an autophagy driver and to be important for energetic stress-induced mitophagy in skeletal muscle, making it a potential mediator the benefit of exercise on mitochondrial remodeling. Here, we employed CRISPR/Cas9-mediated gene editing and generated knock-in mice with a serine-to-alanine mutation of Ulk1. We now report that these mice displayed normal endurance capacity and cardiac function at baseline with a mild impairment of energy metabolism as indicated by accelerated increase of respiratory exchange ratio (RER) during acute exercise stress; however, this was completely corrected by 8 weeks of voluntary running. Ulk1-S555A mice also completely retained the exercise-mediated improvements of endurance capacity. We conclude that Ulk1 phosphorylation at S555 is not required for exercise-mediated improvements of endurance and metabolic capacity in healthy mice.
    Keywords:  Autophagy; Endurance Capacity; Exercise; Metabolism; Mitophagy
    DOI:  https://doi.org/10.1152/japplphysiol.00742.2023
  33. Front Cell Dev Biol. 2024 ;12 1394140
    Progress in the study of autophagy-related proteins affecting resistance to chemotherapeutic drugs in leukemia.
    Meng Li, Jing Li, Shiming Zhang, Linghan Zhou, Yuanyuan Zhu, Shen Li, Qiong Li, Junjie Wang, Ruipeng Song.
      Leukemia is a life-threatening malignant tumor of the hematopoietic system. Currently, the main treatment modalities are chemotherapy and hematopoietic stem cell transplantation. However, increased drug resistance due to decreased sensitivity of leukemia cells to chemotherapeutic drugs presents a major challenge in current treatments. Autophagy-associated proteins involved in autophagy initiation have now been shown to be involved in the development of various types of leukemia cells and are associated with drug resistance. Therefore, this review will explore the roles of autophagy-related proteins involved in four key autophagic processes: induction of autophagy and phagophore formation, phagophore extension, and autophagosome formation, on the development of various types of leukemias as well as drug resistance. Autophagy may become a promising therapeutic target for treating leukemia.
    Keywords:  autophagy-associated proteins; chemotherapeutic drugs; drug tolerance; leukaemia; review
    DOI:  https://doi.org/10.3389/fcell.2024.1394140
  34. Int J Mol Sci. 2024 Jun 06. pii: 6258. [Epub ahead of print]25(11):
    Expression of Wild-Type and Mutant Human TDP-43 in Yeast Inhibits TOROID (TORC1 Organized in Inhibited Domain) Formation and Autophagy Proportionally to the Levels of TDP-43 Toxicity.
    Sangeun Park, Sei-Kyoung Park, Susan W Liebman.
      TDP-43 forms aggregates in the neurons of patients with several neurodegenerative diseases. Human TDP-43 also aggregates and is toxic in yeast. Here, we used a yeast model to investigate (1) the nature of TDP-43 aggregates and (2) the mechanism of TDP-43 toxicity. Thioflavin T, which stains amyloid but not wild-type TDP-43 aggregates, also did not stain mutant TDP-43 aggregates made from TDP-43 with intragenic mutations that increase or decrease its toxicity. However, 1,6-hexanediol, which dissolves liquid droplets, dissolved wild-type or mutant TDP-43 aggregates. To investigate the mechanism of TDP-43 toxicity, the effects of TDP-43 mutations on the autophagy of the GFP-ATG8 reporter were examined. Mutations in TDP-43 that enhance its toxicity, but not mutations that reduce its toxicity, caused a larger reduction in autophagy. TOROID formation, which enhances autophagy, was scored as GFP-TOR1 aggregation. TDP-43 inhibited TOROID formation. TORC1 bound to both toxic and non-toxic TDP-43, and to TDP-43, with reduced toxicity due to pbp1Δ. However, extragenic modifiers and TDP-43 mutants that reduced TDP-43 toxicity, but not TDP-43 mutants that enhanced toxicity, restored TOROID formation. This is consistent with the hypothesis that TDP-43 is toxic in yeast because it reduces TOROID formation, causing the inhibition of autophagy. Whether TDP-43 exerts a similar effect in higher cells remains to be determined.
    Keywords:  PBP1; TDP-43; TIP41; TOR1; TORC1; TOROID; autophagy; yeast
    DOI:  https://doi.org/10.3390/ijms25116258
  35. Pharmacol Rep. 2024 Jun 19.
    The role of glucagon-like peptide-1/GLP-1R and autophagy in diabetic cardiovascular disease.
    Zi Guo.
      Diabetes leads to a significantly accelerated incidence of various related macrovascular complications, including peripheral vascular disease and cardiovascular disease (the most common cause of mortality in diabetes), as well as microvascular complications such as kidney disease and retinopathy. Endothelial dysfunction is the main pathogenic event of diabetes-related vascular disease at the earliest stage of vascular injury. Understanding the molecular processes involved in the development of diabetes and its debilitating vascular complications might bring up more effective and specific clinical therapies. Long-acting glucagon-like peptide (GLP)-1 analogs are currently available in treating diabetes with widely established safety and extensively evaluated efficacy. In recent years, autophagy, as a critical lysosome-dependent self-degradative process to maintain homeostasis, has been shown to be involved in the vascular endothelium damage in diabetes. In this review, the GLP-1/GLP-1R system implicated in diabetic endothelial dysfunction and related autophagy mechanism underlying the pathogenesis of diabetic vascular complications are briefly presented. This review also highlights a possible crosstalk between autophagy and the GLP-1/GLP-1R axis in the treatment of diabetic angiopathy.
    Keywords:  Autophagy; Diabetic angiopathy; Endothelial cell; GLP-1; GLP-1R
    DOI:  https://doi.org/10.1007/s43440-024-00609-1
  36. Int J Mol Sci. 2024 May 22. pii: 5633. [Epub ahead of print]25(11):
    Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes.
    Carly S Pontifex, Mashiat Zaman, Roberto D Fanganiello, Timothy E Shutt, Gerald Pfeffer.
      In this review we examine the functionally diverse ATPase associated with various cellular activities (AAA-ATPase), valosin-containing protein (VCP/p97), its molecular functions, the mutational landscape of VCP and the phenotypic manifestation of VCP disease. VCP is crucial to a multitude of cellular functions including protein quality control, endoplasmic reticulum-associated degradation (ERAD), autophagy, mitophagy, lysophagy, stress granule formation and clearance, DNA replication and mitosis, DNA damage response including nucleotide excision repair, ATM- and ATR-mediated damage response, homologous repair and non-homologous end joining. VCP variants cause multisystem proteinopathy, and pathology can arise in several tissue types such as skeletal muscle, bone, brain, motor neurons, sensory neurons and possibly cardiac muscle, with the disease course being challenging to predict.
    Keywords:  DNA damage response; ERAD; SUMOylation; apoptosis; autophagy; cell cycle control; genetic diagnosis; genotype–phenotype correlation; lysophagy; mitophagy; multisystem proteinopathy; neuron; osteoclast; skeletal muscle; stress granules; ubiquitination; valosin-containing protein
    DOI:  https://doi.org/10.3390/ijms25115633
  37. bioRxiv. 2024 Apr 03. pii: 2024.04.02.587808. [Epub ahead of print]
    Opposing actions of JIP4 and RILPL1 provide antagonistic motor force to dynamically regulate membrane reformation during lysosomal tubulation/sorting driven by LRRK2.
    Luis Bonet-Ponce, Tsion Tegicho, Alexandra Beilina, Jillian H Kluss, Yan Li, Mark R Cookson.
      Lysosomes are dynamic cellular structures that adaptively remodel their membrane in response to stimuli, including membrane damage. We previously uncovered a process we term LYTL (LYsosomal Tubulation/sorting driven by Leucine-Rich Repeat Kinase 2 [LRRK2]), wherein damaged lysosomes generate tubules sorted into mobile vesicles. LYTL is orchestrated by the Parkinson's disease-associated kinase LRRK2 that recruits the motor adaptor protein and RHD family member JIP4 to lysosomes via phosphorylated RAB proteins. To identify new players involved in LYTL, we performed unbiased proteomics on isolated lysosomes after LRRK2 kinase inhibition. Our results demonstrate that there is recruitment of RILPL1 to ruptured lysosomes via LRRK2 activity to promote phosphorylation of RAB proteins at the lysosomal surface. RILPL1, which is also a member of the RHD family, enhances the clustering of LRRK2-positive lysosomes in the perinuclear area and causes retraction of LYTL tubules, in contrast to JIP4 which promotes LYTL tubule extension. Mechanistically, RILPL1 binds to p150 Glued , a dynactin subunit, facilitating the transport of lysosomes and tubules to the minus end of microtubules. Further characterization of the tubulation process revealed that LYTL tubules move along tyrosinated microtubules, with tubulin tyrosination proving essential for tubule elongation. In summary, our findings emphasize the dynamic regulation of LYTL tubules by two distinct RHD proteins and pRAB effectors, serving as opposing motor adaptor proteins: JIP4, promoting tubulation via kinesin, and RILPL1, facilitating tubule retraction through dynein/dynactin. We infer that the two opposing processes generate a metastable lysosomal membrane deformation that facilitates dynamic tubulation events.
    DOI:  https://doi.org/10.1101/2024.04.02.587808
  38. Nat Commun. 2024 Jun 18. 15(1): 5217
    Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease.
    Reji Babygirija, Michelle M Sonsalla, Jericha Mill, Isabella James, Jessica H Han, Cara L Green, Mariah F Calubag, Gina Wade, Anna Tobon, John Michael, Michaela M Trautman, Ryan Matoska, Chung-Yang Yeh, Isaac Grunow, Heidi H Pak, Michael J Rigby, Dominique A Baldwin, Natalie M Niemi, John M Denu, Luigi Puglielli, Judith Simcox, Dudley W Lamming.
      Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. Here, we show that PR promotes leanness and glycemic control in 3xTg mice, specifically rescuing the glucose intolerance of 3xTg females. PR induces sex-specific alterations in circulating and brain metabolites, downregulating sphingolipid subclasses in 3xTg females. PR also reduces AD pathology and mTORC1 activity, increases autophagy, and improves the cognition of 3xTg mice. Finally, PR improves the survival of 3xTg mice. Our results suggest that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.
    DOI:  https://doi.org/10.1038/s41467-024-49589-z
  39. Mol Neurobiol. 2024 Jun 20.
    Inhibition of CSPG-PTPσ Activates Autophagy Flux and Lysosome Fusion, Aids Axon and Synaptic Reorganization in Spinal Cord Injury.
    Hongyu Wang, Naibo Feng, Chungeng Liu, Yongheng Xie, Zipeng Zhou, Haosen Zhao, Guozhi Xiao, Dazhi Yang.
      Chondroitin sulfate proteoglycans (CSPGs) and proteoglycan receptor protein tyrosine phosphatase σ (PTPσ) play a critical role in the pathology of spinal cord injury (SCI). CSPGs can be induced by autophagy inhibition in astrocyte. However, CSPG's impact on autophagy and its role in SCI is still unknown. We investigate intracellular sigma peptide (ISP) targeting PTPσ, its effects on autophagy, and synaptic reorganization in SCI. We found that ISP increased the level of autophagosome marker LC3B-II/I and decreased autophagosome degradation marker p62 in SCI, suggesting activated autophagy flux. ISP restored autophagosome-lysosome fusion-related protein syntaxin 17 (STX17) and lysosome-associated membrane protein 2 (LAMP2), indicating activated autophagosome-lysosome fusion. ISP increased pre-synaptic marker synaptophysin (SYN) and postsynaptic density protein-95 (PSD-95) expression and improved excitatory synapse marker vesicular glutamate transporter 1 (VGLUT1) and SYN in SCI, suggesting improved synaptic reorganization. ISP promoted axon marker neurofilament and growth-related GAP-43 expression in SCI. ISP rescued a preserved number of motor neurons and improved neurobehavioral recovery after SCI. Our study extended the CSPG-PTPσ inhibition role in activating autophagy flux, axon and synaptic reorganization, and functional recovery in SCI.
    Keywords:  Autophagy flux; CSPG; Lysosome fusion; PTPσ; Spinal cord injury
    DOI:  https://doi.org/10.1007/s12035-024-04304-3
  40. Int J Mol Sci. 2024 Jun 04. pii: 6175. [Epub ahead of print]25(11):
    Autophagy Promotes Enrichment of Raft Components within Extracellular Vesicles Secreted by Human 2FTGH Cells.
    Valeria Manganelli, Luciana Dini, Stefano Tacconi, Simone Dinarelli, Antonella Capozzi, Gloria Riitano, Serena Recalchi, Tuba Rana Caglar, Federica Fratini, Roberta Misasi, Maurizio Sorice, Tina Garofalo.
      Autophagy plays a key role in removing protein aggregates and damaged organelles. In addition to its conventional degradative functions, autophagy machinery contributes to the release of cytosolic proteins through an unconventional secretion pathway. In this research, we analyzed autophagy-induced extracellular vesicles (EVs) in HT1080-derived human fibrosarcoma 2FTGH cells using transmission electron microscopy and atomic force microscopy (AFM). We preliminary observed that autophagy induces the formation of a subset of large heterogeneous intracellular vesicular structures. Moreover, AFM showed that autophagy triggering led to a more visible smooth cell surface with a reduced amount of plasma membrane protrusions. Next, we characterized EVs secreted by cells following autophagy induction, demonstrating that cells release both plasma membrane-derived microvesicles and exosomes. A self-forming iodixanol gradient was performed for cell subfractionation. Western blot analysis showed that endogenous LC3-II co-fractionated with CD63 and CD81. Then, we analyzed whether raft components are enriched within EV cargoes following autophagy triggering. We observed that the raft marker GD3 and ER marker ERLIN1 co-fractionated with LC3-II; dual staining by immunogold electron microscopy and coimmunoprecipitation revealed GD3-LC3-II association, indicating that autophagy promotes enrichment of raft components within EVs. Introducing a new brick in the crosstalk between autophagy and the endolysosomal system may have important implications for the knowledge of pathogenic mechanisms, suggesting alternative raft target therapies in diseases in which the generation of EV is active.
    Keywords:  ERLIN1; autophagy; exosomes; extracellular vesicles; lipid rafts
    DOI:  https://doi.org/10.3390/ijms25116175
  41. J Agric Food Chem. 2024 Jun 13.
    Hesperidin Alleviates Hepatic Injury Caused by Deoxynivalenol Exposure through Activation of mTOR and AKT/GSK3β/TFEB Pathways.
    Xin Wang, Hao Chen, Junze Jiang, Jun Ma.
      Deoxynivalenol (DON) is a common agricultural mycotoxin that is chemically stable and not easily removed from cereal foods. When organisms consume food made from contaminated crops, it can be hazardous to their health. Numerous studies in recent years have found that hesperidin (HDN) has hepatoprotective effects on a wide range of toxins. However, few scholars have explored the potential of HDN in attenuating DON-induced liver injury. In this study, we established a low-dose DON exposure model and intervened with three doses of HDN, acting on male C57 BL/6 mice and AML12 cells, which served as in vivo and in vitro models, respectively, to investigate the protective mechanism of HDN against DON exposure-induced liver injury. The results suggested that DON disrupted hepatic autophagic fluxes, thereby impairing liver structure and function, and HDN significantly attenuated these changes. Further studies revealed that HDN alleviated DON-induced excessive autophagy through the mTOR pathway and DON-induced lysosomal dysfunction through the AKT/GSK3β/TFEB pathway. Overall, our study suggested that HDN could ameliorate DON-induced autophagy flux disorders via the mTOR pathway and the AKT/GSK3β/TFEB pathway, thereby reducing liver injury.
    Keywords:  autophagy-lysosome pathway; deoxynivalenol; hesperidin; mice liver
    DOI:  https://doi.org/10.1021/acs.jafc.4c02039
  42. J Mol Histol. 2024 Jun 13.
    SNX14 inhibits autophagy via the PI3K/AKT/mTOR signaling cascade in breast cancer cells.
    Sha Lv, Hongyan Jiang, Lingyan Yu, Yafei Zhang, Liangliang Sun, Junjun Xu.
      BACKGROUND: Sorting nexin 14 (SNX14) is a member of the sorting junction protein family. Its specific roles in cancer development remain unclear. Therefore, in this study, we aimed to determine the effects and underlying mechanisms of SNX14 on autophagy of breast cancer cells to aid in the therapeutic treatment of breast cancer.METHODS: In this study, we performed in vitro experiments to determine the effect of SNX14 on breast cancer cell growth. Moreover, we used an MCF7 breast cancer tumor-bearing mouse model to confirm the effect of SNX14 on tumor cell growth in vivo. We also performed western blotting and quantitative polymerase chain reaction to identify the mechanism by which SNX14 affects breast cancer MCF7 cells.
    RESULTS: We found that SNX14 regulated the onset and progression of breast cancer by promoting the proliferation and inhibiting the autophagy of MCF7 breast cancer cells. In vivo experiments further confirmed that SNX14 knockdown inhibited the tumorigenicity and inhibited the growth of tumor cells in tumor tissues of nude mice. In addition, western blotting analysis revealed that SNX14 modulate the autophagy of MCF7 breast cancer cells via the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin kinase signaling pathway.
    CONCLUSION: Our findings indicate that SNX14 is an essential tumor-promoting factor in the development of breast cancer.
    Keywords:   PI3K/AKT/mTOR ; SNX14 ; Apoptosis; Autophagy; Breast cancer
    DOI:  https://doi.org/10.1007/s10735-024-10209-1
  43. PNAS Nexus. 2024 Jun;3(6): pgae207
    Trophoblast-specific overexpression of the LAT1 increases transplacental transport of essential amino acids and fetal growth in mice.
    Fredrick J Rosario, Kenneth Barentsen, Theresa L Powell, Johann Urschitz, Thomas L Brown, Yoshikatsu Kanai, Thomas Jansson.
      Placental System L amino acid transporter activity is decreased in pregnancies complicated by intrauterine growth restriction (IUGR) and increased in fetal overgrowth. However, it is unknown if changes in the expression/activity of placental Large Neutral Amino Acid Transporter Small Subunit 1 (Slc7a5/LAT1) are mechanistically linked to placental function and fetal growth. We hypothesized that trophoblast-specific Slc7a5 overexpression increases placental transport of essential amino acids, activates the placental mechanistic target of rapamycin (mTOR) signaling, and promotes fetal growth in mice. Using lentiviral transduction of blastocysts with a Slc7a5 transgene, we achieved trophoblast-specific overexpression of Slc7a5 (Slc7a5 OX) with increased fetal (+27%) and placental weights (+10%). Trophoblast-specific Slc7a5 overexpression increased trophoblast plasma membrane (TPM) LAT1 protein abundance and TPM System L transporter (+53%) and System A transporter activity (+ 21%). Slc7a5 overexpression also increased transplacental transport of leucine (+ 85%) but not of the System A tracer, 14C-methylamino isobutyric acid, in vivo. Trophoblast-specific overexpression of Slc7a5 activated placental mTORC1, as assessed by increased (+44%) phosphorylation of S6 ribosomal protein (Ser 235/236), and mTORC2 as indicated by phosphorylation of PKCα-Tyr-657 (+47%) and Akt-Ser 473 (+96%). This is the first demonstration that placental transport of essential amino acids is mechanistically linked to fetal growth. The decreased placental System L activity in human IUGR and the increased placental activity of this transporter in some cases of fetal overgrowth may directly contribute to the development of these pregnancy complications.
    Keywords:  fetal development; leucine; maternal–fetal exchange; mechanistic target of rapamycin; placenta
    DOI:  https://doi.org/10.1093/pnasnexus/pgae207
  44. bioRxiv. 2024 Jun 06. pii: 2024.06.04.597443. [Epub ahead of print]
    Human TSC2 Mutant Cells Exhibit Aberrations in Early Neurodevelopment Accompanied by Changes in the DNA Methylome.
    Mary-Bronwen L Chalkley, Lindsey N Guerin, Tenhir Iyer, Samantha Mallahan, Sydney Nelson, Mustafa Sahin, Emily Hodges, Kevin C Ess, Rebecca A Ihrie.
      Tuberous Sclerosis Complex (TSC) is a debilitating developmental disorder characterized by a variety of clinical manifestations. While benign tumors in the heart, lungs, kidney, and brain are all hallmarks of the disease, the most severe symptoms of TSC are often neurological, including seizures, autism, psychiatric disorders, and intellectual disabilities. TSC is caused by loss of function mutations in the TSC1 or TSC2 genes and consequent dysregulation of signaling via mechanistic Target of Rapamycin Complex 1 (mTORC1). While TSC neurological phenotypes are well-documented, it is not yet known how early in neural development TSC1/2 -mutant cells diverge from the typical developmental trajectory. Another outstanding question is the contribution of homozygous-mutant cells to disease phenotypes and whether such phenotypes are also seen in the heterozygous-mutant populations that comprise the vast majority of cells in patients. Using TSC patient-derived isogenic induced pluripotent stem cells (iPSCs) with defined genetic changes, we observed aberrant early neurodevelopment in vitro , including misexpression of key proteins associated with lineage commitment and premature electrical activity. These alterations in differentiation were coincident with hundreds of differentially methylated DNA regions, including loci associated with key genes in neurodevelopment. Collectively, these data suggest that mutation or loss of TSC2 affects gene regulation and expression at earlier timepoints than previously appreciated, with implications for whether and how prenatal treatment should be pursued.
    DOI:  https://doi.org/10.1101/2024.06.04.597443
  45. Biofactors. 2024 Jun 12.
    Mitigation of experimental ER stress and diabetes mellitus induced peripheral neuropathy by autophagy promoter, 6-BIO.
    Praveen Jaiswar, Mitali Bhate, Avadhesha Surolia.
      Neuropathy occurs due to damage to the peripheral/central nervous system either due to injury, disease, or drug usage. Increased endoplasmic reticulum (ER) stress is observed in neuropathy. ER stress also leads to a block in autophagy amplifying neuropathic pain. 6-Bromoindirubin-3'-oxime (6-BIO) is an inhibitor of GSK-3β which suppresses mTOR activity thereby increasing autophagy. Tunicamycin (TM)-mediated ER stress and diabetic rat models were used to elucidate the role of ER stress and autophagy in mitigation of neuropathic pain by 6-BIO. Pain was assessed by behavioral studies in ER stressed/diabetic rats having neuropathy. Western blotting, RT-PCR, and fluorescence microscopy were used to assess the level of autophagy and ER stress after TM and 6-BIO treatment in SH-SY5Y neurons. Intraplantar injection of TM in rats led to peripheral neuropathy which was reduced upon 6-BIO injection. 6-BIO also reduced pain in animals exhibiting diabetic peripheral neuropathy. Modulation in the markers of autophagy (p-mTOR, LC-3, and SQSTM1/p62) shows that 6-BIO induces autophagolysosome formation post TM treatment. Concomitantly, 6-BIO reduces ER stress and c-Fos expression-a neuronal activity and pain marker. Alleviation of pain by the inhibition of ER stress and increased formation of autolysosomes by 6-BIO can be harnessed for treating peripheral neuropathy.
    Keywords:  6‐BIO; 6‐bromoindirubin‐3′‐oxime; autophagy; diabetic neuropathy; peripheral neuropathy
    DOI:  https://doi.org/10.1002/biof.2088
  46. Nat Rev Rheumatol. 2024 Jun 21.
    Mitophagy as a link between ECM stiffness and chondrocyte senescence.
    Maria Papatriantafyllou.
      
    DOI:  https://doi.org/10.1038/s41584-024-01136-2
  47. Biomed Pharmacother. 2024 Jun 20. pii: S0753-3322(24)00860-6. [Epub ahead of print]177 116976
    Targeting a mTOR/autophagy axis: a double-edged sword of rapamycin in spontaneous miscarriage.
    Meng-Ying Li, Hui-Hui Shen, Xiao-Yan Cao, Xiao-Xiao Gao, Feng-Yuan Xu, Si-Yao Ha, Jian-Song Sun, Song-Ping Liu, Feng Xie, Ming-Qing Li.
      Immune dysfunction is a primary culprit behind spontaneous miscarriage (SM). To address this, immunosuppressive agents have emerged as a novel class of tocolytic drugs, modulating the maternal immune system's tolerance towards the embryo. Rapamycin (PubChem CID:5284616), a dual-purpose compound, functions as an immunosuppressive agent and triggers autophagy by targeting the mTOR pathway. Its efficacy in treating SM has garnered significant research interest in recent times. Autophagy, the cellular process of self-degradation and recycling, plays a pivotal role in numerous health conditions. Research indicates that autophagy is integral to endometrial decidualization, trophoblast invasion, and the proper functioning of decidual immune cells during a healthy pregnancy. Yet, in cases of SM, there is a dysregulation of the mTOR/autophagy axis in decidual stromal cells or immune cells at the maternal-fetal interface. Both in vitro and in vivo studies have highlighted the potential benefits of low-dose rapamycin in managing SM. However, given mTOR's critical role in energy metabolism, inhibiting it could potentially harm the pregnancy. Moreover, while low-dose rapamycin has been deemed safe for treating recurrent implant failure, its potential teratogenic effects remain uncertain due to insufficient data. In summary, rapamycin represents a double-edged sword in the treatment of SM, balancing its impact on autophagy and immune regulation. Further investigation is warranted to fully understand its implications.
    Keywords:  Autophagy; MTOR; Rapamycin; Recurrent implant failure; Spontaneous miscarriage
    DOI:  https://doi.org/10.1016/j.biopha.2024.116976
  48. Pathol Res Pract. 2024 Jun 17. pii: S0344-0338(24)00325-X. [Epub ahead of print]260 155414
    Immunohistochemistry analysis of autophagy-related proteins Beclin-1, p62/SQSTM1, and LC3B in breast carcinoma progression to bone metastasis.
    Paola Maroni, Giovanni Lombardi, Anita Ferraretto, Paola Bendinelli.
      Autophagy is a catabolic pathway involved both in tissue homeostasis and in cellular response to stress. The precise role of autophagy in cancer is still undefined and seems to depend on the tumor stage, appearing tumor-suppressive in physiological conditions and helpful to tumor progression in the established tumor. Here we analyzed by immunohistochemistry Beclin-1, p62, and LC3B, autophagic markers, in human specimens of normal breast, bone metastasis together with pair-matched invasive breast carcinoma of no special type (IBC-NST) as well as non-metastatic breast carcinoma, to disclose the possibility that they could be early prognostic indicators of the evolution of the disease toward the worst outcome. Different regions of metastatic carcinomas, i.e., areas adjacent to the tumor without signs of neoplastic growth, dysplastic lesions, and areas with invasive growth were considered. The pattern of autophagic parameters showed differences among the stages of breast carcinoma progression with a trend that indicated the activation of autophagic process in normal breast (Beclin-1 more elevated than p62), a pattern that was maintained in non-metastatic carcinoma. As the neoplasia proceeds with malignancy, the modification of the pattern of expression of autophagic markers (low ratio between Beclin-1 and p62) in areas of invasive growth of carcinomas suggested inhibition of the process. Of note, the parameters showed a different pattern in bone metastasis with respect to bone metastatic (bm)-IBC-NST, suggesting the reactivation of the autophagic process in the new growth site, helpful to the colonization. The course of autophagy markers during tumor progression could have a prognostic value towards bone metastasis and reveal different roles of the process in different phases of neoplastic growth. The understanding of the role of autophagy in bone metastasis could disclose new therapeutic targets to improve the conditions of patients.
    Keywords:  Autophagy; Beclin-1; Bone metastasis; Breast cancer; Immunohistochemistry; LC3; p62
    DOI:  https://doi.org/10.1016/j.prp.2024.155414
  49. Pharmacol Ther. 2024 Jun 13. pii: S0163-7258(24)00100-1. [Epub ahead of print]260 108680
    UFMylation: An integral post-translational modification for the regulation of proteostasis and cellular functions.
    Xiaohui Wang, Xiaowei Lv, Jingjing Ma, Guoqiang Xu.
      Ubiquitin-fold modifier 1 (UFM1) is covalently conjugated to protein substrates via a cascade of enzymatic reactions, a process known as UFMylation. UFMylation orchestrates an array of vital biological functions, including maintaining endoplasmic reticulum (ER) homeostasis, facilitating protein biogenesis, promoting cellular differentiation, regulating DNA damage response, and participating in cancer-associated signaling pathways. UFMylation has rapidly evolved into one of the forefront research areas within the last few years, yet much remains to be uncovered. In this review, first, UFMylation and its cellular functions associated with diseases are briefly introduced. Then, we summarize the proteomic approaches for identifying UFMylation substrates and explore the impact of UFMylation on gene transcription, protein translation, and maintenance of ER homeostasis. Next, we highlight the intricate regulation between UFMylation and two protein degradation pathways, the ubiquitin-proteasome system and the autophagy-lysosome pathway, and explore the potential of UFMylation system as a drug target. Finally, we discuss emerging perspectives in the UFMylation field. This review may provide valuable insights for drug discovery targeting the UFMylation system.
    Keywords:  ALP; ER homeostasis; Gene transcription; Protein translation; UFMylation; UPS
    DOI:  https://doi.org/10.1016/j.pharmthera.2024.108680
  50. Circulation. 2024 Jun 17.
    Induction of DEPP1 by HIF Mediates Multiple Hallmarks of Ischemic Cardiomyopathy.
    Gregory A Wyant, Qinqin Jiang, Madhu Singh, Shariq Qayyum, Clara Levrero, Bradley A Maron, William G Kaelin.
      BACKGROUND: HIF (hypoxia inducible factor) regulates many aspects of cardiac function. We and others previously showed that chronic HIF activation in the heart in mouse models phenocopies multiple features of ischemic cardiomyopathy in humans, including mitochondrial loss, lipid accumulation, and systolic cardiac dysfunction. In some settings, HIF also causes the loss of peroxisomes. How, mechanistically, HIF promotes cardiac dysfunction is an open question.METHODS: We used mice lacking cardiac pVHL (von Hippel-Lindau protein) to investigate how chronic HIF activation causes multiple features of ischemic cardiomyopathy, such as autophagy induction and lipid accumulation. We performed immunoblot assays, RNA sequencing, mitochondrial and peroxisomal autophagy flux measurements, and live cell imaging on hearts and isolated cardiomyocytes. We used CRISPR-Cas9 gene editing in mice to validate a novel mediator of cardiac dysfunction in the setting of chronic HIF activation.
    RESULTS: We identify a previously unknown pathway by which cardiac HIF activation promotes the loss of mitochondria and peroxisomes. We found that DEPP1 (decidual protein induced by progesterone 1) is induced under hypoxia in a HIF-dependent manner and localizes inside mitochondria. DEPP1 is both necessary and sufficient for hypoxia-induced autophagy and triglyceride accumulation in cardiomyocytes ex vivo. DEPP1 loss increases cardiomyocyte survival in the setting of chronic HIF activation ex vivo, and whole-body Depp1 loss decreases cardiac dysfunction in hearts with chronic HIF activation caused by VHL loss in vivo.
    CONCLUSIONS: Our findings identify DEPP1 as a key component in the cardiac remodeling that occurs with chronic ischemia.
    Keywords:  DEPP1; HIF; VHL; autophagy; cardiomyocyte; hypoxia; mitochondria; peroxisome
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.066628
  51. Biomed Pharmacother. 2024 Jun 14. pii: S0753-3322(24)00802-3. [Epub ahead of print]177 116918
    Erastin promotes random-pattern skin flaps survival by inducing mTORC1-TFEB mediated autophagy.
    Ximiao Chen, Xuwei Zhu, Yu Chen, Zihang Ruan, Yekai Zhang, Hongqiang Wu, Xiaolei Zhang, Weiyang Gao.
      Random-pattern skin flaps are important method for skin reconstruction after defect; however, the distal end of flaps is not easily viable due to inadequate nutrient supply. Erastin is a well-established ferroptosis inducer, but our study found that low-dose of erastin (2 μM) may reduce nutrient deficiency induced cell death in human umbilical vein endothelial cells (HUVECs). RNA-seq analysis suggested that its role was related to autophagy regulation. Follow-up studies have shown that the use of autophagy inhibitors or the knockdown of TFEB in HUVECs can both reduce the anti-apoptotic effect of erastin in HUVECs. Mechanism study demonstrated that erastin can suppress mTORC1 and promote TFEB activity in HUVECs, suggesting that the effect of erastin on the survival of HUVECs under nutrient deprivation conditions is regulated by mTORC1/TFEB. Subsequently, we evaluated the effect of erastin on the survival of random-pattern skin flaps in mice in vivo. On the postoperative day 7, we observed a significant increase in flap survival area, blood perfusion, and microvascular density after erastin treatment; also, erastin treatment showed enhanced autophagy within the ischemic region. In summary, our study demonstrates that low-dose of erastin may suppress cell death in endothelial cells under nutrient deficiency condition, and its effects may relate to the mTORC1-TFEB medicated autophagy regulation, erastin treatment may be a potential therapy for random-pattern skin flaps.
    Keywords:  Autophagy; Erastin; Nutrient deficiency; Random-pattern skin flaps; TFEB
    DOI:  https://doi.org/10.1016/j.biopha.2024.116918
  52. Sci Adv. 2024 Jun 21. 10(25): eadn0014
    Olfaction regulates peripheral mitophagy and mitochondrial function.
    Julian G Dishart, Corinne L Pender, Koning Shen, Hanlin Zhang, Megan Ly, Madison B Webb, Andrew Dillin.
      The central nervous system coordinates peripheral cellular stress responses, including the unfolded protein response of the mitochondria (UPRMT); however, the contexts for which this regulatory capability evolved are unknown. UPRMT is up-regulated upon pathogenic infection and in metabolic flux, and the olfactory nervous system has been shown to regulate pathogen resistance and peripheral metabolic activity. Therefore, we asked whether the olfactory nervous system in Caenorhabditis elegans controls the UPRMT cell nonautonomously. We found that silencing a single inhibitory olfactory neuron pair, AWC, led to robust induction of UPRMT and reduction of oxidative phosphorylation dependent on serotonin signaling and parkin-mediated mitophagy. Further, AWC ablation confers resistance to the pathogenic bacteria Pseudomonas aeruginosa partially dependent on the UPRMT transcription factor atfs-1 and fully dependent on mitophagy machinery. These data illustrate a role for the olfactory nervous system in regulating whole-organism mitochondrial dynamics, perhaps in preparation for postprandial metabolic stress or pathogenic infection.
    DOI:  https://doi.org/10.1126/sciadv.adn0014
  53. Cells. 2024 May 25. pii: 918. [Epub ahead of print]13(11):
    Therapeutic Relevance of Inducing Autophagy in β-Thalassemia.
    Roberto Gambari, Alessia Finotti.
      The β-thalassemias are inherited genetic disorders affecting the hematopoietic system. In β-thalassemias, more than 350 mutations of the adult β-globin gene cause the low or absent production of adult hemoglobin (HbA). A clinical parameter affecting the physiology of erythroid cells is the excess of free α-globin. Possible experimental strategies for a reduction in excess free α-globin chains in β-thalassemia are CRISPR-Cas9-based genome editing of the β-globin gene, forcing "de novo" HbA production and fetal hemoglobin (HbF) induction. In addition, a reduction in excess free α-globin chains in β-thalassemia can be achieved by induction of the autophagic process. This process is regulated by the Unc-51-like kinase 1 (Ulk1) gene. The interplay with the PI3K/Akt/TOR pathway, with the activity of the α-globin stabilizing protein (AHSP) and the involvement of microRNAs in autophagy and Ulk1 gene expression, is presented and discussed in the context of identifying novel biomarkers and potential therapeutic targets for β-thalassemia.
    Keywords:  Ulk1; autophagy; ineffective erythropoiesis; α-globin; β-thalassemia
    DOI:  https://doi.org/10.3390/cells13110918
  54. bioRxiv. 2024 Jun 08. pii: 2024.06.08.598070. [Epub ahead of print]
    Lysosome damage triggers acute formation of ER to lysosomes membrane tethers mediated by the bridge-like lipid transport protein VPS13C.
    Xinbo Wang, Peng Xu, Amanda Bentley-DeSousa, William Hancock-Cerutti, Shujun Cai, Benjamin T Johnson, Francesca Tonelli, Gabriel Talaia, Dario R Alessi, Shawn M Ferguson, Pietro De Camilli.
      Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease (PD). Here we show that VPS13C, a bridge-like lipid transport protein and a PD gene, is a sensor of lysosome stress/damage. Upon lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires release of a brake, most likely an intramolecular interaction within VPS13C, which hinders access of its VAB domain to lysosome-bound Rab7. While another PD protein, LRRK2, is also recruited to stressed/damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the putative role of VPS13 proteins in bulk lipid transport, these findings suggest lipid delivery to lysosomes by VPS13C is part of an early response to lysosome damage.
    DOI:  https://doi.org/10.1101/2024.06.08.598070
  55. Exp Neurol. 2024 Jun 18. pii: S0014-4886(24)00195-X. [Epub ahead of print] 114869
    Interlinked destinies: How ubiquitin-proteasome and autophagy systems underpin neurocognitive outcomes.
    Xin Yang, Julia Duckhorn, John Marshall, Yu-Wen Alvin Huang.
      The protein homeostasis, or proteostasis, is maintained through the coupling of two pivotal systems: the ubiquitin-proteasome and autophagy. Cumulative evidence has suggested E3 ubiquitin ligases specifically play a central role in this coupling, ensuring the regulation of synaptic and cognitive functions. Defects in these ligases have been identified as hallmarks in a range of neurodevelopmental and neurodegenerative disorders. Recent literature has spotlighted the E3 ubiquitin ligase, UBE3A, as a key player in this domain. Dysregulation or loss of UBE3A function has been linked to disrupted proteostasis, leading to synaptic and cognitive anomalies. Notably, such defects are prominently observed in conditions like Angelman syndrome, a neurodevelopmental disorder characterized by severe cognitive impairments. The emerging understanding of UBE3A's role in bridging the ubiquitin-proteasome and autophagy systems offers a promising therapeutic avenue. Targeting the defective pathways caused by UBE3A loss could pave the way for innovative treatments, potentially ameliorating the cognitive deficits observed in neurological disorders like Angelman syndrome. As the scientific community delves deeper into the molecular intricacies of E3 ubiquitin ligases, there is burgeoning hope for devising effective interventions for associated neurological conditions.
    Keywords:  Angelman syndrome; Autophagy; E3 ubiquitin ligase; Synaptic function; Ubiquitin-proteasome system (UPS); Ubiquitin-protein ligase E3A (UBE3A)
    DOI:  https://doi.org/10.1016/j.expneurol.2024.114869
  56. PLoS One. 2024 ;19(6): e0300168
    FABP5-binding lipids regulate autophagy in differentiated SH-SY5Y cells.
    Alejandro Soto-Avellaneda, Alexandra E Oxford, Fabio Halla, Peyton Vasquez, Emily Oe, Anton D Pugel, Alyssa M Schoenfeld, Matthew C Tillman, André Cuevas, Eric A Ortlund, Brad E Morrison.
      The motor features of Parkinson's disease result from loss of dopaminergic neurons in the substantia nigra with autophagy dysfunction being closely linked to this disease. While a large body of work focusing on protein effectors of autophagy has been reported, regulation of autophagy by lipids has garnered far less attention. Therefore, we sought to identify endogenous lipid molecules that act as signaling mediators of autophagy in differentiated SH-SY5Y cells, a commonly used dopaminergic neuron-like cell model. In order to accomplish this goal, we assessed the role of a fatty acid-binding protein (FABP) family member on autophagy due to its function as an intracellular lipid chaperone. We focused specifically upon FABP5 due to its heightened expression in dopaminergic neurons within the substantia nigra and SH-SY5Y cells. Here, we report that knockdown of FABP5 resulted in suppression of autophagy in differentiated SH-SY5Y cells suggesting the possibility of an autophagic role for an interacting lipid. A lipidomic screen of FABP5-interacting lipids uncovered hits that include 5-oxo-eicosatetraenoic acid (5OE) and its precursor metabolite, arachidonic acid (AA). Additionally, other long-chain fatty acids were found to bind FABP5, such as stearic acid (SA), hydroxystearic acid (HSA), and palmitic acid (PA). The addition of 5OE, SA, and HSA but not AA or PA, led to potent inhibition of autophagy in SH-SY5Y cells. To identify potential molecular mechanisms for autophagy inhibition by these lipids, RNA-Seq was performed which revealed both shared and divergent signaling pathways between the lipid-treated groups. These findings suggest a role for these lipids in modulating autophagy through diverse signaling pathways and could represent novel therapeutic targets for Parkinson's disease.
    DOI:  https://doi.org/10.1371/journal.pone.0300168
  57. Curr Opin Cell Biol. 2024 Jun 20. pii: S0955-0674(24)00061-9. [Epub ahead of print]89 102382
    Disruptions in axonal lysosome transport and its contribution to neurological disease.
    Jean-Michel Paumier, Swetha Gowrishankar.
      Lysosomes are central to the maintenance of protein and organelle homeostasis in cells. Optimal lysosome function is particularly critical for neurons which are long-lived, non-dividing and highly polarized with specialized compartments such as axons and dendrites with distinct architecture, cargo, and turnover requirements. In recent years, there has been a growing appreciation for the role played by axonal lysosome transport in regulating neuronal development, its maintenance and functioning. Perturbations to optimal axonal lysosome abundance leading to either strong accumulations or dearth of lysosomes are both linked to altered neuronal health and functioning. In this review we highlight how two critical regulators of axonal lysosome transport and abundance, the small GTPase Arl8 and the adaptor protein JIP3, aid in maintaining axonal lysosome homeostasis and how alterations to their levels and activity could contribute to neurodevelopmental and neurodegenerative diseases.
    DOI:  https://doi.org/10.1016/j.ceb.2024.102382
  58. Front Pharmacol. 2024 ;15 1407336
    Autophagy and inflammation an intricate affair in the management of obesity and metabolic disorders: evidence for novel pharmacological strategies?
    Marzia Friuli, Christian Sepe, Elisabetta Panza, Cristina Travelli, Irene Paterniti, Adele Romano.
      Unhealthy lifestyle habits including a sedentary life, the lack of physical activity, and wrong dietary habits are the major ones responsible for the constant increase of obesity and metabolic disorders prevalence worldwide; therefore, the scientific community pays significant attention to the pharmacotherapy of such diseases, beyond lifestyle interventions, the use of medical devices, and surgical approaches. The intricate interplay between autophagy and inflammation appears crucial to orchestrate fundamental aspects of cellular and organismal responses to challenging stimuli, including metabolic insults; hence, when these two processes are dysregulated (enhanced or suppressed) they produce pathologic effects. The present review summarizes the existing literature reporting the intricate affair between autophagy and inflammation in the context of metabolic disorders, including obesity, diabetes, and liver metabolic diseases (non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)). The evidence collected so far suggests that an alteration of autophagy might lead to maladaptive metabolic and inflammatory responses thus exacerbating the severity of the disease, and the most prominent conclusion underlies that autophagy might exert a protective function by contributing to balance inflammation. However, the complex nature of obesity and metabolic disorders might represent a limit of the studies; indeed, although many pharmacological treatments, producing positive metabolic effects, are also able to modulate autophagic flux and inflammation, it is not clear if the final beneficial effect might occur only by their mechanism of action, rather than because of additionally involved pathways. Finally, although future studies are needed, the observation that anti-obesity and antidiabetic drugs already on the market, including incretin mimetic agents, facilitate autophagy by dampening inflammation, strongly contributes to the idea that autophagy might represent a druggable system for the development of novel pharmacological tools that might represent an attractive strategy for the treatment of obesity and metabolic disorders.
    Keywords:  NAFLD; NASH; autophagy; diabetes; inflammation; metabolic diseases; obesity; therapeutic targets
    DOI:  https://doi.org/10.3389/fphar.2024.1407336
  59. J Am Chem Soc. 2024 Jun 20.
    Lysosome Targeting Chimaeras for Glut1-Facilitated Targeted Protein Degradation.
    Jinyan Luo, Quan Gao, Kui Tan, Shiling Zhang, Weiwei Shi, Lei Luo, Zhiying Li, Ghada E Khedr, Jie Chen, Youwei Xu, Ming Luo, Qi Xing, Jin Geng.
      Targeted protein degradation technology holds great potential in biomedicine, particularly in treating tumors and other protein-related diseases. Research on intracellular protein degradation using molecular glues and PROTAC technology is leading, while research on the degradation of membrane proteins and extracellular proteins through the lysosomal pathway is still in the preclinical stage. The scarcity of useful targets is an immense limitation to technological advancement, making it essential to explore novel, potentially effective approaches for targeted lysosomal degradation. Here, we employed the glucose transporter Glut1 as an innovative lysosome-targeting receptor and devised the Glut1-Facilitated Lysosomal Degradation (GFLD) strategy. We synthesized potential Glut1 ligands via reversible addition-fragmentation chain transfer (RAFT) polymerization and acquired antibody-glycooligomer conjugates through bioorthogonal reactions as lysosome-targeting protein degradation molecules, utilized in the management of PD-L1 high-expressing triple-negative breast cancer. The glucose transporter Glut1 as a lysosome-targeting receptor exhibits potential for the advancement of a broader array of medications in the future.
    DOI:  https://doi.org/10.1021/jacs.4c02463
  60. Adv Sci (Weinh). 2024 Jun 17. e2400480
    Extracellular Matrix Remodeling Alleviates Memory Deficits in Alzheimer's Disease by Enhancing the Astrocytic Autophagy-Lysosome Pathway.
    Qinghu Yang, Chengxiang Yan, Yahan Sun, Zhen Xie, Liang Yang, Ming Jiang, Junjun Ni, Beining Chen, Sen Xu, Zhaoyue Yuan, Yanyan Wu, Xia Liu, Zengqiang Yuan, Zhantao Bai.
      Extracellular matrix (ECM) remodeling is strongly linked to Alzheimer's disease (AD) risk; however, the underlying mechanisms are not fully understood. Here, it is found that the injection of chondroitinase ABC (ChABC), mimicking ECM remodeling, into the medial prefrontal cortex (mPFC) reversed short-term memory loss and reduced amyloid-beta (Aβ) deposition in 5xFAD mice. ECM remodeling also reactivated astrocytes, reduced the levels of aggrecan in Aβ plaques, and enhanced astrocyte recruitment to surrounding plaques. Importantly, ECM remodeling enhanced the autophagy-lysosome pathway in astrocytes, thereby mediating Aβ clearance and alleviating AD pathology. ECM remodeling also promoted Aβ plaque phagocytosis by astrocytes by activating the astrocytic phagocytosis receptor MERTK and promoting astrocytic vesicle circulation. The study identified a cellular mechanism in which ECM remodeling activates the astrocytic autophagy-lysosomal pathway and alleviates AD pathology. Targeting ECM remodeling may represent a potential therapeutic strategy for AD and serve as a reference for the treatment of this disease.
    Keywords:  Alzheimer's disease; astrocyte; autophagy‐lysosome; extracellular matrix remodeling
    DOI:  https://doi.org/10.1002/advs.202400480
  61. ACS Chem Neurosci. 2024 Jun 21.
    β-Synuclein Intermediates α-Synuclein Neurotoxicity in Parkinson's Disease.
    Meiyan Xian, Jingwen Li, Tingting Liu, Kaiying Hou, Lin Sun, Jianshe Wei.
      Parkinson's disease (PD) is the second most common age-related neurodegenerative disease in the world, and synuclein is closely related to the onset and progression of PD. Synuclein is considered a therapeutic target for PD. Recent studies have found that abnormal aggregation of α-synuclein (α-Syn) in the brains of PD patients leads to mitochondrial dysfunction and neuroinflammation. Research in the field of neuroscience has confirmed that β-synuclein (β-Syn) also plays a role in Parkinson's disease. However, there has been little research on the role mechanisms and interactions between β-Syn and α-Syn in PD. Therefore, the purpose of this study is to clarify the relationship between α-Syn, β-Syn, and PD and to explore the roles and interactions of β-Syn and α-Syn in PD.
    Keywords:  Parkinson’s disease; mitochondrial autophagy; neurodegenerative disease; protein aggregation; α-synuclein; β-synuclein
    DOI:  https://doi.org/10.1021/acschemneuro.4c00263
  62. Cell Biol Toxicol. 2024 Jun 20. 40(1): 48
    Endosome mediated nucleocytoplasmic trafficking and endomembrane allocation is crucial to polyglutamine toxicity.
    Yuyu Nan, Wenfeng Chen, Fei Chen, Lili Wei, Aiyuan Zeng, Xiaohui Lin, Wenbin Zhou, Yufeng Yang, Qinghua Li.
      Aggregation of aberrant proteins is a common pathological hallmark in neurodegeneration such as polyglutamine (polyQ) and other repeat-expansion diseases. Here through overexpression of ataxin3 C-terminal polyQ expansion in Drosophila gut enterocytes, we generated an intestinal obstruction model of spinocerebellar ataxia type3 (SCA3) and reported a new role of nuclear-associated endosomes (NAEs)-the delivery of polyQ to the nucleoplasm. In this model, accompanied by the prominently increased RAB5-positive NAEs are abundant nucleoplasmic reticulum enriched with polyQ, abnormal nuclear envelope invagination, significantly reduced endoplasmic reticulum, indicating dysfunctional nucleocytoplasmic trafficking and impaired endomembrane organization. Consistently, Rab5 but not Rab7 RNAi further decreased polyQ-related NAEs, inhibited endomembrane disorganization, and alleviated disease model. Interestingly, autophagic proteins were enriched in polyQ-related NAEs and played non-canonical autophagic roles as genetic manipulation of autophagic molecules exhibited differential impacts on NAEs and SCA3 toxicity. Namely, the down-regulation of Atg1 or Atg12 mitigated while Atg5 RNAi aggravated the disease phenotypes both in Drosophila intestines and compound eyes. Our findings, therefore, provide new mechanistic insights and underscore the fundamental roles of endosome-centered nucleocytoplasmic trafficking and homeostatic endomembrane allocation in the pathogenesis of polyQ diseases.
    Keywords:  Autophagy; Endosome; Inclusion body; Non-canonical role of ATG; Nucleocytoplasmic trafficking; Spinocerebellar ataxia
    DOI:  https://doi.org/10.1007/s10565-024-09891-4
  63. Mol Biol Cell. 2024 Jun 18. mbcE23090344
    A genetically-encoded fluorescence-based reporter to spatiotemporally investigate mannose-6-phosphate pathway.
    Mallika Bhat, Akshaya Nambiar, Lakshmi Edakkandiyil, Irine Maria Abraham, Ritoprova Sen, Mamta Negi, Ravi Manjithaya.
      Maintenance of a pool of active lysosomes with acidic pH and degradative hydrolases is crucial for cell health. Abnormalities in lysosomal function are closely linked to diseases, such as lysosomal storage disorders (LSDs), neurodegeneration, intracellular infections, and cancer among others. Emerging body of research suggests the malfunction of lysosomal hydrolase trafficking pathway to be a common denominator of several disease pathologies. However, available conventional tools to assess lysosomal hydrolase trafficking are insufficient and fail to provide a comprehensive picture about the trafficking flux and location of lysosomal hydrolases. To address some of the shortcomings, we designed a genetically encoded fluorescent reporter containing a lysosomal hydrolase tandemly tagged with pH sensitive and insensitive fluorescent proteins, which can spatio-temporally trace the trafficking of lysosomal hydrolases. As a proof of principle, we demonstrate that the reporter can detect perturbations in hydrolase trafficking, that are induced by pharmacological manipulations and pathophysiological conditions like intracellular protein aggregates. This reporter can effectively serve as a probe for mapping the mechanistic intricacies of hydrolase trafficking pathway in health and disease and is a utilitarian tool to identify genetic and pharmacological modulators of this pathway, with potential therapeutic implications.
    DOI:  https://doi.org/10.1091/mbc.E23-09-0344
  64. Nat Commun. 2024 Jun 19. 15(1): 5206
    The hexosamine biosynthetic pathway rescues lysosomal dysfunction in Parkinson's disease patient iPSC derived midbrain neurons.
    Willayat Y Wani, Friederike Zunke, Nandkishore R Belur, Joseph R Mazzulli.
      Disrupted glucose metabolism and protein misfolding are key characteristics of age-related neurodegenerative disorders including Parkinson's disease, however their mechanistic linkage is largely unexplored. The hexosamine biosynthetic pathway utilizes glucose and uridine-5'-triphosphate to generate N-linked glycans required for protein folding in the endoplasmic reticulum. Here we find that Parkinson's patient midbrain cultures accumulate glucose and uridine-5'-triphosphate, while N-glycan synthesis rates are reduced. Impaired glucose flux occurred by selective reduction of the rate-limiting enzyme, GFPT2, through disrupted signaling between the unfolded protein response and the hexosamine pathway. Failure of the unfolded protein response and reduced N-glycosylation caused immature lysosomal hydrolases to misfold and accumulate, while accelerating glucose flux through the hexosamine pathway rescued hydrolase function and reduced pathological α-synuclein. Our data indicate that the hexosamine pathway integrates glucose metabolism with lysosomal activity, and its failure in Parkinson's disease occurs by uncoupling of the unfolded protein response-hexosamine pathway axis. These findings offer new methods to restore proteostasis by hexosamine pathway enhancement.
    DOI:  https://doi.org/10.1038/s41467-024-49256-3
  65. Front Pharmacol. 2024 ;15 1378358
    The neuroprotective effect of Chinese herbal medicine for cerebral ischemia reperfusion injury through regulating mitophagy.
    Yanling Chen, Yanan Zhang, Qin Wu, Jing Chen, Yihui Deng.
      The incidence of ischemic stroke has been increasing annually with an unfavorable prognosis. Cerebral ischemia reperfusion injury can exacerbate nerve damage. Effective mitochondrial quality control including mitochondrial fission, fusion and autophagy, is crucial for maintaining cellular homeostasis. Several studies have revealed the critical role of mitophagy in Cerebral ischemia reperfusion injury. Cerebral ischemia and hypoxia induce mitophagy, and mitophagy exhibits positive and negative effects in cerebral ischemia reperfusion injury. Studies have shown that Chinese herbal medicine can alleviate Cerebral ischemia reperfusion injury and serve as a neuroprotective agent by inhibiting or promoting mitophagy-mediated pathways. This review focuses on the mitochondrial dynamics and mitophagy-related pathways, as well as the role of mitophagy in ischemia reperfusion injury. Additionally, it discusses the therapeutic potential and benefits of Chinese herbal monomers and decoctions in the treatment of ischemic stroke.
    Keywords:  Chinese herbal medicine; cerebral ischemia reperfusion injury; mitochondrial dynamics; mitophagy; neuroprotective effect
    DOI:  https://doi.org/10.3389/fphar.2024.1378358
  66. Front Pharmacol. 2024 ;15 1398320
    The emerging role and clinicopathological significance of MFSD12 in cancer and lysosomal storage diseases.
    Liqiong Ding.
      MFSD12 protein has recently risen as a key factor in malignancy and plays a potential role in a variety of complex oncogenic signaling cascades. Current studies suggest that MFSD12 has a positive complex role in the growth and progression of tumors such as melanoma, breast cancer, and lung cancer. At the same time, as a transporter of cysteine, MFSD12 is also involved in the development of lysosomal storage diseases. Therefore, MFSD12 may be an effective target to inhibit tumor development, block metastasis, and expand the therapeutic effect. This article reviews the molecular mechanisms of MFSD12 in a variety of cancers and lysosomal storage diseases.
    Keywords:  MFSD12; PI3K; lysosomal storage diseases; lysosome; melanoma; melanosome
    DOI:  https://doi.org/10.3389/fphar.2024.1398320
  67. Plants (Basel). 2024 May 25. pii: 1468. [Epub ahead of print]13(11):
    The Role of Plant Ubiquitin-like Modifiers in the Formation of Salt Stress Tolerance.
    Siarhei A Dabravolski, Stanislav V Isayenkov.
      The climate-driven challenges facing Earth necessitate a comprehensive understanding of the mechanisms facilitating plant resilience to environmental stressors. This review delves into the crucial role of ubiquitin-like modifiers, particularly focusing on ATG8-mediated autophagy, in bolstering plant tolerance to salt stress. Synthesising recent research, we unveil the multifaceted contributions of ATG8 to plant adaptation mechanisms amidst salt stress conditions, including stomatal regulation, photosynthetic efficiency, osmotic adjustment, and antioxidant defence. Furthermore, we elucidate the interconnectedness of autophagy with key phytohormone signalling pathways, advocating for further exploration into their molecular mechanisms. Our findings underscore the significance of understanding molecular mechanisms underlying ubiquitin-based protein degradation systems and autophagy in salt stress tolerance, offering valuable insights for designing innovative strategies to improve crop productivity and ensure global food security amidst increasing soil salinisation. By harnessing the potential of autophagy and other molecular mechanisms, we can foster sustainable agricultural practices and develop stress-tolerant crops resilient to salt stress.
    Keywords:  SUMOylation; autophagy; phytohormones; salt stress; ubiquitin
    DOI:  https://doi.org/10.3390/plants13111468
  68. J Neural Transm (Vienna). 2024 Jun 18.
    In situ stoichiometry amounts of p62 and poly-ubiquitin exceed the increase of alpha-synuclein during degeneration of catecholamine cells induced by autophagy inhibition in vitro.
    Paola Lenzi, Gloria Lazzeri, Michela Ferrucci, Carla Letizia Busceti, Stefano Puglisi-Allegra, Francesco Fornai.
      Neurodegenerative disorders are typically featured by the occurrence of neuronal inclusions. In the case of Parkinson's disease (PD) these correspond to Lewy bodies (LBs), which are routinely defined as proteinaceous inclusions composed of alpha-synuclein (alpha-syn). In turn, alpha-syn is considered to be the key protein in producing PD and fostering its progression. Recent studies challenged such a concept and emphasized the occurrence of other proteins such as p62 and poly-ubiquitin (Poly-ub) in the composition of LBs, which are also composed of large amounts of tubulo-vesicular structures. All these components, which accumulate within the cytosol of affected neurons in PD, may be the consequence of a dysfunction of major clearing pathways. In fact, autophagy-related systems are constantly impaired in inherited PD and genetic models of PD. The present study was designed to validate whether a pharmacological inhibition of autophagy within catecholamine cells produces cell damage and accumulation of specific proteins and tubulo-vesicular structures. The stoichiometry counts of single proteins, which accumulate within catecholamine neurons was carried out along with the area of tubulo-vesicular structures. In these experimental conditions p62 and Poly-ub accumulation exceeded at large the amounts of alpha-syn. In those areas where Poly-ub and p62 were highly expressed, tubulo-vesicular structures were highly represented compared with surrounding cytosol. The present study confirms new vistas about LBs composition and lends substance to the scenario that autophagy inhibition rather than a single protein dysfunction as key determinant of PD.
    Keywords:  Autophagosome; Autophagy; Lewy bodies; Poly-ubiquitin; Proteasome; Sequestosome
    DOI:  https://doi.org/10.1007/s00702-024-02795-x
  69. Autophagy. 2024 Jun 13.
    CCDC50 mediates the clearance of protein aggregates to prevent cellular proteotoxicity.
    Yu Ye, Penghui Jia, Jiafan Miao, Yicheng Wang, Zibo Li, Yuxin Lin, Miao He, Shurui Liu, Bi-Rong Zheng, Junyu Wu, Ji'an Pan, Chun-Mei Li, Panpan Hou, Deyin Guo.
      Protein aggregation caused by the disruption of proteostasis will lead to cellular cytotoxicity and even cell death, which is implicated in multiple neurodegenerative diseases. The elimination of aggregated proteins is mediated by selective macroautophagy receptors, which is termed aggrephagy. However, the identity and redundancy of aggrephagy receptors in recognizing substrates remain largely unexplored. Here, we find that CCDC50, a highly expressed autophagy receptor in brain, is recruited to proteotoxic stresses-induced polyubiquitinated protein aggregates and ectopically expressed aggregation-prone proteins. CCDC50 recognizes and further clears these cytotoxic aggregates through autophagy. The ectopic expression of CCDC50 increases the tolerance to stress-induced proteotoxicity and hence improved cell survival in neuron cells, whereas CCDC50 deficiency caused accumulation of lipid deposits and polyubiquitinated protein conjugates in the brain of one-year-old mice. Our study illustrates how aggrephagy receptor CCDC50 combats proteotoxic stress for the benefit of neuronal cell survival, thus suggesting a protective role in neurotoxic proteinopathy.
    Keywords:  Aggrephagy receptor; CCDC50; neurodegenerative diseases; protein aggregation; proteostasis
    DOI:  https://doi.org/10.1080/15548627.2024.2367183
  70. J Physiol. 2024 Jun 15.
    A multimodal exercise countermeasure prevents the negative impact of head-down tilt bed rest on muscle volume and mitochondrial health in older adults.
    Maude Dulac, Guy Hajj-Boutros, Vita Sonjak, Andréa Faust, Sabah N A Hussain, Stéphanie Chevalier, Isabelle J Dionne, José A Morais, Gilles Gouspillou.
      Mitochondrial dysfunctions are thought to contribute to muscle atrophy and weakness that develop during ageing and mechanical unloading caused by immobilization, bed rest and microgravity. Older adults are at greater risk of developing muscle and mitochondrial dysfunctions in response to unloading. Although exercise is well known to promote muscle and mitochondrial health, its protective effect during mechanical unloading in older adults remains largely unexplored. Here, we investigated the impact of 14 days of head-down tilt bed rest (HDBR) with and without a multimodal exercise countermeasure in older men and women (55-65 years). Leg muscle volume was assessed using magnetic resonance imaging. Biopsies of the vastus lateralis were performed to assess markers of mitochondrial content, respiration, reactive oxygen species (ROS) production and calcium retention capacity (mCRC). Indices of mitochondrial quality control (MQC), including markers of fusion (MFN1 and 2), fission (Drp1), mitophagy (Parkin) and autophagy (p62 and LC3I and II) were measured using immunoblots. Muscle cross-sections were stained for neural cell adhesion molecule (NCAM, a marker of denervation). HDBR triggered muscle atrophy, decreased mitochondrial content and respiration and increased mitochondrial ROS production. HDBR had no impact on mCRC or MQC markers but increased markers of autophagy and denervation. Exercise prevented the deleterious effects of HDBR on leg muscle volume, mitochondrial ROS production and markers of autophagy and denervation. Exercise also increased mitochondrial content and respiration without altering mCRC and MQC markers. Collectively, our results indicate that an exercise countermeasure that can be performed in bed is effective in protecting muscle and mitochondrial health during HDBR in older adults. KEY POINTS: Conditions associated with muscle unloading, such as immobilization, bed rest or microgravity, result in muscle atrophy and weakness, particularly in older adults. Mitochondrial dysfunctions are thought to contribute to muscle atrophy caused by unloading and ageing. However, whether exercise can counteract the deleterious effects of unloading in older adults remains largely unexplored. Here, we report that older adults exposed to 14 days of head-down tilt bed rest (HDBR) displayed upper leg muscle atrophy, a decrease in mitochondrial content and respiration, an increase in H2O2 emission, and an increase in autophagy and denervation markers. No impact of HDBR on mitochondrial quality control was observed. A multimodal exercise countermeasure prevented the deleterious effects of HDBR on upper leg muscle volume, mitochondrial reactive oxygen species emission, and markers of autophagy and denervation and increased mitochondrial content and respiration. These findings highlight the effectiveness of exercise in promoting muscle and mitochondrial health in older adults undergoing bed rest.
    Keywords:  ageing; atrophy; autophagy; disuse; inactivity; mitochondria; mitochondrial dynamics; neuromuscular junction; skeletal muscle; space flight; weakness
    DOI:  https://doi.org/10.1113/JP285897
  71. Cancer Res Commun. 2024 Jun 12.
    Claudin-4 modulates autophagy via SLC1A5/LAT1 as a mechanism to regulate micronuclei.
    Fabian R Villagomez, Julie Lang, Fredrick J Rosario, Daniel Nunez-Avellaneda, Patricia Webb, Margaret Neville, Elizabeth R Woodruff, Benjamin G Bitler.
      Genome instability is a hallmark of cancer crucial for tumor heterogeneity and is often a result of defects in cell division and DNA damage repair. Tumors tolerate genomic instability, but the accumulation of genetic aberrations is regulated to avoid catastrophic chromosomal alterations and cell death. In ovarian cancer tumors, claudin-4 is frequently upregulated and closely associated with genome instability and worse patient outcomes. However, its biological association with regulating genomic instability is poorly understood. Here, we used CRISPR interference and a claudin mimic peptide (CMP) to modulate the claudin-4 expression and its function in vitro and in vivo. We found that claudin-4 promotes a tolerance mechanism for genomic instability through micronuclei generation in tumor cells. Disruption of claudin-4 increased autophagy and was associated with the engulfment of cytoplasm-localized DNA. Mechanistically, we observed that claudin-4 establishes a biological axis with the amino acid transporters SLC1A5 and LAT1, which regulate autophagy upstream of mTOR. Furthermore, the claudin-4/SLC1A5/LAT1 axis was linked to the transport of amino acids across the plasma membrane as one of the potential cellular processes that significantly decreased survival in ovarian cancer patients. Together, our results show that the upregulation of claudin-4 contributes to increasing the threshold of tolerance for genomic instability in ovarian tumor cells by limiting its accumulation through autophagy.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-24-0240
  72. CNS Neurosci Ther. 2024 Jun;30(6): e14800
    Hippocampal mitophagy contributes to spatial memory via maintaining neurogenesis during the development of mice.
    Le Xu, Saboor Saeed, Xinxu Ma, Xufeng Cen, Yifei Sun, Yanan Tian, Xuhong Zhang, Danhua Zhang, Anying Tang, Hetong Zhou, Jianbo Lai, Hongguang Xia, Shaohua Hu.
      BACKGROUND: Impaired mitochondrial dynamics have been identified as a significant contributing factor to reduced neurogenesis under pathological conditions. However, the relationship among mitochondrial dynamics, neurogenesis, and spatial memory during normal development remains unclear. This study aims to elucidate the role of mitophagy in spatial memory mediated by neurogenesis during development.METHODS: Adolescent and adult male mice were used to assess spatial memory performance. Immunofluorescence staining was employed to evaluate levels of neurogenesis, and mitochondrial dynamics were assessed through western blotting and transmission electron microscopy. Pharmacological interventions further validated the causal relationship among mitophagy, neurogenesis, and behavioral performance during development.
    RESULTS: The study revealed differences in spatial memory between adolescent and adult mice. Diminished neurogenesis, accompanied by reduced mitophagy, was observed in the hippocampus of adult mice compared to adolescent subjects. Pharmacological induction of mitophagy in adult mice with UMI-77 resulted in enhanced neurogenesis and prolonged spatial memory retention. Conversely, inhibition of mitophagy with Mdivi-1 in adolescent mice led to reduced hippocampal neurogenesis and impaired spatial memory.
    CONCLUSION: The observed decline in spatial memory in adult mice is associated with decreased mitophagy, which affects neurogenesis in the dentate gyrus. This underscores the therapeutic potential of enhancing mitophagy to counteract age- or disease-related cognitive decline.
    Keywords:  development; mitophagy; neurogenesis; spatial memory
    DOI:  https://doi.org/10.1111/cns.14800
  73. Nat Chem Biol. 2024 Jun 18.
    Quantitative control of subcellular protein localization with a photochromic dimerizer.
    Takato Mashita, Toshiyuki Kowada, Hayashi Yamamoto, Satoshi Hamaguchi, Toshizo Sato, Toshitaka Matsui, Shin Mizukami.
      Artificial control of intracellular protein dynamics with high precision provides deep insight into complicated biomolecular networks. Optogenetics and caged compound-based chemically induced dimerization (CID) systems are emerging as tools for spatiotemporally regulating intracellular protein dynamics. However, both technologies face several challenges for accurate control such as the duration of activation, deactivation rate and repetition cycles. Herein, we report a photochromic CID system that uses the photoisomerization of a ligand so that both association and dissociation are controlled by light, enabling quick, repetitive and quantitative regulation of the target protein localization upon illumination with violet and green light. We also demonstrate the usability of the photochromic CID system as a potential tool to finely manipulate intracellular protein dynamics during multicolor fluorescence imaging to study diverse cellular processes. We use this system to manipulate PTEN-induced kinase 1 (PINK1)-Parkin-mediated mitophagy, showing that PINK1 recruitment to the mitochondria can promote Parkin recruitment to proceed with mitophagy.
    DOI:  https://doi.org/10.1038/s41589-024-01654-w
  74. Phytomedicine. 2024 Mar 04. pii: S0944-7113(24)00172-7. [Epub ahead of print]132 155508
    Natural autophagy activators: A promising strategy for combating photoaging.
    Apeksha Vikram, Sunil Kumar Patel, Arshwinder Singh, Diksha Pathania, Ratan Singh Ray, Atul Kumar Upadhyay, Ashish Dwivedi.
      BACKGROUND: Photodamage to the skin stands out as one of the most widespread epidermal challenges globally. Prolonged exposure to sunlight containing ultraviolet radiation (UVR) instigates stress, thereby compromising the skin's functionality and culminating in photoaging. Recent investigations have shed light on the importance of autophagy in shielding the skin from photodamage. Despite the acknowledgment of numerous phytochemicals possessing photoprotective attributes, their potential to induce autophagy remains relatively unexplored.PURPOSE: Diminished autophagy activity in photoaged skin underscores the potential benefits of restoring autophagy through natural compounds to enhance photoprotection. Consequently, this study aims to highlight the role of natural compounds in safeguarding against photodamage and to assess their potential to induce autophagy via an in-silico approach.
    METHODS: A thorough search of the literature was done using several databases, including PUBMED, Science Direct, and Google Scholar, to gather relevant studies. Several keywords such as Phytochemical, Photoprotection, mTOR, Ultraviolet Radiation, Reactive oxygen species, Photoaging, and Autophagy were utilized to ensure thorough exploration. To assess the autophagy potential of phytochemicals through virtual screening, computational methodologies such as molecular docking were employed, utilizing tools like AutoDock Vina. Receptor preparation for docking was facilitated using MGLTools.
    RESULTS: The initiation of structural and functional deterioration in the skin due to ultraviolet radiation (UVR) or sunlight-induced reactive oxygen species/reactive nitrogen species (ROS/RNS) involves the modulation of various pathways. Natural compounds like phenolics, flavonoids, flavones, and anthocyanins, among others, possess chromophores capable of absorbing light, thereby offering photoprotection by modulating these pathways. In our molecular docking study, these phytochemicals have shown binding affinity with mTOR, a negative regulator of autophagy, indicating their potential as autophagy modulators.
    CONCLUSION: This integrated review underscores the photoprotective characteristics of natural compounds, while the in-silico analysis reveals their potential to modulate autophagy, which could significantly contribute to their anti-photoaging properties. The findings of this study hold promise for the advancement of cosmeceuticals and therapeutics containing natural compounds aimed at addressing photoaging and various skin-related diseases. By leveraging their dual benefits of photoprotection and autophagy modulation, these natural compounds offer a multifaceted approach to combatting skin aging and related conditions.
    Keywords:  Autophagy activators; Molecular docking; Photoaging; Phytochemicals; UV radiation
    DOI:  https://doi.org/10.1016/j.phymed.2024.155508
  75. Chin J Nat Med. 2024 Jun;pii: S1875-5364(24)60654-0. [Epub ahead of print]22(6): 515-529
    Paeoniflorin alleviates depression by inhibiting the activation of NLRP3 inflammasome via promoting mitochondrial autophagy.
    Lili Su, Pengli Guo, Xiangjuan Guo, Zhongmei He, Yan Zhao, Ying Zong, Jianming Li, Weijia Chen, Rui DU.
      Depression ranks among the most common neuropsychiatric disorders globally. Current studies examining the roles of inflammation and mitochondrial autophagy in the antidepressant efficacy of paeoniflorin (PF) are sparse. This study aimed to elucidate PF's antidepressant mechanism by promoting autophagy and inhibiting NLRP3 inflammasome activation using chronic unpredictable mild stimulation (CUMS)-induced C57BL/6 mouse models in vivo and corticosterone (CORT)-induced HT22 cell models in vitro. Results demonstrated that PF enhanced the viability of HT22 cells following CORT exposure, restored mitochondrial membrane potential (MMP), reduced reactive oxygen species accumulation, increased LC3 fluorescence intensity, and suppressed inflammatory cytokine secretion and inflammation activation. Additionally, PF ameliorated depressive behaviors induced by CUMS and improved damage in hippocampal neurons. It also reduced the expression of NLRP3, ASC, Caspase-1, IL-1β, and the assembly of the NLRP3 inflammasome. Moreover, PF upregulated the expression of autophagy-related proteins in the hippocampus, facilitating the clearance of damaged mitochondria and enhancing autophagy. The role of autophagy in PF's antidepressant effects was further confirmed through the use of the autophagy inhibitor 3-methyladenine (3-MA), which reduced the efficacy of PF. In conclusion, PF effectively improved depressive behaviors in CUMS-induced mice and reduced NLRP3-mediated inflammation both in vivo and in vitro, likely via the induction of autophagy.
    Keywords:  Autophagy; Depression; NLRP3 inflammasome; Paeoniflorin
    DOI:  https://doi.org/10.1016/S1875-5364(24)60654-0
  76. Exp Gerontol. 2024 Jun 18. pii: S0531-5565(24)00125-6. [Epub ahead of print]194 112483
    Autophagy markers LC3 and p62 in aging lumbar motor neurons.
    Sepideh Jahanian, Miguel Pareja-Cajiao, Heather M Gransee, Gary C Sieck, Carlos B Mantilla.
      Autophagy is a ubiquitous process through which damaged cytoplasmic structures are recycled and degraded within cells. Aging can affect autophagy regulation in different steps leading to the accumulation of damaged organelles and proteins, which can contribute to cell dysfunction and death. Motor neuron (MN) loss and sarcopenia are prominent features of neuromuscular aging. Previous studies on phrenic MNs showed increased levels of the autophagy proteins LC3 and p62 in 24 month compared to 6 month old mice, consistent with the onset of diaphragm muscle sarcopenia. In the present study, we hypothesized that aging leads to increased expression of the autophagy markers LC3 and p62 in single lumbar MNs. Expression of LC3 and p62 in lumbar MNs (spinal levels L1-L6) was assessed using immunofluorescence and confocal imaging of male and female mice at 6, 18 and 24 months of age, reflecting 100 %, 90 % and 75 % survival, respectively. A mixed linear model with animal as a random effect was used to compare relative LC3 and p62 expression in choline acetyl transferase-positive MNs across age groups. Expression of LC3 and p62 decreased in the white matter of the lumbar spinal cord with aging, with ~29 % decrease in LC3 and ~ 7 % decrease in p62 expression at 24 months of age compared to 6 months of age. There was no change in LC3 or p62 expression in the gray matter with age. LC3 expression in MNs relative to white matter increased significantly with age, with 150 % increase at 24 months of age compared to 6 months of age. Similarly, p62 expression in MNs relative to white matter increased significantly with age, with ~14 % increase at 24 months of age compared to 6 months of age. No effect of sex or MN pool was observed in LC3 and p62 expression in MNs. Overall, these data suggest autophagy impairment during elongation (increased LC3) and degradation (increased p62) phases with aging in lumbar MNs.
    Keywords:  Aging; Autophagy; Motor neuron; Neuromuscular dysfunction; Spinal cord
    DOI:  https://doi.org/10.1016/j.exger.2024.112483
  77. Int J Biol Sci. 2024 ;20(8): 2904-2921
    Metallothionein 3 Potentiates Pulmonary Artery Smooth Muscle Cell Proliferation by Promoting Zinc-MTF1-ATG5 Axis-mediated Autophagosome Formation.
    Tianxin Xiong, Yi Li, Molin Yang, Bo Huo, Xian Guo, Liyuan Liu, Yanxin Huang, Xuehai Zhu, Qinghua Hu, Xiang Wei, Ding-Sheng Jiang, Xin Yi.
      Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the critical pathological mechanisms of pulmonary hypertension (PH), and therefore is gradually being adopted as an important direction for the treatment of PH. Metallothioneins (MTs) have been reported to be associated with PH, but the underlying mechanisms are not fully understood. Here, we demonstrated that the expression level of metallothionein 3 (MT3) was significantly increased in pulmonary arterioles from PH patients and chronic hypoxia-induced rat and mouse PH models, as well as in hypoxia-treated human PASMCs. Knockdown of MT3 significantly inhibited the proliferation of human PASMCs by arresting the cell cycle in the G1 phase, while overexpression of MT3 had the opposite effect. Mechanistically, we found that MT3 increased the intracellular zinc (Zn2+) concentration to enhance the transcriptional activity of metal-regulated transcription factor 1 (MTF1), which promoted the expression of autophagy-related gene 5 (ATG5), facilitating autophagosome formation. More importantly, MT3-induced autophagy and proliferation of human PASMCs were largely prevented by knockdown of MTF1 and ATG5. Therefore, in this study, we identified MT3-Zinc-MTF1-ATG5 as a novel pathway that affects PASMC proliferation by regulating autophagosome formation, suggesting that MT3 may be a novel target for the treatment of PH.
    Keywords:  ATG5; Autophagosome formation; MTF1; Metallothionein 3; Pulmonary artery smooth muscle cells; Zn2+
    DOI:  https://doi.org/10.7150/ijbs.92992
  78. Int J Mol Sci. 2024 Jun 03. pii: 6162. [Epub ahead of print]25(11):
    Mitochondrial Dysfunction in Systemic Lupus Erythematosus with a Focus on Lupus Nephritis.
    Matthieu Halfon, Aurel T Tankeu, Camillo Ribi.
      Systemic lupus erythematosus (SLE) is an autoimmune disease affecting mostly women of child-bearing age. Immune dysfunction in SLE results from disrupted apoptosis which lead to an unregulated interferon (IFN) stimulation and the production of autoantibodies, leading to immune complex formation, complement activation, and organ damage. Lupus nephritis (LN) is a common and severe complication of SLE, impacting approximately 30% to 40% of SLE patients. Recent studies have demonstrated an alteration in mitochondrial homeostasis in SLE patients. Mitochondrial dysfunction contributes significantly to SLE pathogenesis by enhancing type 1 IFN production through various pathways involving neutrophils, platelets, and T cells. Defective mitophagy, the process of clearing damaged mitochondria, exacerbates this cycle, leading to increased immune dysregulation. In this review, we aim to detail the physiopathological link between mitochondrial dysfunction and disease activity in SLE. Additionally, we will explore the potential role of mitochondria as biomarkers and therapeutic targets in SLE, with a specific focus on LN. In LN, mitochondrial abnormalities are observed in renal cells, correlating with disease progression and renal fibrosis. Studies exploring cell-free mitochondrial DNA as a biomarker in SLE and LN have shown promising but preliminary results, necessitating further validation and standardization. Therapeutically targeting mitochondrial dysfunction in SLE, using drugs like metformin or mTOR inhibitors, shows potential in modulating immune responses and improving clinical outcomes. The interplay between mitochondria, immune dysregulation, and renal involvement in SLE and LN underscores the need for comprehensive research and innovative therapeutic strategies. Understanding mitochondrial dynamics and their impact on immune responses offers promising avenues for developing personalized treatments and non-invasive biomarkers, ultimately improving outcomes for LN patients.
    Keywords:  interferon; kidney; lupus; lupus nephritis; mitochondria; mitochondrial DNA; mitophagy
    DOI:  https://doi.org/10.3390/ijms25116162
  79. Sci Rep. 2024 06 17. 14(1): 13981
    M133S mutation possibly involve in the ER stress and mitophagy pathway in maintenance hemodialysis patients with occult hepatitis B infection.
    Yurong Zou, Sipei Chen, Yiyuan Cui, Yang Zou.
      Occult hepatitis B virus infection (OBI) is characterized by the presence of HBV DNA in the absence of detectable HBsAg. OBI is an important risk factor for cirrhosis and hepatocellular carcinoma, but its pathogenesis has not been fully elucidated. Mutations in the HBV preS/S genes can lead to impaired secretion of either HBsAg or S-protein resulting in the accumulation of defective viruses or S protein in cells. In our previous work, the M133S mutation was present in the HBV S gene of maintenance hemodialysis (MHD) patients with OBI. In this study, we investigated the potential role of amino acid substitutions in S proteins in S protein production and secretion through the construction of mutant S gene plasmids, structural prediction, transcriptome sequencing analysis, and in vitro functional studies. Protein structure prediction showed that the S protein M133S mutant exhibited hydrophilic modifications, with greater aggregation and accumulation of the entire structure within the membrane phospholipid bilayer. Differential gene enrichment analysis of transcriptome sequencing data showed that differentially expressed genes were mainly concentrated in protein processing in the endoplasmic reticulum (ER). The expression of heat shock family proteins and ER chaperone molecules was significantly increased in the wild-type and mutant groups, whereas the expression of mitochondria-associated proteins was decreased. Immunofluorescence staining and protein blotting showed that the endoplasmic reticulum-associated protein PDI, the autophagy marker LC3, and the lysosome-associated protein LAMP2 co-localized with the S proteins in the wild-type and mutant strains, and their expression was increased. The mitochondria-associated TOMM20 protein was also co-expressed with the S protein, but expression was significantly reduced in the mutant. The M133S mutation in the S gene is expressed as a defective and misfolded protein that accumulates in the endoplasmic reticulum causing secretion-impaired endoplasmic reticulum stress, which in turn triggers mitochondrial autophagy and recruits lysosomes to fuse with the autophagosome, leading to mitochondrial clearance. This study preliminarily demonstrated that the mutation of M133S in the S gene can cause OBI and is associated with disease progression, providing a theoretical basis for the diagnosis and treatment of OBI.
    Keywords:  Endoplasmic reticulum (ER); Gene mutations; Maintenance hemodialysis (MHD); Mitophagy; Occult hepatitis B virus infection (OBI)
    DOI:  https://doi.org/10.1038/s41598-024-64943-3
  80. Int J Mol Sci. 2024 May 23. pii: 5691. [Epub ahead of print]25(11):
    Ovarian Cancer Cell-Conditioning Medium Induces Cancer-Associated Fibroblast Phenoconversion through Glucose-Dependent Inhibition of Autophagy.
    Alessandra Ferraresi, Carlo Girone, Chinmay Maheshwari, Letizia Vallino, Danny N Dhanasekaran, Ciro Isidoro.
      One aspect of ovarian tumorigenesis which is still poorly understood is the tumor-stroma interaction, which plays a major role in chemoresistance and tumor progression. Cancer-associated fibroblasts (CAFs), the most abundant stromal cell type in the tumor microenvironment, influence tumor growth, metabolism, metastasis, and response to therapy, making them attractive targets for anti-cancer treatment. Unraveling the mechanisms involved in CAFs activation and maintenance is therefore crucial for the improvement of therapy efficacy. Here, we report that CAFs phenoconversion relies on the glucose-dependent inhibition of autophagy. We show that ovarian cancer cell-conditioning medium induces a metabolic reprogramming towards the CAF-phenotype that requires the autophagy-dependent glycolytic shift. In fact, 2-deoxy-D-glucose (2DG) strongly hampers such phenoconversion and, most importantly, induces the phenoreversion of CAFs into quiescent fibroblasts. Moreover, pharmacological inhibition (by proline) or autophagy gene knockdown (by siBECN1 or siATG7) promotes, while autophagy induction (by either 2DG or rapamycin) counteracts, the metabolic rewiring induced by the ovarian cancer cell secretome. Notably, the nutraceutical resveratrol (RV), known to inhibit glucose metabolism and to induce autophagy, promotes the phenoreversion of CAFs into normal fibroblasts even in the presence of ovarian cancer cell-conditioning medium. Overall, our data support the view of testing autophagy inducers for targeting the tumor-promoting stroma as an adjuvant strategy to improve therapy success rates, especially for tumors with a highly desmoplastic stroma, like ovarian cancer.
    Keywords:  autophagy; cancer cell secretome; hexokinase 2; metabolic reprogramming; ovarian cancer; resveratrol; reverse Warburg effect; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms25115691
  81. Nat Commun. 2024 Jun 19. 15(1): 5188
    Arabidopsis CaLB1 undergoes phase separation with the ESCRT protein ALIX and modulates autophagosome maturation.
    Niccolò Mosesso, Niharika Savant Lerner, Tobias Bläske, Felix Groh, Shane Maguire, Marie Laura Niedermeier, Eliane Landwehr, Karin Vogel, Konstanze Meergans, Marie-Kristin Nagel, Malte Drescher, Florian Stengel, Karin Hauser, Erika Isono.
      Autophagy is relevant for diverse processes in eukaryotic cells, making its regulation of fundamental importance. The formation and maturation of autophagosomes require a complex choreography of numerous factors. The endosomal sorting complex required for transport (ESCRT) is implicated in the final step of autophagosomal maturation by sealing of the phagophore membrane. ESCRT-III components were shown to mediate membrane scission by forming filaments that interact with cellular membranes. However, the molecular mechanisms underlying the recruitment of ESCRTs to non-endosomal membranes remain largely unknown. Here we focus on the ESCRT-associated protein ALG2-interacting protein X (ALIX) and identify Ca2+-dependent lipid binding protein 1 (CaLB1) as its interactor. Our findings demonstrate that CaLB1 interacts with AUTOPHAGY8 (ATG8) and PI(3)P, a phospholipid found in autophagosomal membranes. Moreover, CaLB1 and ALIX localize with ATG8 on autophagosomes upon salt treatment and assemble together into condensates. The depletion of CaLB1 impacts the maturation of salt-induced autophagosomes and leads to reduced delivery of autophagosomes to the vacuole. Here, we propose a crucial role of CaLB1 in augmenting phase separation of ALIX, facilitating the recruitment of ESCRT-III to the site of phagophore closure thereby ensuring efficient maturation of autophagosomes.
    DOI:  https://doi.org/10.1038/s41467-024-49485-6
  82. Cell Stress Chaperones. 2024 Jun 14. pii: S1355-8145(24)00078-6. [Epub ahead of print]
    Mild heat shock at 40ºC increases levels of autophagy: role of Nrf2.
    Mélanie Grondin, Claire Chabrol, Diana A Averill-Bates.
      The exposure to low doses of stress induces an adaptive survival response that involves upregulation of cellular defense systems such as heat shock proteins (Hsp), anti-apoptosis proteins and antioxidants. Exposure of cells to elevated, non-lethal temperatures (39-41°C) is an adaptive survival response known as thermotolerance, which protects cells against subsequent lethal stress such as heat shock (>41.5°C). However, the initiating factors in this adaptive survival response are not understood. This study aims to determine whether autophagy can be activated by heat shock at 40°C, and if this response is mediated by the transcription factor Nrf2. Thermotolerant cells, which were developed during 3h at 40°C, were resistant to caspase activation at 42°C. Autophagy was activated when cells were heated from 5 to 60min at 40°C. Levels of acidic vesicular organelles (AVO) and autophagy proteins Beclin-1, LC3-II/LC3-I, Atg7, Atg5, Atg12-Atg5 and p62 were increased. When Nrf2 was overexpressed or depleted in cells, levels of AVOs and autophagy proteins were higher in unstressed cells, compared to wild type. Stress induced by mild heat shock at 40ºC further increased levels of most autophagy proteins in cells with overexpression or depletion of Nrf2. Colocalization of p62 and Keap1 occurred. When Nrf2 levels are low, activation of autophagy would likely compensate as a defense mechanism to protect cells against stress. Improved understanding of autophagy in the context of cellular responses to physiological heat shock could be useful for cancer treatment by hyperthermia and the protective role of adaptive responses against environmental stresses.
    Keywords:  Adaptive survival response; Autophagy; Heat shock; Nrf2; Thermotolerance
    DOI:  https://doi.org/10.1016/j.cstres.2024.06.001
  83. J Nutr Biochem. 2024 Jun 19. pii: S0955-2863(24)00127-X. [Epub ahead of print] 109694
    CTRP9 alleviates diet induced obesity through increasing lipolysis mediated by enhancing autophagy-initiation complex formation.
    Shengyun Lei, Xuehui Li, Anju Zuo, Shiyan Ruan, Yuan Guo.
      Recently, emerging evidence has suggested that obesity become a prevalent health threat worldwide. Reportedly, CTRP9 can ameliorate HFD induced obesity. However, the molecular mechanism underlying the role of CTRP9 in obesity remains elusive. In this study, we reported its major function in the regulation of lipolysis. First, we found that the expression of CTRP9 was decreased in mature adipocytes and white adipose tissue of obese mice. Then, we showed that overexpression adipose tissue CTRP9 alleviated diet-induced obesity and adipocytes hypertrophy, improved glucose intolerance and raised energy expenditure. Moreover, CTRP9 increased the lipolysis in vitro and vivo. Additionally, we determined that CTRP9 enhanced autophagy flux in adipocytes. Intriguingly, knock down Beclin1 by SiRNA abolished the effect of CTRP9 on lipolysis. Mechanically, CTRP9 enhanced the expression of SNX26. We demonstrated that SNX26 was a component of the ATG14L-Beclin1-VPS34 complex and enhanced the assembly of the autophagy-initiation complex. Collectively, our results suggested that CTRP9 alleviated diet induced obesity through enhancing lipolysis mediated by autophagy-initiation complex formation.
    Keywords:  CTRP9.Obesity. Lipolysis. SNX26.Autophagy-initiation complex
    DOI:  https://doi.org/10.1016/j.jnutbio.2024.109694
  84. Commun Biol. 2024 Jun 17. 7(1): 732
    Tumor suppressor Par-4 activates autophagy-dependent ferroptosis.
    Karthikeyan Subburayan, Faisal Thayyullathil, Siraj Pallichankandy, Anees Rahman Cheratta, Ameer Alakkal, Mehar Sultana, Nizar Drou, Muhammad Arshad, L Palanikumar, Mazin Magzoub, Vivek M Rangnekar, Sehamuddin Galadari.
      Ferroptosis is a unique iron-dependent form of non-apoptotic cell death characterized by devastating lipid peroxidation. Whilst growing evidence suggests that ferroptosis is a type of autophagy-dependent cell death, the underlying molecular mechanisms regulating ferroptosis are largely unknown. In this study, through an unbiased RNA-sequencing screening, we demonstrate the activation of a multi-faceted tumor-suppressor protein Par-4/PAWR during ferroptosis. Functional studies reveal that genetic depletion of Par-4 effectively blocks ferroptosis, whereas Par-4 overexpression sensitizes cells to undergo ferroptosis. More importantly, we have determined that Par-4-triggered ferroptosis is mechanistically driven by the autophagic machinery. Upregulation of Par-4 promotes activation of ferritinophagy (autophagic degradation of ferritin) via the nuclear receptor co-activator 4 (NCOA4), resulting in excessive release of free labile iron and, hence, enhanced lipid peroxidation and ferroptosis. Inhibition of Par-4 dramatically suppresses the NCOA4-mediated ferritinophagy signaling axis. Our results also establish that Par-4 activation positively correlates with reactive oxygen species (ROS) production, which is critical for ferritinophagy-mediated ferroptosis. Furthermore, Par-4 knockdown effectively blocked ferroptosis-mediated tumor suppression in the mouse xenograft models. Collectively, these findings reveal that Par-4 has a crucial role in ferroptosis, which could be further exploited for cancer therapy.
    DOI:  https://doi.org/10.1038/s42003-024-06430-z
  85. Curr Mol Med. 2024 Jun 11.
    Astragaloside IV Protects Against Podocyte Injury by Upregulating Mitophagy via the Mfn2/Pink1/Parkin Axis.
    Yuan Yuan, Yufan Wu, Minhui He, Xue Jiang.
      BACKGROUND: Podocyte injury is the most important pathological hallmark of kidney diseases. Autophagy is a critical factor that involves podocyte injury. Here, we sought to determine whether Astragaloside IV (AS-IV) was able to improve renal function and reverse podocyte injury through the regulation of autophagy.METHODS: Using the Adriamycin (ADR) mice model, cultured immortalized mouse podocytes were exposed to AS-IV. Western blotting, immunofluorescence, and histochemistry were used to analyze markers of autophagy, mitochondrial dysfunction, podocyte apoptosis, and glomerulopathy in the progression of focal segmental glomerular sclerosis.
    RESULTS: We observed that AS-IV can inhibit podocyte apoptosis, increased reactive oxygen species (ROS) generation, mitochondrial fragmentation, and dysfunction by inducing the Mfn2/Pink1/Parkin mitophagy pathway both in vivo and in vitro. Overexpression of Mfn2 reduced puromycin aminonucleoside (PAN)-induced podocyte injury, while downregulation of Mfn2 expression limited the renal protective effect of AS-IV by regulating mitophagy.
    CONCLUSION: AS-IV ameliorates renal function and renal pathological changes in ADR mice and inhibits PAN-induced podocyte injury by directly enhancing Mfn2/Pink1/Parkin-associated autophagy.
    Keywords:  Astragaloside IV; FSGS.; mitofusin 2; mitophagy; podocyte
    DOI:  https://doi.org/10.2174/0115665240310818240531080353
  86. Free Radic Biol Med. 2024 Jun 18. pii: S0891-5849(24)00529-X. [Epub ahead of print]
    Autophagic degradation of DHCR7 activates AKT3 and promotes sevoflurane-induced hippocampal neuroinflammation in neonatal mice.
    Qi Hou, Junhu Yuan, Shuai Li, Jianhui Ma, Weiwei Li, Bo Zhang, Xinhua Zhao, Fanyu Zhang, Yiming Ma, Hui Zheng, Hongying Wang.
      Repeated sevoflurane exposure in neonatal mice triggers neuroinflammation with detrimental effects on cognitive function. Yet, the mechanism of the sevoflurane-induced cytokine response is largely unknown. In this study, we reveal that 3-MA, an autophagy inhibitor, attenuated the sevoflurane-induced neuroinflammation and cognitive dysfunction, including the decreased freezing time and fewer platform crossings, in the neonate mice. 3-Methyladenine (3-MA) suppressed sevoflurane-induced expression of interleukin-6 and tumor necrosis factor-alpha in vitro. Moreover, sevoflurane activates IRF3, facilitating cytokine transcription in an AKT3-dependent manner. Mechanistically, sevoflurane-induced autophagic degradation of dehydrocholesterol-reductase-7 (DHCR7) resulted in accumulations of its substrate 7-dehydrocholesterol (7-DHC), mimicking the effect of sevoflurane on AKT3 activation and IRF3-driven cytokine expression. 3-MA significantly reversed sevoflurane-induced DHCR7 degradation, AKT phosphorylation, IRF3 activation, and the accumulation of 7-DHC in the hippocampal CA1 region. These findings pave the way for additional investigations aimed at developing novel strategies to mitigate postoperative cognitive impairment in pediatric patients.
    Keywords:  AKT3; autophagy; dehydrocholesterol-reductase 7; interferon regulatory Factor 3; neuroinflammation; sevoflurane
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.06.012
  87. Biomed Pharmacother. 2024 Jul;pii: S0753-3322(24)00775-3. [Epub ahead of print]176 116891
    Autophagy: A potential target for natural products in the treatment of ulcerative colitis.
    Wei Zhang, Menglong Zou, Jia Fu, Yin Xu, Ying Zhu.
      Ulcerative colitis (UC) is a chronic inflammatory bowel disease primarily affecting the mucosa of the colon and rectum. UC is characterized by recurrent episodes, often necessitating lifelong medication use, imposing a significant burden on patients. Current conventional and advanced treatments for UC have the disadvantages of insufficient efficiency, susceptibility to drug resistance, and notable adverse effects. Therefore, developing effective and safe drugs has become an urgent need. Autophagy is an intracellular degradation process that plays an important role in intestinal homeostasis. Emerging evidence suggests that aberrant autophagy is involved in the development of UC, and modulating autophagy can effectively alleviate experimental colitis. A growing number of studies have established that autophagy can interplay with endoplasmic reticulum stress, gut microbiota, apoptosis, and the NLRP3 inflammasome, all of which contribute to the pathogenesis of UC. In addition, a variety of intestinal epithelial cells, including absorptive cells, goblet cells, and Paneth cells, as well as other cell types like neutrophils, antigen-presenting cells, and stem cells in the gut, mediate the development of UC through autophagy. To date, many studies have found that natural products hold the potential to exert therapeutic effects on UC by regulating autophagy. This review focuses on the possible effects and pharmacological mechanisms of natural products to alleviate UC with autophagy as a potential target in recent years, aiming to provide a basis for new drug development.
    Keywords:  Autophagy; Inflammatory bowel disease; Natural products; Ulcerative colitis
    DOI:  https://doi.org/10.1016/j.biopha.2024.116891
  88. Cell Death Differ. 2024 Jun 19.
    Atg7 autophagy-independent role on governing neural stem cell fate could be potentially applied for regenerative medicine.
    Yao Shen, Tingting Li, Chengyang Sun, Xin Cheng, Zhi Chen, Guang Wang, Xuesong Yang.
      A literature review showed that Atg7 biological role was associated with the development and pathogenesis of nervous system, but very few reports focused on Atg7 role on neurogenesis at the region of spinal cord, so that we are committed to explore the subject. Atg7 expression in neural tube is incrementally increased during neurogenesis. Atg7 neural-specific knockout mice demonstrated the impaired motor function and imbalance of neuronal and glial cell differentiation during neurogenesis, which was similarly confirmed in primary neurosphere culture and reversely verified by Atg7 overexpression in unilateral neural tubes of gastrula chicken embryos. Furthermore, activating autophagy in neural stem cells (NSCs) of neurospheres did not rescue Atg7 deficiency-suppressed neuronal differentiation, but Atg7 overexpression on the basis of autophagy inhibition could reverse Atg7 deficiency-suppressed neuronal differentiation, which provides evidence for the existence of Atg7 role of autophagy-independent function. The underlying mechanism is that Atg7 deficiency directly caused the alteration of cell cycle length of NSCs, which is controlled by Atg7 through specifically binding Mdm2, thereby affecting neuronal differentiation during neurogenesis. Eventually, the effect of overexpressing Atg7-promoting neuronal differentiation was proved in spinal cord injury model as well. Taken together, this study revealed that Atg7 was involved in regulating neurogenesis by a non-autophagic signaling process, and this finding also shed light on the potential application in regenerative medicine.
    DOI:  https://doi.org/10.1038/s41418-024-01330-5
  89. Eur J Pharmacol. 2024 Jun 14. pii: S0014-2999(24)00431-X. [Epub ahead of print]977 176743
    Cytarabine prevents neuronal damage by enhancing AMPK to stimulate PINK1 / Parkin-involved mitophagy in Parkinson's disease model.
    Lanxin Li, Yang Zhang, Zhengqian Chen, Can Xu, Zhongqiu Xu, Haitao Pei, Wei Wang, Ruyong Yao, Cui Hao.
      Parkinson's disease (PD) is a common age-related neurodegenerative disorder, which may be largely due to the mitochondrial dysfunction and impaired mitophagy. Thus, it is of great importance to seek novel therapeutic strategies for PD targeting mitochondrial function and mitophagy. Cytarabine is a marine-derived antimetabolite used in the treatment of acute leukemia, which is also used in the study of the nervous system. In this study, we found that cytarabine pretreatment significantly inhibited the apoptosis and necrosis in the ROT-induced SH-SY5Y cell PD model and reduced the oxidative stress, as evidenced by the reduced MDA levels and the increased levels of SOD, GSH, and total antioxidant capacity. Cytarabine can also enhance mitochondrial vitality, improve mitochondrial respiratory function, and preserve mitochondrial morphology. Cytarabine also enhanced the expression of the mitophagy-related proteins PINK1, Parkin, VDAC1, and DJ-1, and its actions can be reversed by treatment with AMPK inhibitor - Compound C (CC), suggesting that AMPK activation may be involved in cytarabine-enhanced mitophagy. Furthermore, cytarabine can also ameliorate the motor symptoms in the MPTP-induced PD-like mice model, and attenuate the neuropathy in the substantia nigra (SN) of PD mice, while Compound C antagonized cytarabine's beneficial effects. In summary, marine-derived compound cytarabine could resist neurological damage both in vitro and in vivo by activating AMPK to increase PINK1/Parkin-induced mitophagy, serving as a promising disease modulator for treating neurodegenerative disease.
    Keywords:  AMPK; Mitochondrial; Mitophagy; Neuroprotection; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.ejphar.2024.176743
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