bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024‒02‒18
eighty-two papers selected by
Viktor Korolchuk, Newcastle University
  1. Impaired lysosomal acidity maintenance in acid lipase-deficient cells leads to defective autophagy.
  2. The HRI branch of the integrated stress response selectively triggers mitophagy.
  3. The role of ATG9 vesicles in autophagosome biogenesis.
  4. NPFs-mediated actin cytoskeleton: a new viewpoint on autophagy regulation.
  5. Human YKT6 forms priming complex with STX17 and SNAP29 to facilitate autophagosome-lysosome fusion.
  6. Did mitophagy follow the origin of mitochondria?
  7. Molecular structures and function of the autophagosome-lysosome fusion machinery.
  8. Mitochondrial Calcium Transport During Autophagy Initiation.
  9. The Drosophila ZNRF1/2 homologue, detour, interacts with HOPS complex and regulates autophagy.
  10. Rapamycin protects Sertoli cells against BPA-induced autophagy disorders.
  11. Dysfunctional Mitochondria Clearance in Situ: Mitophagy in Obesity and Diabetes-Associated Cardiometabolic Diseases.
  12. The role of SARS-CoV-2 ORF7a in autophagy flux disruption: implications for viral infection and pathogenesis.
  13. Targeting autophagy drug discovery: Targets, indications and development trends.
  14. Ubiquitin in autophagy and non-protein ubiquitination.
  15. Relationships between protein degradation, cellular senescence, and organismal aging.
  16. Cathepsin L prevents the accumulation of alpha-synuclein fibrils in the cell.
  17. STING guides the STX17-SNAP29-VAMP8 complex assembly to control autophagy.
  18. Molecular insights into aggrephagy: Their cellular functions in the context of neurodegenerative diseases.
  19. Phospholipase D mediates glutamine-induced mTORC1 ac-tivation to promote porcine intestinal epithelial cell prolifer-ation.
  20. The role of mitophagy in metabolic diseases and its exercise intervention.
  21. Roles of autophagy in killing of mycobacterial pathogens by host macrophages - Effects of some medicinal plants.
  22. Disruption of Autophagic Flux and Treatment with the PDPK1 Inhibitor GSK2334470 Synergistically Inhibit Renal Cell Carcinoma Pathogenesis.
  23. In vivo CRISPR knockout screen identifies p47 as a suppressor of HER2+ breast cancer metastasis by regulating NEMO trafficking and autophagy flux.
  24. Transcription factor EB modulates the homeostasis of reactive oxygen species in intestinal epithelial cells to alleviate inflammatory bowel disease.
  25. Repositioning of ezetimibe for the treatment of idiopathic pulmonary fibrosis.
  26. A cardiomyocyte-based biosensing platform for dynamic and quantitative investigation of excessive autophagy.
  27. Defective autophagy and autophagy activators in Myasthenia Gravis: a rare entity and unusual scenario.
  28. Transcription factor EB-mediated autophagy affects cell migration and inhibits apoptosis to promote endometriosis.
  29. DNALI1 Promotes Neurodegeneration after Traumatic Brain Injury via Inhibition of Autophagosome-Lysosome Fusion.
  30. Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.
  31. Yapping at the autophagy door? The answer is flowing in the kidney proximal tubule.
  32. Lipopolysaccharide inhibits osteoblast formation and receptor activator of nuclear factor-κB ligand degradation via autophagy inhibition.
  33. VPS13C regulates phospho-Rab10-mediated lysosomal function in human dopaminergic neurons.
  34. LDO proteins and Vac8 form a vacuole-lipid droplet contact site to enable starvation-induced lipophagy in yeast.
  35. VHL suppresses autophagy and tumor growth through PHD1-dependent Beclin1 hydroxylation.
  36. Annexin A7 mediates lysosome repair independently of ESCRT-III.
  37. In vitro modulation of mTOR and mGlur5 influence α-synuclein accumulation.
  38. Molecular docking targeting autophagy pathway mediate abrogation of NASH by specific functional foods: update review.
  39. Reticulophagy mediated by the V-ATPase-ATG16L1-LC3C axis.
  40. Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB.
  41. Hyperacetylated microtubules assist porcine deltacoronavirus nsp8 to degrade MDA5 via SQSTM1/p62-dependent selective autophagy.
  42. NSD1 supports cell growth and regulates autophagy in HPV-negative head and neck squamous cell carcinoma.
  43. Endothelium-specific deletion of p62 causes organ fibrosis and cardiac dysfunction.
  44. All-trans retinoic acid induces lipophagy through the activation of the AMPK-Beclin1 signaling pathway and reduces Rubicon expression in adipocytes.
  45. Characterization of tomato autophagy-related SlCOST family genes.
  46. MCU promotes the migration of glioma cells by activating p38 through TFEB-mediated autophagy.
  47. Heavy Metal Scavenger Metallothionein Rescues Against Cold Stress-Evoked Myocardial Contractile Anomalies Through Regulation of Mitophagy.
  48. Stromal interaction molecule 1/microtubule-associated protein 1A/1B-light chain 3B complex induces metastasis of hepatocellular carcinoma by promoting autophagy.
  49. Melatonin-mediated regulation of autophagy is independent of ABA under drought stress in sensitive variety of Gossypium hirsutum L.
  50. ALS-Associated TDP-43 Dysfunction Compromises UPF1-Dependent mRNA Metabolism Pathways Including Alternative Polyadenylation and 3'UTR Length.
  51. miR-193b-5p promotes GCRV replication by inhibiting autophagy via targeting deptor in grass carp (Ctenopharyngodon idellus).
  52. Distinct roles of LARP1 and 4EBP1/2 in regulating translation and stability of 5'TOP mRNAs.
  53. TRAF2 decrease promotes the TGF-β-mTORC1 signal in MAFLD-HCC through enhancing AXIN1-mediated Smad7 degradation.
  54. Regulation of mitophagy and mitochondrial function: Natural compounds as potential therapeutic strategies for Parkinson's disease.
  55. From the regulatory mechanism of TFEB to its therapeutic implications.
  56. Hexokinase 1 and 2 mediates glucose utilization to regulate the synthesis of kappa casein via ribosome protein subunit 6 kinase 1 in bovine mammary epithelial cells.
  57. Casein kinase 1 controls components of a TORC2 signaling network in budding yeast.
  58. Melatonin-Loaded Nanoparticles Augment Mitophagy to Retard Parkinson's Disease.
  59. Ca 2+ -sensor ALG-2 engages ESCRTs to enhance lysosomal membrane resilience to osmotic stress.
  60. Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.
  61. Autophagy-related gene model as a novel risk factor for schizophrenia.
  62. The host mannose-6-phosphate pathway and viral infection.
  63. Restrained Mitf-associated autophagy by Mulberroside A ameliorates osteoclastogenesis and counteracts OVX-Induced osteoporosis in mice.
  64. Autophagy-modulating biomaterials: multifunctional weapons to promote tissue regeneration.
  65. Linear motifs regulating protein secretion, sorting and autophagy in Leishmania parasites are diverged with respect to their host equivalents.
  66. Amphiregulin improves ventricular remodeling after myocardial infarction by modulating autophagy and apoptosis.
  67. Renal aging and mitochondrial quality control.
  68. Fish Uses CTLA-4 Immune Checkpoint to Suppress mTORC1-Controlled T-Cell Glycolysis and Immunity.
  69. CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer.
  70. Rational design of mitochondria-targeted fluorescent biosensors for in vivo elucidation of the interaction between breast cancer metastasis and mitochondrial autophagy.
  71. Mitochondrial derived vesicle-carrying protein MIGA2 promotes copper-induced autophagosomes-lysosomes fusion by regulating ATG14.
  72. Autophagy in Multiple Sclerosis: Phagocytosis and Autophagy of Oligodendrocyte Precursor Cells.
  73. A neuron-glia lipid metabolic cycle couples daily sleep to mitochondrial homeostasis.
  74. The role of lysosomes in airborne particulate matter-induced pulmonary toxicity.
  75. PI3K-AKT/mTOR signalling in psychiatric disorders: a valuable target to stimulate or suppress?
  76. Trifluoperazine activates AMPK / mTOR / ULK1 signaling pathway to induce mitophagy in osteosarcoma cells.
  77. Increased extracellular matrix stiffness regulates myofibroblast transformation through induction of autophagy-mediated Kindlin-2 cytoplasmic translocation.
  78. Fusion-fission-mitophagy cycling and metabolic reprogramming coordinate nerve growth factor (NGF)-dependent neuronal differentiation.
  79. Roles and mechanisms of optineurin in bone metabolism.
  80. Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway.
  81. AAA237, an SKP2 inhibitor, suppresses glioblastoma by inducing BNIP3-dependent autophagy through the mTOR pathway.
  82. Still water run deep: Therapeutic TP effect of ucMSC-Ex via regulating mTOR to enhance autophagy.
  1. J Biol Chem. 2024 Feb 12. pii: S0021-9258(24)00119-4. [Epub ahead of print] 105743
    Impaired lysosomal acidity maintenance in acid lipase-deficient cells leads to defective autophagy.
    Takahito Moriwaki, Seigo Terawaki, Takanobu Otomo.
      The lysosome is an acid organelle that contains a variety of hydrolytic enzymes and plays a significant role in intracellular degradation to maintain cellular homeostasis. Genetic variants in lysosome-related genes can lead to severe congenital diseases, such as lysosomal storage diseases. In the present study, we investigated the impact of depleting lysosomal acid lipase A (LIPA), a lysosomal esterase that metabolizes esterified cholesterol or triglyceride, on lysosomal function. Under nutrient-rich conditions, LIPA gene knockout (LIPAKO) cells exhibited impaired autophagy, whereas, under starved conditions, they showed normal autophagy. The cause underlying the differential autophagic activity was increased sensitivity of LIPAKO cells to ammonia which was produced from L-glutamine in the medium. Further investigation revealed that ammonia did not affect upstream signals involved in autophagy induction, autophagosome-lysosome fusion, and hydrolytic enzyme activities in LIPAKO cells. On the other hand, LIPAKO cells showed defective lysosomal acidity upon ammonia loading. Microscopic analyses revealed that lysosomes of LIPAKO cells enlarged, whereas the amount of lysosomal proton pump V-ATPase did not proportionally increase. Since the enlargement of lysosomes in LIPAKO cells was not normalized under starved conditions, this is the primary change that occurred in the LIPAKO cells, and autophagy was affected by impaired lysosomal function under the specific conditions. These findings expand our comprehension of the pathogenesis of Wolman's disease, which is caused by a defect in the LIPA gene, and suggest that conditions, such as hyperlipidemia, may easily disrupt lysosomal functions.
    Keywords:  LIPA; V-ATPase; ammonia; autophagy; lysosomal acidity
    DOI:  https://doi.org/10.1016/j.jbc.2024.105743
  2. Mol Cell. 2024 Feb 06. pii: S1097-2765(24)00052-2. [Epub ahead of print]
    The HRI branch of the integrated stress response selectively triggers mitophagy.
    Yogaditya Chakrabarty, Zheng Yang, Hsiuchen Chen, David C Chan.
      To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson's disease related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery that is normally used for translational initiation to trigger mitophagy in response to mitochondrial damage.
    Keywords:  autophagy; integrated stress response; iron metabolism; mitochondria; mitophagy; organelle quality control
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.016
  3. J Mol Biol. 2024 Feb 09. pii: S0022-2836(24)00061-5. [Epub ahead of print] 168489
    The role of ATG9 vesicles in autophagosome biogenesis.
    Elisabeth Holzer, Sascha Martens, Susanna Tulli.
      Autophagy mediates the degradation and recycling of cellular material in the lysosomal system. Dysfunctional autophagy is associated with a plethora of diseases including uncontrolled infections, cancer and neurodegeneration. In macroautophagy (hereafter autophagy) this material is encapsulated in double membrane vesicles, the autophagosomes, which form upon induction of autophagy. The precursors to autophagosomes, referred to as phagophores, first appear as small flattened membrane cisternae, which gradually enclose the cargo material as they grow. The assembly of phagophores during autophagy initiation has been a major subject of investigation over the past decades. A special focus has been ATG9, the only conserved transmembrane protein among the core machinery. The majority of ATG9 localizes to small Golgi-derived vesicles. Here we review the recent advances and breakthroughs regarding our understanding of how ATG9 and the vesicles it resides in serve to assemble the autophagy machinery and to establish membrane contact sites for autophagosome biogenesis. We also highlight open questions in the field that need to be addressed in the years to come.
    Keywords:  ATG2; ATG9; Macroautophagy; endoplasmic reticulum; lipid synthesis; lipid transfer; membrane contact site; membrane traffic
    DOI:  https://doi.org/10.1016/j.jmb.2024.168489
  4. Cell Commun Signal. 2024 Feb 12. 22(1): 111
    NPFs-mediated actin cytoskeleton: a new viewpoint on autophagy regulation.
    Yuan Dong, Chengshi Quan.
      Macroautophagy/autophagy is a lysosome-dependent catabolic process induced by various cellular stress conditions, maintaining the homeostasis of cells, tissues and organs. Autophagy is a series of membrane-related events involving multiple autophagy-related (ATG) proteins. Most studies to date have focused on various signaling pathways affecting ATG proteins to control autophagy. However, mounting evidence reveals that the actin cytoskeleton acts on autophagy-associated membranes to regulate different events of autophagy. The actin cytoskeleton assists in vesicle formation and provides the mechanical forces for cellular activities that involve membrane deformation. Although the interaction between the actin cytoskeleton and membrane makes the role of actin in autophagy recognized, how the actin cytoskeleton is recruited and assembles on membranes during autophagy needs to be detailed. Nucleation-promoting factors (NPFs) activate the Arp2/3 complex to produce actin cytoskeleton. In this review, we summarize the important roles of the actin cytoskeleton in autophagy regulation and focus on the effect of NPFs on actin cytoskeleton assembly during autophagy, providing new insights into the occurrence and regulatory mechanisms of autophagy. Video Abstract.
    Keywords:  Actin cytoskeleton; Autophagic lysosome reformation; Autophagosome formation; Autophagy; Nucleation-promoting factors
    DOI:  https://doi.org/10.1186/s12964-023-01444-2
  5. Cell Rep. 2024 Feb 09. pii: S2211-1247(24)00088-3. [Epub ahead of print]43(2): 113760
    Human YKT6 forms priming complex with STX17 and SNAP29 to facilitate autophagosome-lysosome fusion.
    Denghao Zheng, Mindan Tong, Shen Zhang, Yi Pan, Yanxiang Zhao, Qing Zhong, Xiaoxia Liu.
      Autophagy is crucial for degrading and recycling cellular components. Fusion between autophagosomes and lysosomes is pivotal, directing autophagic cargo to degradation. This process is driven by STX17-SNAP29-VAMP8 and STX7-SNAP29-YKT6 in mammalian cells. However, the interaction between STX17 and YKT6 and its significance remain to be revealed. In this study, we challenge the notion that STX17 and YKT6 function independently in autophagosome-lysosome fusion. YKT6, through its SNARE domain, forms a complex with STX17 and SNAP29 on autophagosomes, enhancing autophagy flux. VAMP8 displaces YKT6 from this complex, leading to the formation of the fusogenic complex STX17-SNAP29-VAMP8. We demonstrated that the YKT6-SNAP29-STX17 complex facilitates both lipid and content mixing driven by STX17-SNAP29-VAMP8, suggesting a priming role of YKT6 for efficient membrane fusion. Our results provide a potential regulation mechanism of autophagosome-lysosome fusion, highlighting the importance of YKT6 and its interactions with STX17 and SNAP29 in promoting autophagy flux.
    Keywords:  CP: Cell biology; SNAREs; SXT17; YKT6; autophagosome-lysosome fusion; autophagy; autophagy flux; priming complex
    DOI:  https://doi.org/10.1016/j.celrep.2024.113760
  6. Autophagy. 2024 Feb 15. 1-9
    Did mitophagy follow the origin of mitochondria?
    Mauro Degli Esposti.
      Mitophagy is the process of selective autophagy that removes superfluous and dysfunctional mitochondria. Mitophagy was first characterized in mammalian cells and is now recognized to follow several pathways including basal forms in specific organs. Mitophagy pathways are regulated by multiple, often interconnected factors. The present review aims to streamline this complexity and evaluate common elements that may define the evolutionary origin of mitophagy. Key issues surrounding mitophagy signaling at the mitochondrial surface may fundamentally derive from mitochondrial membrane dynamics. Elements of such membrane dynamics likely originated during the endosymbiosis of the alphaproteobacterial ancestor of our mitochondria but underwent an evolutionary leap forward in basal metazoa that determined the currently known variations in mitophagy signaling.Abbreviations: AGPAT, 1-acylglycerol-3-phosphate O-acyltransferase; ATG, autophagy related; BCL2L13, BCL2 like 13; BNIP3, BCL2 interacting protein 3; BNIP3L, BCL2 interacting protein 3 like; CALCOCO, calcium binding and coiled-coil domain; CL, cardiolipin; ER, endoplasmic reticulum; ERMES, ER-mitochondria encounter structure; FBXL4, F-box and leucine rich repeat protein 4; FUNDC1, FUN14 domain containing 1; GABARAPL1, GABA type A receptor associated protein like 1; HIF, hypoxia inducible factor; IMM, inner mitochondrial membrane; LBPA/BMP, lysobisphosphatidic acid; LIR, LC3-interacting region; LPA, lysophosphatidic acid; MAM, mitochondria-associated membranes; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MCL, monolysocardiolipin; ML, maximum likelihood; NBR1, NBR1 autophagy cargo receptor; OMM, outer mitochondrial membrane; PA, phosphatidic acid; PACS2, phosphofurin acidic cluster sorting protein 2; PC/PLC, phosphatidylcholine; PE, phosphatidylethanolamine; PHB2, prohibitin 2; PINK1, PTEN induced kinase 1; PtdIns, phosphatidylinositol; SAR, Stramenopiles, Apicomplexa and Rhizaria; TAX1BP1, Tax1 binding protein 1; ULK1, unc-51 like autophagy activating kinase 1; VDAC/porin, voltage dependent anion channel.
    Keywords:  BNIP3; cardiolipin; evolution; membrane dynamics; mitochondria; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2307215
  7. Autophagy Rep. 2024 ;pii: 2305594. [Epub ahead of print]3(1):
    Molecular structures and function of the autophagosome-lysosome fusion machinery.
    Jiajie Diao, Calvin K Yip, Qing Zhong.
      Macroautophagy (also known as autophagy) plays a pivotal role in maintaining cellular homeostasis. The terminal step of the multi-step autophagy degradation pathway involves fusion between the cargo-laden, double-membraned autophagosome and the lytic organelle lysosome/vacuole. Over the past decade, various core components of the molecular machinery that execute this critical terminal autophagy event have been identified. This review highlights recent advances in understanding the molecular structures, biochemical functions, and regulatory mechanisms of key components of this highly sophisticated machinery including the SNARE fusogens, tethering factors, Rab GTPases and associated guanine nucleotide exchange factors, and other accessory factors.
    Keywords:  Autophagy; EPG5; HOPS; Mon1-Ccz1; Rab7; SNARE; autophagosome-lysosome fusion; syntaxin-17; tethering factors
    DOI:  https://doi.org/10.1080/27694127.2024.2305594
  8. Mitochondrial Commun. 2024 ;2 14-20
    Mitochondrial Calcium Transport During Autophagy Initiation.
    Sujyoti Chandra, Parul Katiyar, Aarooran S Durairaj, Xinnan Wang.
      While it has been shown that Ca2+ dynamics at the ER membrane is essential for the initiation of certain types of autophagy such as starvation-induced autophagy, how mitochondrial Ca2+ transport changes during the first stage of autophagy is not systemically characterized. An investigation of mitochondrial Ca2+ dynamics during autophagy initiation may help us determine the relationship between autophagy and mitochondrial Ca2+ fluxes. Here we examine acute mitochondrial and ER calcium responses to a panel of autophagy inducers in different cell types. Mitochondrial Ca2+ transport and Ca2+ transients at the ER membrane are triggered by different autophagy inducers. The mitophagy-inducer-initiated mitochondrial Ca2+ uptake relies on mitochondrial calcium uniporter and may decelerate the following mitophagy. In neurons derived from a Parkinson's patient, mitophagy-inducer-triggered mitochondrial Ca2+ influx is faster, which may slow the ensuing mitophagy.
    Keywords:  ER Ca2+ transient; IP3R; MCU; Parkinson; RyR; autophagy; mitochondrial Ca2+ uptake; mitophagy
    DOI:  https://doi.org/10.1016/j.mitoco.2024.01.002
  9. Commun Biol. 2024 Feb 15. 7(1): 183
    The Drosophila ZNRF1/2 homologue, detour, interacts with HOPS complex and regulates autophagy.
    Shannon Nicolson, Jantina A Manning, Yoon Lim, Xin Jiang, Erica Kolze, Sonia Dayan, Ruchi Umargamwala, Tianqi Xu, Jarrod J Sandow, Andrew I Webb, Sharad Kumar, Donna Denton.
      Autophagy, the process of elimination of cellular components by lysosomal degradation, is essential for animal development and homeostasis. Using the autophagy-dependent Drosophila larval midgut degradation model we identified an autophagy regulator, the RING domain ubiquitin ligase CG14435 (detour). Depletion of detour resulted in increased early-stage autophagic vesicles, premature tissue contraction, and overexpression of detour or mammalian homologues, ZNRF1 and ZNRF2, increased autophagic vesicle size. The ablation of ZNRF1 or ZNRF2 in mammalian cells increased basal autophagy. We identified detour interacting proteins including HOPS subunits, deep orange (dor/VPS18), Vacuolar protein sorting 16A (VPS16A), and light (lt/VPS41) and found that detour promotes their ubiquitination. The detour mutant accumulated autophagy-related proteins in young adults, displayed premature ageing, impaired motor function, and activation of innate immunity. Collectively, our findings suggest a role for detour in autophagy, likely through regulation of HOPS complex, with implications for healthy aging.
    DOI:  https://doi.org/10.1038/s42003-024-05834-1
  10. Food Chem Toxicol. 2024 Feb 14. pii: S0278-6915(24)00076-0. [Epub ahead of print] 114510
    Rapamycin protects Sertoli cells against BPA-induced autophagy disorders.
    Junyu Nie, Zhimin Mao, Xuhui Zeng, Xiuling Zhao.
      Bisphenol A (BPA) is a well-known environmental contaminant that can negatively impact reproductive function. Disruption of autophagy is implicated in BPA-induced cell injury, the specific molecular mechanisms through which BPA affects autophagy in Sertoli cells are still unknown. In the present study, TM4 cells were exposed to various doses of BPA (10, 100, and 200 μM), and the results indicated that BPA exposure led to the accumulation of autophagosomes, this change was accompanied by increased expression of p-mTOR and decreased expression of Atg12, a protein involved in regulating autophagy initiation. Additionally, BPA exposure upregulated the expression levels of p62, a protein involved in autophagic degradation. The inhibition of autophagy initiation and autophagic degradation contributes to the accumulation of autophagosomes. Further studies showed that BPA exposure didn't affect the expression of the lysosome protein LAMP1; however, decreased cytoplasmic retention of acridine orange in TM4 cells may explain the disruption of autophagy. The role of rapamycin and chloroquine (CQ), an autophagy inhibitor that impairs lysosomal degradation also confirmed the effect of BPA on autophagy regulation. Specifically, rapamycin can protect Sertoli cells against BPA-induced cell injury by promoting autophagy. These findings contribute to our understanding of the mechanisms underlying reproductive toxicity caused by BPA.
    Keywords:  Autophagy; Bisphenol A; Rapamycin; mTOR pathway
    DOI:  https://doi.org/10.1016/j.fct.2024.114510
  11. Diabetes Metab J. 2024 Feb 15.
    Dysfunctional Mitochondria Clearance in Situ: Mitophagy in Obesity and Diabetes-Associated Cardiometabolic Diseases.
    Songling Tang, Di Hao, Wen Ma, Lian Liu, Jiuyu Gao, Peng Yao, Haifang Yu, Lu Gan, Yu Cao.
      Several mitochondrial dysfunctions in obesity and diabetes include impaired mitochondrial membrane potential, excessive mitochondrial reactive oxygen species generation, reduced mitochondrial DNA, increased mitochondrial Ca2+ flux, and mitochondrial dynamics disorders. Mitophagy, specialized autophagy, is responsible for clearing dysfunctional mitochondria in physiological and pathological conditions. As a paradox, inhibition and activation of mitophagy have been observed in obesity and diabetes-related heart disorders, with both exerting bidirectional effects. Suppressed mitophagy is beneficial to mitochondrial homeostasis, also known as benign mitophagy. On the contrary, in most cases, excessive mitophagy is harmful to dysfunctional mitochondria elimination and thus is defined as detrimental mitophagy. In obesity and diabetes, two classical pathways appear to regulate mitophagy, including PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent mitophagy and receptors/adapters-dependent mitophagy. After the pharmacologic interventions of mitophagy, mitochondrial morphology and function have been restored, and cell viability has been further improved. Herein, we summarize the mitochondrial dysfunction and mitophagy alterations in obesity and diabetes, as well as the underlying upstream mechanisms, in order to provide novel therapeutic strategies for the obesity and diabetes-related heart disorders.
    Keywords:  Diabetes mellitus; Heart diseases; Mitophagy; Obesity; PTEN-induced putative kinase; Parkin protein
    DOI:  https://doi.org/10.4093/dmj.2023.0213
  12. Autophagy. 2024 Feb 15. 1-3
    The role of SARS-CoV-2 ORF7a in autophagy flux disruption: implications for viral infection and pathogenesis.
    Shun Li, Hao Zhang, Weichen Li, Jingbo Zhai, Xiaobo Li, Chunfu Zheng.
      Although alterations in the autophagy-lysosome pathway have been observed in the SARS-CoV-2 infection and invasion process since the outbreak of the coronavirus disease in 2019, the in-depth mechanism of autophagic and lysosomal reprogramming by SARS-CoV-2 has yet to be well identified. Our recent study unveiled a pivotal role played by the open reading frame 7a (ORF7a) protein in the SARS-CoV-2 genome, particularly in the modulation of macroautophagy/autophagy flux and function during viral infection and pathogenesis. Our study elucidated the underlying molecular mechanisms by which SARS-CoV-2 ORF7a intercepts autophagic flux, evades host autophagy-lysosome degradation, and accelerates viral infection and progeny germination. Furthermore, our study highlights that ORF7a can be a therapeutic target, and glecaprevir may hold potential as a drug against SARS-CoV-2 by targeting ORF7a. The key observations revealed in this study also contribute to a growing understanding of the function of SARS-CoV-2 ORF7a and the mechanisms underlying COVID-2019 treatment.
    Keywords:  Autophagy; COVID-19; ORF7a; SARS-CoV-2; lysosome
    DOI:  https://doi.org/10.1080/15548627.2024.2312787
  13. Eur J Med Chem. 2024 Jan 23. pii: S0223-5234(23)01084-X. [Epub ahead of print]267 116117
    Targeting autophagy drug discovery: Targets, indications and development trends.
    Mengjia Jiang, Wayne Wu, Zijie Xiong, Xiaoping Yu, Zihong Ye, Zhiping Wu.
      Autophagy plays a vital role in sustaining cellular homeostasis and its alterations have been implicated in the etiology of many diseases. Drugs development targeting autophagy began decades ago and hundreds of agents were developed, some of which are licensed for the clinical usage. However, no existing intervention specifically aimed at modulating autophagy is available. The obstacles that prevent drug developments come from the complexity of the actual impact of autophagy regulators in disease scenarios. With the development and application of new technologies, several promising categories of compounds for autophagy-based therapy have emerged in recent years. In this paper, the autophagy-targeted drugs based on their targets at various hierarchical sites of the autophagic signaling network, e.g., the upstream and downstream of the autophagosome and the autophagic components with enzyme activities are reviewed and analyzed respectively, with special attention paid to those at preclinical or clinical trials. The drugs tailored to specific autophagy alone and combination with drugs/adjuvant therapies widely used in clinical for various diseases treatments are also emphasized. The emerging drug design and development targeting selective autophagy receptors (SARs) and their related proteins, which would be expected to arrest or reverse the progression of disease in various cancers, inflammation, neurodegeneration, and metabolic disorders, are critically reviewed. And the challenges and perspective in clinically developing autophagy-targeted drugs and possible combinations with other medicine are considered in the review.
    Keywords:  Autophagy; Autophagy-related diseases; Compounds; Drug discovery; Selective autophagy receptors
    DOI:  https://doi.org/10.1016/j.ejmech.2023.116117
  14. Nat Struct Mol Biol. 2024 Feb;31(2): 208-209
    Ubiquitin in autophagy and non-protein ubiquitination.
    Noboru Mizushima.
      
    DOI:  https://doi.org/10.1038/s41594-024-01217-6
  15. J Biochem. 2024 Feb 13. pii: mvae016. [Epub ahead of print]
    Relationships between protein degradation, cellular senescence, and organismal aging.
    Jun Hamazaki, Shigeo Murata.
      Aging is a major risk factor for many diseases. Recent studies have shown that age-related disruption of proteostasis leads to the accumulation of abnormal proteins and that dysfunction of the two major intracellular proteolytic pathways, the ubiquitin-proteasome pathway, and the autophagy-lysosome pathway, is largely responsible for this process. Conversely, it has been shown that activation of these proteolytic pathways may contribute to lifespan extension and suppression of pathological conditions, making it a promising intervention for anti-aging. This review provides an overview of the important role of intracellular protein degradation in aging and summarizes how the disruption of proteostasis is involved in age-related diseases.
    Keywords:  aging; autophagy; proteasome; proteostasis; senescence
    DOI:  https://doi.org/10.1093/jb/mvae016
  16. Genes Cells. 2024 Feb 17.
    Cathepsin L prevents the accumulation of alpha-synuclein fibrils in the cell.
    Ayumi Matsuki, Yoshihisa Watanabe, Sho Hashimoto, Atsushi Hoshino, Satoaki Matoba.
      The deposition of α-synuclein (α-Syn) fibrils in neuronal cells has been implicated as a causative factor in Parkinson's disease (PD) and dementia with Lewy Bodies (DLB). α-Syn can be degraded by autophagy, proteasome, and chaperone-mediated autophagy, and previous studies have suggested the potency of certain cathepsins, lysosomal proteases, for α-Syn degradation. However, no studies have comprehensively evaluated all cathepsins. Here, we evaluated the efficacy of all 15 cathepsins using a cell model of α-Syn fibril propagation and found that overexpression of cathepsin L (CTSL) was the most effective in preventing the accumulation of α-Syn aggregates. CTSL-mediated degradation of α-Syn aggregates was dependent on the autophagy machinery, and CTSL itself promoted autophagy flux. Interestingly, CTSL was effective in autophagic degradation of wild-type (WT) α-Syn, but not in the case of A53T and E46K missense mutations, which are causative for familial PD. These results suggest that CTSL is a potential therapeutic strategy for sporadic PD pathology in WT α-Syn.
    Keywords:  autophagy flux; cathepsin L; degradation; α-Synuclein
    DOI:  https://doi.org/10.1111/gtc.13099
  17. Cell Insight. 2024 Apr;3(2): 100147
    STING guides the STX17-SNAP29-VAMP8 complex assembly to control autophagy.
    Xiaoyu Song, Yufeng Xi, Ming Dai, Tao Li, Shihao Du, Yuxin Zhu, Mengjie Li, Yunze Li, Siqi Liu, Xia Ding, Xuebiao Yao, Ying Lai, Xing Liu.
      The stimulator of interferon genes (STING) plays a pivotal role in orchestrating innate immunity, and dysregulated activity of STING has been implicated in the pathogenesis of autoimmune diseases. Recent findings suggest that bacterial infection activates STING, relieving ER stress, and triggers non-canonical autophagy by spatially regulating STX17. Despite these insights, the precise mechanism governing the dynamics of autophagosome fusion elicited by STING remains unclear. In this study, we demonstrate that dynamic STING activation guides the autophagy flux, mirroring the trajectory of canonical autophagy adaptors. STING engages in a physical interaction with STX17, and agonist-induced phosphorylation or degradation alleviates STING's inhibitory effects on the assembly of the STX17-SNAP29-VAMP8 complex. Consistent with these findings, degradation-deficient mutants hinder autophagy flux by impeding STX17-mediated autophagosome-lysosome fusion. Moreover, STING mutants associated with lupus disrupt the assembly of the STX17-SNAP29-VAMP8 complex and autophagy process, which lead to persistent STING activation and elevated IFN-β production. Our results highlight that the intracellular trajectory of STING, coupled with autophagy flux, guides the assembly and membrane fusion of the STX17-SNAP29-VAMP8 complex, ensuring the accurate regulation of innate immunity.
    Keywords:  Autophagy; Innate immunity; Phosphorylation; STING; STX17
    DOI:  https://doi.org/10.1016/j.cellin.2024.100147
  18. J Mol Biol. 2024 Feb 13. pii: S0022-2836(24)00065-2. [Epub ahead of print] 168493
    Molecular insights into aggrephagy: Their cellular functions in the context of neurodegenerative diseases.
    Valentín Cóppola Segovia, Fulvio Reggiori.
      Protein homeostasis or proteostasis is an equilibrium of biosynthetic production, folding and transport of proteins, and their timely and efficient degradation. Proteostasis is guaranteed by a network of protein quality control systems aimed at maintaining the proteome functional and avoiding accumulation of potentially cytotoxic proteins. Terminal unfolded and dysfunctional proteins can be directly turned over by the ubiquitin-proteasome system (UPS) or first amassed into aggregates prior to degradation. Aggregates can also be disposed into lysosomes by a selective type of autophagy known as aggrephagy, which relies on a set of so-called selective autophagy receptors (SARs) and adaptor proteins. Failure in eliminating aggregates, also due to defects in aggrephagy, can have devastating effects as underscored by several neurodegenerative diseases or proteinopathies, which are characterized by the accumulation of aggregates mostly formed by a specific disease-associated, aggregate-prone protein depending on the clinical pathology. Despite its medical relevance, however, the process of aggrephagy is far from being understood. Here we review the findings that have helped in assigning a possible function to specific SARs and adaptor proteins in aggrephagy in the context of proteinopathies, and also highlight the interplay between aggrephagy and the pathogenesis of proteinopathies.
    Keywords:  Aggregate; Aggrephagy; Alzheimer’s disease; Autophagy; Huntington’s disease; Neurodegenerative diseases; Parkinson’s disease; Selective autophagy receptors; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; proteinopathies
    DOI:  https://doi.org/10.1016/j.jmb.2024.168493
  19. J Nutr. 2024 Feb 14. pii: S0022-3166(24)00096-8. [Epub ahead of print]
    Phospholipase D mediates glutamine-induced mTORC1 ac-tivation to promote porcine intestinal epithelial cell prolifer-ation.
    Min Zhu, En-Qing Lu, Ling Yan, Guowei Liu, Ke Huang, E Xu, Yi-Yu Zhang, Xiang-Guang Li.
      BACKGROUND: The intestinal epithelium is one of the fastest self-renewal tissues in the body, and glutamine plays a crucial role in providing carbon and nitrogen for biosynthesis. In intestinal homeostasis, phosphorylation-mediated signaling networks that cause altered cell proliferation, differentiation, and metabolic regulation have been observed. However, our understanding of how glutamine affects protein phosphorylation in the intestinal epithelium is limited, and identifying the essential signaling pathways involved in regulating intestinal epithelial cell growth is particularly challenging.OBJECTIVE: This study aimed to identify the essential proteins and signaling pathways involved in glutamine's promotion of porcine intestinal epithelial cell (IPEC-J2) proliferation.
    METHODS: Phosphoproteomics was applied to describe the protein phosphorylation landscape under glutamine treatment. Kinase-Substrate Enrichment Analysis (KSEA) was subjected to predict kinase activity, and validated by RT-qPCR and Western blotting. CCK8, Glutamine rescue experiment, Chloroquine (CQ) treatment, and FIPI inhibition assay revealed the possible underlying mechanism of glutamine promoting IEPC-J2 cell proliferation.
    RESULTS: In this study, glutamine starvation was found to significantly suppress the proliferation of intestinal epithelial cells and change phosphoproteomic profiles with 575 downregulated sites and 321 upregulated sites. Interestingly, phosphorylation of 4EBP1 at position Thr70 was decreased, which is a crucial downstream of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Further studies showed that glutamine supplementation rescued cell proliferation and mTORC1 activity, dependent on lysosomal function and phospholipase D (PLD) activation.
    CONCLUSIONS: In conclusion, glutamine activates mTORC1 signaling dependent on PLD and a functional lysosome to promote intestinal epithelial cell proliferation. This discovery provides new insight into regulating the homeostasis of the intestinal epithelium, particularly in pig production.
    Keywords:  cell proliferation; glutamine; intestinal epithelium; mTORC1; phospholipase D
    DOI:  https://doi.org/10.1016/j.tjnut.2024.02.010
  20. Front Physiol. 2024 ;15 1339128
    The role of mitophagy in metabolic diseases and its exercise intervention.
    Shaokai Tang, Yuanwen Geng, Qinqin Lin.
      Mitochondria are energy factories that sustain life activities in the body, and their dysfunction can cause various metabolic diseases that threaten human health. Mitophagy, an essential intracellular mitochondrial quality control mechanism, can maintain cellular and metabolic homeostasis by removing damaged mitochondria and participating in developing metabolic diseases. Research has confirmed that exercise can regulate mitophagy levels, thereby exerting protective metabolic effects in metabolic diseases. This article reviews the role of mitophagy in metabolic diseases, the effects of exercise on mitophagy, and the potential mechanisms of exercise-regulated mitophagy intervention in metabolic diseases, providing new insights for future basic and clinical research on exercise interventions to prevent and treat metabolic diseases.
    Keywords:  exercise; exerkine; metabolic disease; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.3389/fphys.2024.1339128
  21. Eur J Microbiol Immunol (Bp). 2024 Feb 13.
    Roles of autophagy in killing of mycobacterial pathogens by host macrophages - Effects of some medicinal plants.
    Yutaka Tatano, Toshiaki Shimizu, Chiaki Sano, Haruaki Tomioka.
      Autophagy is a cellular stress-induced intracellular process, through which damaged cellular components are decomposed via lysosomal degradation. This process plays important roles in host innate immunity, particularly the elimination of intracellular pathogens inside host macrophages. A more detailed understanding of the roles of autophagic events in the effective manifestation of macrophagic antimycobacterial activity is needed. Furthermore, the effects of medicinal plants on macrophagic autophagy response to mycobacterial infection need to be clarified. We herein examined the significance of autophagic events in the manifestation of host immunity during mycobacterial infection, by performing a literature search using PubMed. Recent studies demonstrated that autophagy up-regulated macrophage functions related to the intracellular killing of mycobacteria, even when pathogens were residing within the cytoplasm of macrophages. The majority of medicinal plants potentiated macrophagic autophagy, thereby enhancing their antimycobacterial functions. In contrast, most medicinal plants down-regulate the development and activation of the Th17 cell population, which reduces macrophage antimycobacterial activity. These opposing effects of medicinal plants on macrophage autophagy (enhancement) and Th17 cell functions (inhibition) may provide a plausible explanation for the clinical observation of their modest efficacy in the treatment of mycobacterial infections.
    Keywords:  autophagy; host defense system; macrophages; medicinal plants; mycobacteria
    DOI:  https://doi.org/10.1556/1886.2023.00062
  22. J Cancer. 2024 ;15(5): 1429-1441
    Disruption of Autophagic Flux and Treatment with the PDPK1 Inhibitor GSK2334470 Synergistically Inhibit Renal Cell Carcinoma Pathogenesis.
    Wei Zhou, Ji Huang, Chuansheng Huang, Gongxian Wang, Xinhua Tu.
      Background: Renal cell carcinoma (RCC) frequently exhibits activating PI3K-Akt-mTOR pathway mutations. 3-Phosphoinositide-dependent kinase 1 (PDPK1 or PDK1) has been established to play a pivotal role in modulating PI3K pathway signaling. mTOR is the main autophagy-initiating factor. However, limited advances have been made in understanding the relationship between PDPK1 and autophagy in RCC. Methods: GSK2334470 (GSK470), a novel and highly specific inhibitor of PDPK1, was selected to investigate the anticancer effects in two RCC cell lines. Cell growth was assessed by CCK-8 test and colony formation. Changes in the protein levels of key Akt/mTOR pathway components and apoptosis markers were assessed by Western blotting. Autophagy was assessed by using LC3B expression, transmission electron microscopy, and a tandem mRFP-EGFP-LC3 construct. The effect of PDPK1 and autophagy inhibitor chloroquine in RCC in vivo was examined in a mouse tumor-bearing model. Results: GSK470 significantly inhibited cell proliferation and induces apoptosis in A498 and 786-O RCC cells. GSK470 downregulates the phosphorylation of PDPK1, thereby inhibiting downstream phosphorylation of Akt1 at Thr308 and Ser473 and mTOR complex 1 (mTORC1) activity. Treatment with insulin-like growth factor-1 (IGF-1) partially restored GSK470-induced behaviors/activities. Interestingly, treatment of A498 and 786-O cells with GSK470 or siPDPK1 induced significant increases in the hallmarks of autophagy, including autophagosome accumulation, autophagic flux, and LC3B expression. Importantly, GSK470 and chloroquine synergistically inhibited the growth of RCC cells in vitro and in xenograft models, supporting the protective role of autophagy activation upon blockade of the PDPK1-Akt-mTOR signaling pathway. Conclusion: Our study provides new insight into PDPK1 inhibition combined with autophagy inhibition as a useful treatment strategy for RCC.
    Keywords:  3-Phosphoinositide-dependent kinase 1; Autophagy; PI3K-Akt-mTOR pathway; Renal cell carcinoma; Targeted therapy
    DOI:  https://doi.org/10.7150/jca.92521
  23. Cell Rep. 2024 Feb 15. pii: S2211-1247(24)00108-6. [Epub ahead of print]43(2): 113780
    In vivo CRISPR knockout screen identifies p47 as a suppressor of HER2+ breast cancer metastasis by regulating NEMO trafficking and autophagy flux.
    Mingang Hao, Peixin Lu, Sarah Sotropa, Kanakaraju Manupati, Syn Kok Yeo, Jun-Lin Guan.
      Autophagy is a conserved cellular process, and its dysfunction is implicated in cancer and other diseases. Here, we employ an in vivo CRISPR screen targeting genes implicated in the regulation of autophagy to identify the Nsfl1c gene encoding p47 as a suppressor of human epidermal growth factor receptor 2 (HER2)+ breast cancer metastasis. p47 ablation specifically increases metastasis without promoting primary mammary tumor growth. Analysis of human breast cancer patient databases and tissue samples indicates a correlation of lower p47 expression levels with metastasis and decreased survival. Mechanistic studies show that p47 functions in the repair of lysosomal damage for autophagy flux and in the endosomal trafficking of nuclear factor κB essential modulator for lysosomal degradation to promote metastasis. Our results demonstrate a role and mechanisms of p47 in the regulation of breast cancer metastasis. They highlight the potential to exploit p47 as a suppressor of metastasis through multiple pathways in HER2+ breast cancer cells.
    Keywords:  CP: Cancer; CP: Cell biology; CRISPR screen; NF-κB signaling; autophagy; breast cancer; metastasis; p47
    DOI:  https://doi.org/10.1016/j.celrep.2024.113780
  24. Biochim Biophys Acta Mol Basis Dis. 2024 Feb 09. pii: S0925-4439(24)00054-1. [Epub ahead of print] 167065
    Transcription factor EB modulates the homeostasis of reactive oxygen species in intestinal epithelial cells to alleviate inflammatory bowel disease.
    Tianci Zhang, Roufei Zhang, Wei Liu, Yucheng Qi, Hongyi Wang, Hu Zhang, Zhixiong Xiao, Stephen J Pandol, Yuan-Ping Han, Xiaofeng Zheng.
      Transcription factor EB (TFEB), a master lysosomal biogenesis and autophagy regulator, is crucial for cellular homeostasis, and its abnormality is related to diverse inflammatory diseases. Genetic variations in autophagic genes are associated with susceptibility to inflammatory bowel disease (IBD); however, little is known about the role and mechanism of TFEB in disease pathogenesis. In this study, we found that the genetic deletion of TFEB in mouse intestinal epithelial cells (IEC) caused intestinal barrier dysfunction, leading to increased susceptibility to experimental colitis. Mechanistically, TFEB functionally protected IEC in part through peroxisome proliferator-activated receptor gamma coactivator 1alpha (TFEB-PGC1α axis) induction, which consequently suppressed reactive oxygen species. TFEB can directly regulate PGC-1α transcription to control antioxidation level. Notably, TFEB expression is impaired and downregulated in the colon tissues of IBD patients. Collectively, our results indicate that intestinal TFEB participates in oxidative stress regulation and attenuates IBD progression.
    Keywords:  Inflammatory bowel disease; Intestinal epithelial cell; Peroxisome proliferator-activated receptor gamma coactivator 1alpha; Reactive oxygen species; Transcription factor EB
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167065
  25. Eur Respir J. 2024 Feb 15. pii: 2300580. [Epub ahead of print]
    Repositioning of ezetimibe for the treatment of idiopathic pulmonary fibrosis.
    Chanho Lee, Se Hyun Hyun, Jisu Han, Ju Hye Shin, Byunghun Yoo, Yu Seol Lee, Jeong Su Park, Beom Jin Lim, Jin Gu Lee, Young Sam Kim, Song Yee Kim, Soo Han Bae.
      We previously identified ezetimibe, an inhibitor of Niemann-Pick C1-like intracellular cholesterol transporter 1 and European Medicines Agency-approved lipid-lowering agent, as a potent autophagy activator. However, its efficacy against pulmonary fibrosis has not yet been evaluated. This study aimed to determine whether ezetimibe has therapeutic potential against idiopathic pulmonary fibrosis. Primary lung fibroblasts isolated from both humans and mice were employed for mechanistic in vitro experiments. mRNA sequencing of human lung fibroblasts and gene set enrichment analysis were performed to explore the therapeutic mechanism of ezetimibe. A bleomycin-induced pulmonary fibrosis mouse model was used to examine in vivo efficacy of the drug. Tandem fluorescent-tagged microtubule-associated protein 1 light chain 3 transgenic mice were used to measure autophagic flux. Finally, the medical records of patients with idiopathic pulmonary fibrosis from three different hospitals were retrospectively reviewed, and analyses on survival and lung function were conducted to determine the benefits of ezetimibe. Ezetimibe inhibited myofibroblast differentiation by restoring the mechanistic target of rapamycin complex 1-autophagy axis with fine control of intracellular cholesterol distribution. Serum response factor, a potential autophagic substrate, was identified as a primary downstream effector in this process. Similarly, ezetimibe ameliorated bleomycin-induced pulmonary fibrosis in mice by inhibiting mechanistic target of rapamycin complex 1 activity and increasing autophagic flux, as observed in mouse lung samples. Patients with idiopathic pulmonary fibrosis who regularly used ezetimibe showed decreased rates of all-cause mortality and lung function decline. In conclusion, our study presents ezetimibe as a potential novel therapeutic for idiopathic pulmonary fibrosis.
    DOI:  https://doi.org/10.1183/13993003.00580-2023
  26. Biosens Bioelectron. 2024 Feb 13. pii: S0956-5663(24)00118-0. [Epub ahead of print]251 116113
    A cardiomyocyte-based biosensing platform for dynamic and quantitative investigation of excessive autophagy.
    Cheng-Wen He, Chunlian Qin, Yi Zhang, Yan Zhang, Kaiqiang Li, Yuqun Cai, Wei Zhang, Ning Hu, Zhen Wang.
      Autophagy is an important physiological phenomenon in eukaryotes that helps maintain the cellular homeostasis. Autophagy is involved in the development of various cardiovascular diseases, affecting the maintenance of cardiac function and disease prognosis. Physiological levels of autophagy serve as a defense mechanism for cardiomyocytes against environmental stimuli, but an overabundance of autophagy may contribute to the development of cardiovascular diseases. However, conventional biological methods are difficult to monitor the autophagy process in a dynamic and chronic manner. Here, we developed a cardiomyocyte-based biosensing platform that records electrophysiological evolutions in action potentials to reflect the degree of autophagy. Different concentrations of rapamycin-mediated autophagy were administrated in the culture environment to simulate the autophagy model. Moreover, the 3-methyladenine (3-MA)-mediated autophagy inhibition was also investigated the protection on the autophagy. The recorded action potentials can precisely reflect different degrees of autophagy. Our study confirms the possibility of visualizing and characterizing the process of cardiomyocyte autophagy using cardiomyocyte-based biosensing platform, allowing to monitor the whole autophagy process in a non-invasive, real-time, and continuous way. We believe it will pave a promising avenue to precisely study the autophagy-related cardiovascular diseases.
    Keywords:  Autophagy; Cardiomyocytes-based biosensing; Drug screening; Electrophysiological recording
    DOI:  https://doi.org/10.1016/j.bios.2024.116113
  27. Autophagy. 2024 Feb 12.
    Defective autophagy and autophagy activators in Myasthenia Gravis: a rare entity and unusual scenario.
    Ghassan M Sulaiman, Hayder M Al-Kuraishy, Majid S Jabir, Hamdoon A Mohammed, Ali I Al-Gareeb, Salim Albukhaty, Daniel J Klionsky, Mosleh M Abomughaid.
      Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ) that results from autoantibodies against nicotinic acetylcholine receptors (nAchRs) at NMJs. These autoantibodies are mainly originated from autoreactive B cells that bind and destroy nAchRs at NMJs preventing nerve impulses from activating the end-plates of skeletal muscle. Indeed, immune dysregulation plays a crucial role in the pathogenesis of MG. Autoreactive B cells are increased in MG due to the defect in the central and peripheral tolerance mechanisms. As well, autoreactive T cells are augmented in MG due to the diversion of regulatory T (Treg) cells or a defect in thymic anergy leading to T cell-mediated autoimmunity. Furthermore, macroautophagy/autophagy, which is a conserved cellular catabolic process, plays a critical role in autoimmune diseases by regulating antigen presentation, survival of immune cells and cytokine-mediated inflammation. Abnormal autophagic flux is associated with different autoimmune disorders. Autophagy regulates the connection between innate and adaptive immune responses by controlling the production of cytokines and survival of Tregs. As autophagy is involved in autoimmune disorders, it may play a major role in the pathogenesis of MG. Therefore, this mini-review aims to demonstrate the potential role of autophagy and autophagy activators in MG.
    Keywords:  Autophagy; autophagy activators; myasthenia gravis
    DOI:  https://doi.org/10.1080/15548627.2024.2315893
  28. Apoptosis. 2024 Feb 15.
    Transcription factor EB-mediated autophagy affects cell migration and inhibits apoptosis to promote endometriosis.
    Qiuyu Chen, Yi Zhou, Mengqi Yu, Sennan Zhu, Jindan Sun, Wenzhuo Du, Ziqi Chen, Jiayu Tao, Xiao Feng, Qiong Zhang, Yu Zhao.
      Autophagy has emerged as an important process of cell metabolism. With continuous in-depth research on autophagy, TFEB has been a key transcription factor regulating autophagy levels in recent years. Studies have established that TFEB regulates autophagy and apoptosis in various diseases. However, the relationship between TFEB and the pathogenesis of endometriosis remains unclear. This study aimed to investigate the effect of TFEB on the mechanism of endometriosis progression. The results showed that TFEB and autophagy-related protein LC3 are highly expressed in ectopic endometrium of patients with endometriosis, overexpression of TFEB in cultured human endometrial stromal cells (HESCs) by lentivirus not only promoted autophagy but also inhibited apoptosis. In addition, the migration and invasion ability of HESCs were enhanced by TFEB overexpression. Furthermore, inhibiting autophagy with specific inhibitors can attenuate migration and invasion of HESCs induced by TFEB. The rat models of endometriosis show that TFEB knockdown can suppress lesion growth in vivo. Our results suggest that autophagy may be involved in the progression mechanism of endometriosis, and the mechanism of autophagy disorder in endometriosis is probably related to TFEB. TFEB may be a key molecule in promoting endometriosis.
    Keywords:  Apoptosis; Autophagy; Endometriosis; LC3; TFEB
    DOI:  https://doi.org/10.1007/s10495-024-01939-4
  29. Adv Sci (Weinh). 2024 Feb 13. e2306399
    DNALI1 Promotes Neurodegeneration after Traumatic Brain Injury via Inhibition of Autophagosome-Lysosome Fusion.
    Xulong Ding, Shuqiang Cao, Qing Wang, Bin Du, Kefeng Lu, Shiqian Qi, Ying Cheng, Qing-Zhang Tuo, Weibo Liang, Peng Lei.
      Traumatic brain injury (TBI) leads to progressive neurodegeneration that may be caused by chronic traumatic encephalopathy (CTE). However, the precise mechanism remains unclear. Herein, the study identifies a crucial protein, axonemal dynein light intermediate polypeptide 1 (DNALI1), and elucidated its potential pathogenic role in post-TBI neurodegeneration. The DNALI1 gene is systematically screened through analyses of Aging, Dementia, and TBI studies, confirming its elevated expression both in vitro and in vivo. Moreover, it is observed that altered DNALI1 expression under normal conditions has no discernible effect. However, upon overexpression, DNALI1 inhibits autophagosome-lysosome fusion, reduces autophagic flux, and exacerbates cell death under pathological conditions. DNALI1 silencing significantly enhances autophagic flux and alleviates neurodegeneration in a CTE model. These findings highlight DNALI1 as a potential key target for preventing TBI-related neurodegeneration.
    Keywords:  DNALI1; autophagy; chronic traumatic encephalopathy; neurodegeneration; traumatic brain injury
    DOI:  https://doi.org/10.1002/advs.202306399
  30. Nat Commun. 2024 Feb 10. 15(1): 1252
    Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.
    Annabel Qi En Ng, Seow Neng Chan, Jun Wei Pek.
      Mitochondria are inherited exclusively from the mothers and are required for the proper development of embryos. Hence, germline mitochondrial quality is highly regulated during oogenesis to ensure oocyte viability. How nutrient availability influences germline mitochondrial quality control is unclear. Here we find that fasting leads to the accumulation of mitochondrial clumps and oogenesis arrest in Drosophila. Fasting induces the downregulation of the DIP1-Clueless pathway, leading to an increase in the expression of a stable intronic sequence RNA called sisR-1. Mechanistically, sisR-1 localizes to the mitochondrial clumps to inhibit the poly-ubiquitination of the outer mitochondrial protein Porin/VDAC1, thereby suppressing p62-mediated mitophagy. Alleviation of the fasting-induced high sisR-1 levels by either sisR-1 RNAi or refeeding leads to mitophagy, the resumption of oogenesis and an improvement in oocyte quality. Thus, our study provides a possible mechanism by which fasting can improve oocyte quality by modulating the mitochondrial quality control pathway. Of note, we uncover that the sisR-1 response also regulates mitochondrial clumping and oogenesis during protein deprivation, heat shock and aging, suggesting a broader role for this mechanism in germline mitochondrial quality control.
    DOI:  https://doi.org/10.1038/s41467-024-45651-y
  31. Autophagy. 2024 Feb 16.
    Yapping at the autophagy door? The answer is flowing in the kidney proximal tubule.
    Aurore Claude-Taupin, Fabiola Terzi, Patrice Codogno, Nicolas Dupont.
      Shear stress induced by urinary flow stimulates macroautophagy (hereafter referred to as autophagy) in kidney proximal tubule epithelial cells. Autophagy and selective degradation of lipid droplets by lipophagy contribute to tubule homeostasis by the production of ATP and control of epithelial cell size. Autophagy/lipophagy is controlled by a signaling cascade emanating from the primary cilium, localized at the apical side of epithelial cells. Downstream of the primary cilium, AMPK controls mitochondrial biogenesis on the one hand and autophagy/lipophagy on the other hand, which together increase fatty acid production that fuels oxidative phosphorylation to increase energy production. Recently, we reported that the co-transcriptional factors YAP1 and WWTR1/TAZ act downstream of AMPK to control autophagy. In fact, YAP1 and the transcription factor TEAD control the expression of RUBCN/rubicon. Under shear stress, YAP1 is excluded from the nucleus in a SIRT1-dependent manner to favor autophagic flux by downregulating the expression of RUBCN. When simulating in vitro a pathological urinary flow in murine proximal tubule kidney epithelial cells, we observe the nuclear retention of YAP1 and, consequently, high expression of RUBCN and inhibition of autophagic flux. Importantly, these findings were confirmed in biopsies of patients suffering from diabetic nephropathy, a major cause of chronic kidney disease.
    Keywords:  Kidney; YAP-TAZ; macroautophagy; shear stress
    DOI:  https://doi.org/10.1080/15548627.2024.2319023
  32. Endocr J. 2024 Feb 14.
    Lipopolysaccharide inhibits osteoblast formation and receptor activator of nuclear factor-κB ligand degradation via autophagy inhibition.
    Huaizhi Zhang, Jianhua Lin, Xu Chen, Jianhui Dai, Haibin Lin.
      Lipopolysaccharide (LPS) and Receptor Activator of Nuclear Factor-κB Ligand (RANKL) are the two important factors causing bone loss, which is an important pathogenesis for osteoporosis. However, the relationship between LPS and RANKL is not yet clear. LPS can be involved in the weakened osteoblast formation as an autophagy regulator, and osteoblasts and their precursors are the source cells for RANKL production. Our study aimed to explore the relationship between autophagy changes and RANKL production during LPS-regulated osteoblasts. Our results showed that LPS inhibited autophagy (LC3 conversion and autophagosome formation) and enhanced the protein and mRNA expression of RANKL in MC3T3-E1 osteoblast precursor line. Autophagy upregulation with Rapamycin over BECN1 overexpression rescued LPS-inhibited osteoblast formation and -promoted RANKL protein production in MC3T3-E1 cells. In vivo experiments supported that damaged bone mass, bone microstructure, osteoblastic activity (ALP and P1NP production by ELISA assays) and enhanced RANKL production by LPS administration were partially rescued by Rapamycin application. In conclusion, LPS can inhibit autophagy in osteoblast precursors, thereby inhibiting osteoblast formation and RANKL autophagic degradation.
    Keywords:  Autophagy; Lipopolysaccharide; Osteoblast; Osteoclast; Receptor activator of nuclear factor-κB ligand
    DOI:  https://doi.org/10.1507/endocrj.EJ23-0484
  33. J Cell Biol. 2024 May 06. pii: e202304042. [Epub ahead of print]223(5):
    VPS13C regulates phospho-Rab10-mediated lysosomal function in human dopaminergic neurons.
    Leonie F Schrӧder, Wesley Peng, Ge Gao, Yvette C Wong, Michael Schwake, Dimitri Krainc.
      Loss-of-function mutations in VPS13C are linked to early-onset Parkinson's disease (PD). While VPS13C has been previously studied in non-neuronal cells, the neuronal role of VPS13C in disease-relevant human dopaminergic neurons has not been elucidated. Using live-cell microscopy, we investigated the role of VPS13C in regulating lysosomal dynamics and function in human iPSC-derived dopaminergic neurons. Loss of VPS13C in dopaminergic neurons disrupts lysosomal morphology and dynamics with increased inter-lysosomal contacts, leading to impaired lysosomal motility and cellular distribution, as well as defective lysosomal hydrolytic activity and acidification. We identified Rab10 as a phospho-dependent interactor of VPS13C on lysosomes and observed a decreased phospho-Rab10-mediated lysosomal stress response upon loss of VPS13C. These findings highlight an important role of VPS13C in regulating lysosomal homeostasis in human dopaminergic neurons and suggest that disruptions in Rab10-mediated lysosomal stress response contribute to disease pathogenesis in VPS13C-linked PD.
    DOI:  https://doi.org/10.1083/jcb.202304042
  34. Dev Cell. 2024 Feb 03. pii: S1534-5807(24)00034-0. [Epub ahead of print]
    LDO proteins and Vac8 form a vacuole-lipid droplet contact site to enable starvation-induced lipophagy in yeast.
    Irene Álvarez-Guerra, Emma Block, Filomena Broeskamp, Sonja Gabrijelčič, Terence Infant, Ana de Ory, Lukas Habernig, Claes Andréasson, Tim P Levine, Johanna L Höög, Sabrina Büttner.
      Lipid droplets (LDs) are fat storage organelles critical for energy and lipid metabolism. Upon nutrient exhaustion, cells consume LDs via gradual lipolysis or via lipophagy, the en bloc uptake of LDs into the vacuole. Here, we show that LDs dock to the vacuolar membrane via a contact site that is required for lipophagy in yeast. The LD-localized LDO proteins carry an intrinsically disordered region that directly binds vacuolar Vac8 to form vCLIP, the vacuolar-LD contact site. Nutrient limitation drives vCLIP formation, and its inactivation blocks lipophagy, resulting in impaired caloric restriction-induced longevity. We establish a functional link between lipophagy and microautophagy of the nucleus, both requiring Vac8 to form respective contact sites upon metabolic stress. In sum, we identify the tethering machinery of vCLIP and find that Vac8 provides a platform for multiple and competing contact sites associated with autophagy.
    Keywords:  Ldo16; Ldo45; NVJ; lipid droplets; lipophagy; membrane contact sites; nucleus-vacuole junction; nutrient limitation; vCLIP; vacuole-lipid droplet contact site
    DOI:  https://doi.org/10.1016/j.devcel.2024.01.014
  35. EMBO J. 2024 Feb 15.
    VHL suppresses autophagy and tumor growth through PHD1-dependent Beclin1 hydroxylation.
    Zheng Wang, Meisi Yan, Leiguang Ye, Qimin Zhou, Yuran Duan, Hongfei Jiang, Lei Wang, Yuan Ouyang, Huahe Zhang, Yuli Shen, Guimei Ji, Xiaohan Chen, Qi Tian, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Leina Ma, Bo Lei, Zhimin Lu, Daqian Xu.
      The Von Hippel-Lindau (VHL) protein, which is frequently mutated in clear-cell renal cell carcinoma (ccRCC), is a master regulator of hypoxia-inducible factor (HIF) that is involved in oxidative stresses. However, whether VHL possesses HIF-independent tumor-suppressing activity remains largely unclear. Here, we demonstrate that VHL suppresses nutrient stress-induced autophagy, and its deficiency in sporadic ccRCC specimens is linked to substantially elevated levels of autophagy and correlates with poorer patient prognosis. Mechanistically, VHL directly binds to the autophagy regulator Beclin1, after its PHD1-mediated hydroxylation on Pro54. This binding inhibits the association of Beclin1-VPS34 complexes with ATG14L, thereby inhibiting autophagy initiation in response to nutrient deficiency. Expression of non-hydroxylatable Beclin1 P54A abrogates VHL-mediated autophagy inhibition and significantly reduces the tumor-suppressing effect of VHL. In addition, Beclin1 P54-OH levels are inversely correlated with autophagy levels in wild-type VHL-expressing human ccRCC specimens, and with poor patient prognosis. Furthermore, combined treatment of VHL-deficient mouse tumors with autophagy inhibitors and HIF2α inhibitors suppresses tumor growth. These findings reveal an unexpected mechanism by which VHL suppresses tumor growth, and suggest a potential treatment for ccRCC through combined inhibition of both autophagy and HIF2α.
    Keywords:  Autophagy; Beclin1; Hydroxylation; VHL; ccRCC
    DOI:  https://doi.org/10.1038/s44318-024-00051-2
  36. Front Cell Dev Biol. 2023 ;11 1211498
    Annexin A7 mediates lysosome repair independently of ESCRT-III.
    Malene Laage Ebstrup, Stine Lauritzen Sønder, Ditte Louise Fogde, Anne Sofie Busk Heitmann, Tiina Naumanen Dietrich, Catarina Dias, Marja Jäättelä, Kenji Maeda, Jesper Nylandsted.
      Lysosomes are crucial organelles essential for various cellular processes, and any damage to them can severely compromise cell viability. This study uncovers a previously unrecognized function of the calcium- and phospholipid-binding protein Annexin A7 in lysosome repair, which operates independently of the Endosomal Sorting Complex Required for Transport (ESCRT) machinery. Our research reveals that Annexin A7 plays a role in repairing damaged lysosomes, different from its role in repairing the plasma membrane, where it facilitates repair through the recruitment of ESCRT-III components. Notably, our findings strongly suggest that Annexin A7, like the ESCRT machinery, is dispensable for membrane contact site formation within the newly discovered phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway. Instead, we speculate that Annexin A7 is recruited to damaged lysosomes and promotes repair through its membrane curvature and cross-linking capabilities. Our findings provide new insights into the diverse mechanisms underlying lysosomal membrane repair and highlight the multifunctional role of Annexin A7 in membrane repair.
    Keywords:  Annexin A7; ER-lysosome membrane contact sites (MCSs); L-Leucyl-L-Leucine O-methyl ester (LLOMe); endosomal sorting complexes required for transport III (ESCRT-III); lysosomal integrity; lysosomal membrane permeabilization; lysosome membrane repair; organelle repair
    DOI:  https://doi.org/10.3389/fcell.2023.1211498
  37. Mol Brain. 2024 Feb 15. 17(1): 9
    In vitro modulation of mTOR and mGlur5 influence α-synuclein accumulation.
    Viktoria Xing, Kyle Biggar, Stephen S G Ferguson, Shawn Hayley.
      One of the main hallmarks of Parkinson's disease (PD) is abnormal alpha-synuclein (α-syn) aggregation which forms the main component of intracellular Lewy body inclusions. This short report used preformed α-syn fibrils, as well as an A53T mutant α-syn adenovirus to mimic conditions of pathological protein aggregation in dopaminergic human derived SH-SY5Y neural cells. Since there is evidence that the mTOR pathway and glutamatergic signaling each influence protein aggregation, we also assessed the impact of the mTOR inhibitor, rapamycin and the mGluR5 allosteric modulator, CTEP. We found that both rapamycin and CTEP induced a significant reduction of α-syn fibrils in SH-SY5Y cells and this effect was associated with a reduction in mTOR signaling and enhancement in autophagic pathway factors. These data support the possibility that CTEP (or rapamycin) might be a useful pharmacological approach to target abnormal α-syn accumulation by promoting intracellular degradation or enhanced clearance.
    Keywords:  In vitro; Parkinson’s disease; mGluR5; mTOR; α-synuclein
    DOI:  https://doi.org/10.1186/s13041-023-01074-2
  38. Nat Prod Res. 2024 Feb 16. 1-24
    Molecular docking targeting autophagy pathway mediate abrogation of NASH by specific functional foods: update review.
    Merehan Alaa-ElDin Mohamed, Shaimaa Rihan, Mustafa M M Elbakry, Said S Moselhy.
      Autophagy is a very well-conserved self-digestive mechanism that transports unwanted or disposable cytoplasmic debris to lysosomes for destruction, including misfolded proteins and damaged organelles. Advanced liver illnesses can develop from the prevalent clinical condition known as non-alcoholic steatohepatitis (NASH). There is no effective treatment, is still unclear. Therefore, in order to create novel therapeutics, it is necessary to comprehend the pathogenic pathways causing disease onset and progression. Natural components from medicinal plants are currently the subject of a larger number of studies since they provide fresh promise for NASH. This review provided an overview of the aetiology of NASH, in addition the role of natural products as alternative or complementary therapeutic agent for management of NASH via autophagy induction. It was concluded that, alternative and complementary supplement of natural functional food as Arabica coffee that rich with chlorogenic acid targeting autophagy mechanism mediate amelioration effect of NASH.
    Keywords:  Coffee Arabica; NASH; Natural components; autophagy
    DOI:  https://doi.org/10.1080/14786419.2024.2316328
  39. Autophagy. 2024 Feb 15. 1-2
    Reticulophagy mediated by the V-ATPase-ATG16L1-LC3C axis.
    Yiwei Sun, Xi Wang.
      The lysosomal degradation of the endoplasmic reticulum (ER), known as "reticulophagy", is important for protein quality control and organelle turnover. Here we present a noncanonical reticulophagy occurring at ER exit sites (ERESs) induced by the misfolded SERPINA1/α1-antitrypsin (AAT) mutant, Z-AAT. The accumulation of Z-AAT arrests ER-to-Golgi transport, and recruits V-ATPase and ATG16L1 to mediate LC3C decoration of ERESs. Consequently, the receptor RETREG1/FAM134B-2 is recruited by lipidated LC3C to initiate reticulophagy. Furthermore, the blockade of ER export acts as a universal signal to activate reticulophagy mediated by the V-ATPase-ATG16L1-LC3C axis. This study sheds light on the mechanism of how ERESs switch from ER export to reticulophagy for quality control.
    Keywords:  ATG16L1; COPII; ER exit sites; SEC24C; V-ATPase; endoplasmic reticulum; protein quality control; reticulophagy; α1-antitrypsin
    DOI:  https://doi.org/10.1080/15548627.2024.2317116
  40. iScience. 2024 Mar 15. 27(3): 108959
    Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB.
    Melania Scarcella, Gianluca Scerra, Mariangela Ciampa, Marianna Caterino, Michele Costanzo, Laura Rinaldi, Antonio Feliciello, Serenella Anzilotti, Chiara Fiorentino, Maurizio Renna, Margherita Ruoppolo, Luigi Michele Pavone, Massimo D'Agostino, Valeria De Pasquale.
      Mucopolysaccharidoses (MPSs) are lysosomal disorders with neurological involvement for which no cure exists. Here, we show that recombinant NK1 fragment of hepatocyte growth factor rescues substrate accumulation and lysosomal defects in MPS I, IIIA and IIIB patient fibroblasts. We investigated PI3K/Akt pathway, which is of crucial importance for neuronal function and survival, and demonstrate that PI3K inhibition abolishes NK1 therapeutic effects. We identified that autophagy inhibition, by Beclin1 silencing, reduces MPS IIIB phenotype and that NK1 downregulates autophagic-lysosome (ALP) gene expression, suggesting a possible contribution of autophagosome biogenesis in MPS. Indeed, metabolomic analyses revealed defects of mitochondrial activity accompanied by anaerobic metabolism and inhibition of AMP-activated protein kinase (AMPK), which acts on metabolism and autophagy, rescues lysosomal defects. These results provide insights into the molecular mechanisms of MPS IIIB physiopathology, supporting the development of new promising approaches based on autophagy inhibition and metabolic rewiring to correct lysosomal pathology in MPSs.
    Keywords:  Cell biology; Human metabolism
    DOI:  https://doi.org/10.1016/j.isci.2024.108959
  41. J Virol. 2024 Feb 14. e0000324
    Hyperacetylated microtubules assist porcine deltacoronavirus nsp8 to degrade MDA5 via SQSTM1/p62-dependent selective autophagy.
    Zhuang Li, Yinan Lai, Runhui Qiu, Wenbing Tang, Jie Ren, Shaobo Xiao, Puxian Fang, Liurong Fang.
      The microtubule (MT) is a highly dynamic polymer that functions in various cellular processes through MT hyperacetylation. Thus, many viruses have evolved mechanisms to hijack the MT network of the cytoskeleton to allow intracellular replication of viral genomic material. Coronavirus non-structural protein 8 (nsp8), a component of the viral replication transcriptional complex, is essential for viral survival. Here, we found that nsp8 of porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus with a zoonotic potential, inhibits interferon (IFN)-β production by targeting melanoma differentiation gene 5 (MDA5), the main pattern recognition receptor for coronaviruses in the cytoplasm. Mechanistically, PDCoV nsp8 interacted with MDA5 and induced autophagy to degrade MDA5 in wild-type cells, but not in autophagy-related (ATG)5 or ATG7 knockout cells. Further screening for autophagic degradation receptors revealed that nsp8 interacts with sequestosome 1/p62 and promotes p62-mediated selective autophagy to degrade MDA5. Importantly, PDCoV nsp8 induced hyperacetylation of MTs, which in turn triggered selective autophagic degradation of MDA5 and subsequent inhibition of IFN-β production. Overall, our study uncovers a novel mechanism employed by PDCoV nsp8 to evade host innate immune defenses. These findings offer new insights into the interplay among viruses, IFNs, and MTs, providing a promising target to develop anti-viral drugs against PDCoV.IMPORTANCECoronavirus nsp8, a component of the viral replication transcriptional complex, is well conserved and plays a crucial role in viral replication. Exploration of the role mechanism of nsp8 is conducive to the understanding of viral pathogenesis and development of anti-viral strategies against coronavirus. Here, we found that nsp8 of PDCoV, an emerging enteropathogenic coronavirus with a zoonotic potential, is an interferon antagonist. Further studies showed that PDCoV nsp8 interacted with MDA5 and sequestosome 1/p62, promoting p62-mediated selective autophagy to degrade MDA5. We further found that PDCoV nsp8 could induce hyperacetylation of MT, therefore triggering selective autophagic degradation of MDA5 and inhibiting IFN-β production. These findings reveal a novel immune evasion strategy used by PDCoV nsp8 and provide insights into potential therapeutic interventions.
    Keywords:  MDA5; microtubule hyperacetylation; nsp8; porcine deltacoronavirus; selective autophagy
    DOI:  https://doi.org/10.1128/jvi.00003-24
  42. Cell Death Discov. 2024 Feb 13. 10(1): 75
    NSD1 supports cell growth and regulates autophagy in HPV-negative head and neck squamous cell carcinoma.
    Iuliia Topchu, Igor Bychkov, Demirkan Gursel, Petr Makhov, Yanis Boumber.
      Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Despite advances in therapeutic management and immunotherapy, the 5-year survival rate for head and neck cancer remains at ~66% of all diagnosed cases. A better definition of drivers of HPV-negative HNSCC that are targetable points of tumor vulnerability could lead to significant clinical advances. NSD1 is a histone methyltransferase that catalyzes histone H3 lysine 36 di-methylation (H3K36me2); mutations inactivating NSD1 have been linked to improved outcomes in HNSCC. In this study, we show that NSD1 induces H3K36me2 levels in HNSCC and that the depletion of NSD1 reduces HNSCC of cell growth in vitro and in vivo. We also find that NSD1 strongly promotes activation of the Akt/mTORC1 signaling pathway. NSD1 depletion in HNSCC induces an autophagic gene program activation, causes accumulation of the p62 and LC3B-II proteins, and decreases the autophagic signaling protein ULK1 at both protein and mRNA levels. Reflecting these signaling defects, the knockdown of NSD1 disrupts autophagic flux in HNSCC cells. Taken together, these data identify positive regulation of Akt/mTORC1 signaling and autophagy as novel NSD1 functions in HNSCC, suggesting that NSD1 may be of value as a therapeutic target in this cancer.
    DOI:  https://doi.org/10.1038/s41420-024-01842-6
  43. J Transl Med. 2024 Feb 16. 22(1): 161
    Endothelium-specific deletion of p62 causes organ fibrosis and cardiac dysfunction.
    Jing Feng, Yan Li, Yu Zhang, Shengnan Sun, Jian Sun, Quanlin Xu, Xingzhao Ji, Yi Liu, Qiang Wan.
      BACKGROUND: The autophagy adapter SQSTM1/p62 is crucial for maintaining homeostasis in various organs and cells due to its protein-protein interaction domains and involvement in diverse physiological and pathological processes. Vascular endothelium cells play a unique role in vascular biology and contribute to vascular health.METHODS: Using the Cre-loxP system, we generated mice with endothelium cell-specific knockout of p62 mediated by Tek (Tek receptor tyrosine kinase)-cre to investigate the essential role of p62 in the endothelium. In vitro, we employed protein mass spectrometry and IPA to identify differentially expressed proteins upon knockdown of p62. Immunoprecipitation assays were conducted to demonstrate the interaction between p62 and FN1 or LAMC2 in human umbilical vein endothelium cells (HUVECs). Additionally, we identified the degradation pathway of FN1 and LAMC2 using the autophagy inhibitor 3-methyladenine (3-MA) or proteasome inhibitor MG132. Finally, the results of immunoprecipitation demonstrated that the interaction between p62 and LAMC2 was abolished in the PB1 truncation group of p62, while the interaction between p62 and FN1 was abolished in the UBA truncation group of p62.
    RESULTS: Our findings revealed that p62 Endo mice exhibited heart, lung, and kidney fibrosis compared to littermate controls, accompanied by severe cardiac dysfunction. Immunoprecipitation assays provided evidence of p62 acting as an autophagy adapter in the autophagy-lysosome pathway for FN1 and LAMC2 degradation respectively through PB1 and UBA domain with these proteins rather than proteasome system.
    CONCLUSIONS: Our study demonstrates that defects in p62 within endothelium cells induce multi-organ fibrosis and cardiac dysfunction in mice. Our findings indicate that FN1 and LAMC2, as markers of (EndoMT), have detrimental effects on HUVECs and elucidate the autophagy-lysosome degradation mechanism of FN1 and LAMC2.
    Keywords:  Cardiac dysfunction; Endothelium cells; Fibronectin1; Fibrosis; Lamininγ2; SQSTM1/p62
    DOI:  https://doi.org/10.1186/s12967-024-04946-w
  44. J Nutr Biochem. 2024 Feb 01. pii: S0955-2863(24)00022-6. [Epub ahead of print]126 109589
    All-trans retinoic acid induces lipophagy through the activation of the AMPK-Beclin1 signaling pathway and reduces Rubicon expression in adipocytes.
    Yuki Mori, Masashi Masuda, Risa Yoshida-Shimizu, Saki Aoyagi, Yuichiro Adachi, Anh The Nguyen, Yusuke Maruyama, Yosuke Okumura, Yuki Kamei, Maiko Sakai, Kohta Ohnishi, Hirokazu Ohminami, Yutaka Taketani.
      Lipophagy is defined as a lipolysis pathway that degrades lipid droplet (LD) via autophagy. All-trans retinoic acid (atRA), a metabolite of vitamin A, stimulates lipolysis through hormone-sensitive lipase and β-oxidation. However, the regulation of lipolysis by atRA-induced autophagy in adipocytes remains unclear. In this study, we investigated the effect of atRA on autophagy in epididymal fat of mice and the molecular mechanisms of autophagy in 3T3-L1 adipocytes. Western blotting showed that atRA decreased the expression of p62, a cargo receptor for autophagic degradation, and increased the expression of the lipidated LC3B (LC3B-II), an autophagy marker, in epididymal fat. Next, we confirmed that atRA increased autophagic flux in differentiated 3T3-L1 cells using the GFP-LC3-RFP-LC3ΔG probe. Immunofluorescent staining revealed that the colocalization of LC3B with perilipin increased in differentiated 3T3-L1 cells treated with atRA. The knockdown of Atg5, an essential gene in autophagy induction, partly suppressed the atRA-induced release of non-esterified fatty acid (NEFA) from LDs in differentiated 3T3-L1 cells. atRA time-dependently elicited the phosphorylation of AMPK and Beclin1, autophagy-inducing factors, in mature 3T3-L1 adipocytes. Inversely, atRA decreased the protein expression of Rubicon, an autophagy repressor, in differentiated 3T3-L1 cells and epididymal fat. Interestingly, the expression of ALDH1A1, atRA-synthesizing enzymes, increased in epididymal fat with decreased protein expression of Rubicon in aged mice. These results suggest that atRA may partially induce lipolysis through lipophagy by activating the AMPK-Beclin1 signaling pathway in the adipocytes and increased atRA levels may contribute to decreased Rubicon expression in the epididymal fat of aged mice. (248/250 words).
    Keywords:  ALDH1A1; Aged; Atra; Autophagy; Lipolysis
    DOI:  https://doi.org/10.1016/j.jnutbio.2024.109589
  45. Plant Sci. 2024 Feb 13. pii: S0168-9452(24)00059-1. [Epub ahead of print]342 112032
    Characterization of tomato autophagy-related SlCOST family genes.
    Jiaojiao Wang, Yanjie Li, Yue Niu, Yao Liu, Qian Zhang, Yonglun Lv, Shuxia Li, Xinhua Wang, Yan Bao.
      Autophagy is a eukaryote-specific cellular process that can engulf unwanted targets with double-membrane autophagosomes and subject them to the vacuole or lysosome for breaking down and recycling, playing dual roles in plant growth and environmental adaptions. However, perception of specific environmental signals for autophagy induction is largely unknown, limiting its application in agricultural usage. Identification of plant-unique DUF641 family COST1 (Constitutively Stressed 1) protein directly links drought perception and autophagy induction, shedding light on manipulating autophagy for breeding stress tolerant crops. In this study, we performed a genome-wide analysis of DUF641/COST family in tomato, and identified five SlCOST genes SlCOST1, -2, -3, -4, and -5. SlCOST genes show both overlapping and distinct expression patterns in plant growth and stress responding. In addition, SlCOST1, -3, -4, -5 proteins demonstrate co-localization with autophagy adaptor protein ATG8e, and all five SlCOST proteins show interactions ATG8e in planta. However, only SlCOST1, the closest ortholog of Arabidopsis AtCOST1, can restore cost1 mutant to WT level, suggesting conserved role of COST1 and functional diversification of SlCOST family in tomato. Our study provides clues for future investigation of autophagy-related COST family and its promising implementations in breeding crops with robust environmental plasticity.
    Keywords:  ATG8; Autophagy; COST; DUF641; SlCOST; Stress tolerance; Tomato
    DOI:  https://doi.org/10.1016/j.plantsci.2024.112032
  46. J Cancer. 2024 ;15(5): 1257-1270
    MCU promotes the migration of glioma cells by activating p38 through TFEB-mediated autophagy.
    Jialong Chen, Renjian Lu, Yongming Peng, Yixi Lai, ZiWei Cai, Dongyan Zheng, Ailan Xie, Kailun Huang, Congmin Liang, He Zhang.
      Changes in calcium signalling are crucial for the development of glioma cells. Whether mitochondrial calcium balance is involved in glial cell development is still unknown. Mitochondrial Calcium Uniporter (MCU) plays an important role in regulating glioma progression. In this work, we found that MCU and p38 expression were positively correlated with glioma grade and the degree tumour progression. MCU increases glioma cell migration by upregulating p38. Furthermore, p38 promotes glioma progression by activating Transcription Factor EB (TFEB)-mediated autophagy. Thus, MCU promotes glioma cell migration by activating autophagy in a p38/TFEB pathway-dependent manner, which provides a theoretical basis for new therapeutic targets for gliomas.
    Keywords:  Autophagy; Glioma; MCU; migration; p38
    DOI:  https://doi.org/10.7150/jca.89485
  47. Cardiovasc Toxicol. 2024 Feb 14.
    Heavy Metal Scavenger Metallothionein Rescues Against Cold Stress-Evoked Myocardial Contractile Anomalies Through Regulation of Mitophagy.
    Zhaohui Pei, Yayuan Xiong, Shasha Jiang, Rui Guo, Wei Jin, Jun Tao, Zhenzhong Zhang, Yingmei Zhang, Yunzeng Zou, Yan Gong, Jun Ren.
      Cold stress prompts an increased prevalence of cardiovascular morbidity yet the underneath machinery remains unclear. Oxidative stress and autophagy appear to contribute to cold stress-induced cardiac anomalies. Our present study evaluated the effect of heavy metal antioxidant metallothionein on cold stress (4 °C)-induced in cardiac remodeling and contractile anomalies and cell signaling involved including regulation of autophagy and mitophagy. Cold stress (3 weeks) prompted interstitial fibrosis, mitochondrial damage (mitochondrial membrane potential and TEM ultrastructure), oxidative stress (glutathione, reactive oxygen species and superoxide), lipid peroxidation, protein injury, elevated left ventricular (LV) end systolic and diastolic diameters, decreased fractional shortening, ejection fraction, Langendorff heart function, cardiomyocyte shortening, maximal velocities of shortening/relengthening, and electrically stimulated intracellular Ca2+ rise along with elongated relaxation duration and intracellular Ca2+ clearance, the responses of which were overtly attenuated or mitigated by metallothionein. Levels of apoptosis, cell death (Bax and loss of Bcl2, IL-18), and autophagy (LC3BII-to-LC3BI ratio, Atg7 and Beclin-1) were overtly upregulated with comparable p62 under cold stress. Cold stress also evoked elevated mitophagy (decreased TOM20, increased Parkin and FUNDC1 with unaltered BNIP3). Cold stress overtly dampened phosphorylation of autophagy/mitophagy inhibitory molecules Akt and mTOR, stimulated and suppressed phosphorylation of ULK1 and eNOS, respectively, in the absence of altered pan protein levels. Cold stress-evoked responses in cell death, autophagy, mitophagy and their regulatory domains were overtly attenuated or ablated by metallothionein. Suppression of autophagy and mitophagy with 3-methyladenine, bafilomycin A1, cyclosporine A, and liensinine rescued hypothermia-instigated cardiomyocyte LC3B puncta formation and mechanical anomalies. Our findings support a protective nature for metallothionein in deep hypothermia-evoked cardiac abnormalities associated with regulation of autophagy and mitophagy.
    Keywords:  Autophagy; Cold stress; Metallothionein; Mitophagy; Myocardial function
    DOI:  https://doi.org/10.1007/s12012-023-09823-4
  48. MedComm (2020). 2024 Feb;5(2): e482
    Stromal interaction molecule 1/microtubule-associated protein 1A/1B-light chain 3B complex induces metastasis of hepatocellular carcinoma by promoting autophagy.
    Jingchun Wang, Qichao Xie, Lei Wu, Yu Zhou, Yanquan Xu, Yu Chen, Jiangang Zhang, Ran Ren, Shiming Yang, Yongsheng Li, Huakan Zhao.
      Metastasis is the leading cause of death in hepatocellular carcinoma (HCC) patients, and autophagy plays a crucial role in this process by orchestrating epithelial-mesenchymal transition (EMT). Stromal interaction molecule 1 (STIM1), a central regulator of store-operated calcium entry (SOCE) in nonexcitable cells, is involved in the development and spread of HCC. However, the impact of STIM1 on autophagy regulation during HCC metastasis remains unclear. Here, we demonstrate that STIM1 is temporally regulated during autophagy-induced EMT in HCC cells, and knocking out (KO) STIM1 significantly reduces both autophagy and EMT. Interestingly, STIM1 enhances autophagy through both SOCE-dependent and independent pathways. Mechanistically, STIM1 directly interacts with microtubule-associated protein 1A/1B-light chain 3B (LC3B) to form a complex via the sterile-α motif (SAM) domain, which promotes autophagosome formation. Furthermore, deletion of the SAM domain of STIM1 abolishes its binding with LC3B, leading to a decrease in autophagy and EMT in HCC cells. These findings unveil a novel mechanism by which the STIM1/LC3B complex mediates autophagy and EMT in HCC cells, highlighting a potential target for preventing HCC metastasis.
    Keywords:  autophagy; epithelial–mesenchymal transition/EMT; hepatocellular carcinoma/HCC; microtubule‐associated protein 1A/1B‐light chain 3B/LC3B; stromal interaction molecule 1/STIM1
    DOI:  https://doi.org/10.1002/mco2.482
  49. Plant Physiol Biochem. 2024 Feb 07. pii: S0981-9428(24)00077-9. [Epub ahead of print]207 108409
    Melatonin-mediated regulation of autophagy is independent of ABA under drought stress in sensitive variety of Gossypium hirsutum L.
    Laha Supriya, Deepika Dake, Mehanathan Muthamilarasan, Gudipalli Padmaja.
      Autophagy is a highly conserved process that plays a crucial role in adaptation of plants to stress conditions. Melatonin and abscisic acid (ABA) share an antagonistic relationship; however, both are reported to elevate autophagy individually. Here, we report that melatonin alleviates drought stress effects like wilting and stunted growth in 18-day-old plants of drought-sensitive variety of cotton (Gossypium hirsutum L.) and improves the plant growth, chlorophyll content, photosynthetic efficiency, and sugar metabolism and transport. Melatonin priming increased the endogenous melatonin content (5.02-times) but decreased the ABA (2.63-times) by reducing NCED3 expression as compared to unprimed plants under drought. Also, elevated expression of ATG8c and ATG8f correlated with higher lipidated-ATG8 levels and modulation of RAPTOR1 suggesting a higher occurrence of autophagy and regulation of plant growth in primed stressed plants. Additionally, decreased TPS63 and increased TPP22 expression could have lowered the accumulation of trehalose-6-P (T6P) in primed stressed plants thus contributing to autophagy progression. Priming also enhanced the expression of MAPK6 and RAF18, and increased the transcript/protein levels of SnRK2.6 and KIN10, which is pointing towards melatonin's beneficial effect on autophagy under drought. Despite higher ABA content, elevated TPS63 and downregulated TPP22 could have hindered autophagy induction in unprimed stressed plants. Although fluridone treatment reduced the ABA content, the expression of SnRK2.6 and KIN10 remained unaltered in fluridone-treated and untreated primed plants indicating the ABA-independent expression. These results suggest that the melatonin-mediated activation of MAPK contributes to the ABA-independent activation of SnRK2, consequently, SnRK1 and autophagy under drought.
    Keywords:  ABA; Autophagy; Cotton; Drought; MAPK; Melatonin; Sugars
    DOI:  https://doi.org/10.1016/j.plaphy.2024.108409
  50. bioRxiv. 2024 Feb 02. pii: 2024.01.31.578311. [Epub ahead of print]
    ALS-Associated TDP-43 Dysfunction Compromises UPF1-Dependent mRNA Metabolism Pathways Including Alternative Polyadenylation and 3'UTR Length.
    Francesco Alessandrini, Matthew Wright, Tatsuaki Kurosaki, Lynne E Maquat, Evangelos Kiskinis.
      UPF1-mediated decay entails several mRNA surveillance pathways that play a crucial role in cellular homeostasis. However, the precise role of UPF1 in postmitotic neurons remains unresolved, as does its activity in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease characterized by TDP-43 pathology and disrupted mRNA metabolism. Here, we used human iPSC-derived spinal motor neurons (MNs) to identify mRNAs subject to UPF1 degradation by integrating RNA-seq before and after UPF1 knockdown with RIP-seq to identify RNAs that co-immunoprecipitate with the active form of phosphorylated UPF1. We define a stringent set of bona fide UPF1 targets in MNs that are functionally enriched for autophagy and structurally enriched for GC-rich and long 3' UTRs but not for premature termination codon (PTC)-containing transcripts. TDP-43 depletion in iPSC-derived MNs reduces UPF1 phosphorylation and consequently post-transcriptional upregulation of UPF1 targets, suggesting that TDP-43 dysfunction compromises UPF1-mediated mRNA surveillance. Intriguingly, our datasets reveal that UPF1 and TDP-43 regulate alternative polyadenylation and 3'UTR length of mRNAs associated with synaptic and axonal function, a process that we find to be compromised in ALS models in vitro and ALS patient tissue. Our study provides a comprehensive description of UPF1-mediated mRNA decay activity in neurons, reveals overlapping roles between UPF1 and TDP-43 in regulating 3'UTR length, and offers novel insight into the intricate interplay between RNA metabolism and neurodegeneration in ALS.
    DOI:  https://doi.org/10.1101/2024.01.31.578311
  51. Fish Shellfish Immunol. 2024 Feb 14. pii: S1050-4648(24)00097-4. [Epub ahead of print] 109453
    miR-193b-5p promotes GCRV replication by inhibiting autophagy via targeting deptor in grass carp (Ctenopharyngodon idellus).
    Hongyan Yu, Zheyan Chen, Qiaozhen Yu, Yubang Shen, Lang Gui, Xiaoyan Xu, Jiale Li.
      miRNAs are increasingly recognized for their crucial role in autophagy processes. Recent research has highlighted the significant function of autophagy in modulating immune responses. Within this context, specific miRNAs have been identified as indirect mediators of immune functions through their modulation of autophagy. In this study, we verified that miR-193b-5p simultaneously targeted the grass carp autophagy-related gene deptor, thereby reducing autophagy levels in CIK cells. Moreover, we found the expression levels of miR-193b-5p and deptor responding to pathogen infections in the GCRV-infected CIK cells. Notably, the overexpression of miR-193b-5p was found to induce the GCRV replication and reduce the irf3, irf7 and IFN1 expression. These findings also demonstrated that grass carp miR-193b-5p impacted the proliferation, migration, and antiapoptotic abilities of CIK cells. All the above results indicated that miR-193b-5p was linked to grass carp autophagy and played a vital role in antiviral immunity by targeting deptor. Our study may provide important insights into autophagy-related miRNAs and their roles in defense and immune mechanisms against pathogens in teleost.
    Keywords:  Autophagy; GCRV; Grass carp; miR-193b-5p
    DOI:  https://doi.org/10.1016/j.fsi.2024.109453
  52. Sci Adv. 2024 Feb 16. 10(7): eadi7830
    Distinct roles of LARP1 and 4EBP1/2 in regulating translation and stability of 5'TOP mRNAs.
    Tobias Hochstoeger, Panagiotis Papasaikas, Ewa Piskadlo, Jeffrey A Chao.
      A central mechanism of mTOR complex 1 (mTORC1) signaling is the coordinated translation of ribosomal protein and translation factor mRNAs mediated by the 5'-terminal oligopyrimidine motif (5'TOP). Recently, La-related protein 1 (LARP1) was proposed to be the specific regulator of 5'TOP mRNA translation downstream of mTORC1, while eIF4E-binding proteins (4EBP1/2) were suggested to have a general role in translational repression of all transcripts. Here, we use single-molecule translation site imaging of 5'TOP and canonical mRNAs to study the translation of single mRNAs in living cells. Our data reveal that 4EBP1/2 has a dominant role in repression of translation of both 5'TOP and canonical mRNAs during pharmacological inhibition of mTOR. In contrast, we find that LARP1 selectively protects 5'TOP mRNAs from degradation in a transcriptome-wide analysis of mRNA half-lives. Our results clarify the roles of 4EBP1/2 and LARP1 in regulating 5'TOP mRNAs and provide a framework to further study how these factors control cell growth during development and disease.
    DOI:  https://doi.org/10.1126/sciadv.adi7830
  53. FASEB J. 2024 Feb 29. 38(4): e23491
    TRAF2 decrease promotes the TGF-β-mTORC1 signal in MAFLD-HCC through enhancing AXIN1-mediated Smad7 degradation.
    Zhonglin Li, Jinfang Zhao, Ya Wu, Siyuan Fan, Hang Yuan, Jing Xia, Lilin Hu, Jingze Yang, Jiazheng Liu, Xuefeng Wu, Rong Lin, Ling Yang.
      According to recent research, metabolic-associated fatty liver disease (MAFLD) has emerged as an important underlying etiology of hepatocellular carcinoma (HCC). However, the molecular mechanism of MAFLD-HCC is still unclear. Tumor necrosis factor receptor-associated factor 2 (TRAF2) is the key molecule to mediate the signal of inflammatory NF-κB pathway. This study aims to investigate the potential dysregulation of TRAF2 and its biological function in MAFLD-HCC. Huh7 TRAF2-/- demonstrated increased tumor formation ability compared to huh7 TRAF2+/+ when stimulated with transforming growth factor-β (TGF-β). The decisive role of TGF-β in the development of MAFLD-HCC was confirmed through the specific depletion of TGF-β receptor II gene in the hepatocytes (Tgfbr2ΔHep) of mice. In TRAF2-/- cells treated with TGF-β, both the glycolysis rate and lipid synthesis were enhanced. We proved the signal of the mechanistic target of rapamycin complex 1 (mTORC1) could be activated in the presence of TGF-β, and was enhanced in TRAF2-/- cells. The coimmunoprecipitation (co-IP) experiments revealed that TRAF2 fortified the Smurf2-mediated ubiquitination degradation of AXIN1. Hence, TRAF2 depletion resulted in increased Smad7 degradation induced by AXIN1, thus promoting the TGF-β signal. We also discovered that PLX-4720 could bind with AXIN1 and restrained the tumor proliferation of TRAF2-/- in mice fed with high-fat diet (HFD). Our findings indicate that TRAF2 plays a significant role in the pathogenesis of MAFLD-HCC. The reduction of TRAF2 expression leads to the enhancement of the TGF-β-mTORC1 pathway by facilitating AXIN1-mediated Smad7 degradation.
    Keywords:  AXIN1; MAFLD; TGF-β; TRAF2; hepatoma; mTORC1
    DOI:  https://doi.org/10.1096/fj.202302307R
  54. Phytother Res. 2024 Feb 14.
    Regulation of mitophagy and mitochondrial function: Natural compounds as potential therapeutic strategies for Parkinson's disease.
    Hao Liang, Zhenwang Ma, Wei Zhong, Jia Liu, Kazuo Sugimoto, Hong Chen.
      Mitochondrial damage is associated with the development of Parkinson's disease (PD), indicating that mitochondrial-targeted treatments could hold promise as disease-modifying approaches for PD. Notably, natural compounds have demonstrated the ability to modulate mitochondrial-related processes. In this review article, we discussed the possible neuroprotective mechanisms of natural compounds against PD in modulating mitophagy and mitochondrial function. A comprehensive literature search on natural compounds related to the treatment of PD by regulating mitophagy and mitochondrial function was conducted from PubMed, Web of Science and Chinese National Knowledge Infrastructure databases from their inception until April 2023. We summarize recent advancements in mitophagy's molecular mechanisms, including upstream and downstream processes, and its relationship with PD-related genes or proteins. Importantly, we highlight how natural compounds can therapeutically regulate various mitochondrial processes through multiple targets and pathways to alleviate oxidative stress, neuroinflammation, Lewy's body aggregation and apoptosis, which are key contributors to PD pathogenesis. Unlike the single-target strategy of modern medicine, natural compounds provide neuroprotection against PD by modulating various mitochondrial-related processes, including ameliorating mitophagy by targeting the PINK1/parkin pathway, the NIX/BNIP3 pathway, and autophagosome formation (i.e., LC3 and p62). Given the prevalence of mitochondrial damage in various neurodegenerative diseases, exploring the exact mechanism of natural compounds on mitophagy and mitochondrial dysfunction could shed light on the development of highly effective disease-modifying or adjuvant therapies targeting PD and other neurodegenerative disorders.
    Keywords:  Parkinson's disease; mitochondrial function; mitophagy; natural compounds; therapy
    DOI:  https://doi.org/10.1002/ptr.8156
  55. Cell Death Discov. 2024 Feb 16. 10(1): 84
    From the regulatory mechanism of TFEB to its therapeutic implications.
    Huixia Chen, Siqiao Gong, Hongyong Zhang, Yongming Chen, Yonghan Liu, Junfeng Hao, Huafeng Liu, Xiaoyu Li.
      Transcription factor EB (TFEB), known as a major transcriptional regulator of the autophagy-lysosomal pathway, regulates target gene expression by binding to coordinated lysosomal expression and regulation (CLEAR) elements. TFEB are regulated by multiple links, such as transcriptional regulation, post-transcriptional regulation, translational-level regulation, post-translational modification (PTM), and nuclear competitive regulation. Targeted regulation of TFEB has been victoriously used as a treatment strategy in several disease models such as ischemic injury, lysosomal storage disorders (LSDs), cancer, metabolic disorders, neurodegenerative diseases, and inflammation. In this review, we aimed to elucidate the regulatory mechanism of TFEB and its applications in several disease models by targeting the regulation of TFEB as a treatment strategy.
    DOI:  https://doi.org/10.1038/s41420-024-01850-6
  56. Anim Nutr. 2024 Mar;16 338-349
    Hexokinase 1 and 2 mediates glucose utilization to regulate the synthesis of kappa casein via ribosome protein subunit 6 kinase 1 in bovine mammary epithelial cells.
    Tianyu Yang, Jia Guo, Han Song, Osmond Datsomor, Yuhang Chen, Maocheng Jiang, Kang Zhan, Guoqi Zhao.
      Glucose plays a vital part in milk protein synthesis through the mTOR signaling pathway in bovine mammary epithelial cells (BMEC). The objectives of this study were to determine how glucose affects hexokinase (HK) activity in BMEC and investigate the regulatory effect of HK in kappa casein (CSN3) synthesis via the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in BMEC. For this, HK1 and HK2 were knocked out in BMEC using the CRISPR/Cas9 system. The gene and protein expression, glucose uptake, and cell proliferation were measured. We found that glucose uptake, cell proliferation, CSN3 gene expression levels, and expression of HK1 and HK2 increased with increasing glucose concentrations. Notably, glucose uptake was significantly reduced in HK2 knockout (HK2KO) BMEC treated with 17.5 mM glucose. Moreover, under the same glucose treatment conditions, the proliferative ability and abundance of CSN3 were significantly diminished in both HK1 knockout (HK1KO) and HK2KO BMEC compared with that in wild-type BEMC. We further observed that the phosphorylation levels of ribosome protein subunit 6 kinase 1 (S6K1) were reduced in HK1KO and HK2KO BMEC following treatment with 17.5 mM glucose. As expected, the levels of glucose-6-phosphate and the mRNA expression levels of glycolysis-related genes were decreased in both HK1KO and HK2KO BMEC following glucose treatment. These results indicated that the knockout of HK1 and HK2 inhibited cell proliferation and CSN3 expression in BMEC under glucose treatment, which may be associated with the inactivation of the S6K1 and inhibition of glycolysis.
    Keywords:  Bovine mammary epithelial cell; Glucose; Hexokinase; Kappa casein; Mechanistic target of rapamycin complex 1 signaling pathway; Milk protein
    DOI:  https://doi.org/10.1016/j.aninu.2024.01.001
  57. bioRxiv. 2024 Jan 31. pii: 2024.01.30.578072. [Epub ahead of print]
    Casein kinase 1 controls components of a TORC2 signaling network in budding yeast.
    Rafael Lucena, Akshi Jasani, Steph Anastasia, Douglas Kellogg, Maria Alcaide-Gavilan.
      Tor kinases play diverse and essential roles in control of nutrient signaling and cell growth. Tor kinases are assembled into two large multiprotein complexes referred to as Tor Complex 1 and Tor Complex 2 (TORC1 and TORC2). In budding yeast, TORC2 controls a signaling network that relays signals regarding carbon source that strongly influence growth rate and cell size. However, the mechanisms that control TORC2 signaling are poorly understood. Activation of TORC2 requires Mss4, a phosphoinositol kinase that initiates assembly of a multi-protein complex at the plasma membrane that recruits and activates downstream targets of TORC2. Localization of Mss4 to the plasma membrane is controlled by phosphorylation and previous work suggested that yeast homologs of casein kinase 1γ, referred to as Yck1 and Yck2, control phosphorylation of Mss4. Here, we generated a new analog-sensitive allele of YCK2 and used it to test whether Yck1/2 influence signaling in the TORC2 network. We found that multiple components of the TORC2 network are strongly influenced by Yck1/2 signaling.
    DOI:  https://doi.org/10.1101/2024.01.30.578072
  58. ACS Appl Mater Interfaces. 2024 Feb 12.
    Melatonin-Loaded Nanoparticles Augment Mitophagy to Retard Parkinson's Disease.
    Liku Biswal, Mohammed Nadim Sardoiwala, Avinash Chandra Kushwaha, Syamantak Mukherjee, Surajit Karmakar.
      The molecular pathways that melatonin follows as a Parkinson's disease (PD) antagonist remain poorly elucidated, despite it being a safe and a potential neurotherapeutic drug with a few limitations such as less bioavailability, premature oxidation, brain delivery, etc. Here, we used a biocompatible protein (HSA) nanocarrier for the delivery of melatonin to the brain. This nanomelatonin showed better antioxidative and neuroprotective properties, and it not only improves mitophagy to remove unhealthy mitochondria but also improves mitochondrial biogenesis to counteract rotenone-induced toxicity in an in vitro PD model. We also showed BMI1, a member of the PRC1 complex that regulates mitophagy, whose protein expression was enhanced after nanomelatonin dosage. These effects were translated to a rodent model, where nanomelatonin improves the TH+ve neuron population in SNPC and protects against rotenone-mediated toxicity. Our findings highlight the significantly better in vitro and in vivo neuroprotective effect of nanomelatonin as well as the molecular/cellular dynamics it influences to regulate mitophagy as a measure of the potential therapeutic candidate for PD.
    Keywords:  BMI1; PTEN; Parkinson’s disease; melatonin; mitophagy
    DOI:  https://doi.org/10.1021/acsami.3c17092
  59. bioRxiv. 2024 Feb 04. pii: 2024.02.04.578682. [Epub ahead of print]
    Ca 2+ -sensor ALG-2 engages ESCRTs to enhance lysosomal membrane resilience to osmotic stress.
    Wei Chen, Madeline M Motsinger, Jiaqian Li, Kevin P Bohannon, Phyllis I Hanson.
      Lysosomes are central players in cellular catabolism, signaling, and metabolic regulation. Cellular and environmental stresses that damage lysosomal membranes can compromise their function and release toxic content into the cytoplasm. Here, we examine how cells respond to osmotic stress within lysosomes. Using sensitive assays of lysosomal leakage and rupture, we examine acute effects of the cathepsin C-metabolized osmotic disruptant glycyl-L-phenylalanine 2-naphthylamide (GPN). Our findings reveal that widely used concentrations of GPN rupture only a small fraction of lysosomes, but surprisingly trigger Ca 2+ release from nearly all. Chelating cytoplasmic Ca 2+ using BAPTA makes lysosomes more likely to rupture under GPN-induced stress, suggesting that Ca 2+ plays a role in protecting or rapidly repairing lysosomal membranes. Mechanistically, we establish that GPN causes the Ca 2+ -sensitive protein Apoptosis Linked Gene-2 (ALG-2) and interacting ESCRT proteins to redistribute onto lysosomes, improving their resistance to membrane stress created by GPN as well as the lysosomotropic drug chlorpromazine. Furthermore, we show that activating the cation channel TRPML1, with or without blocking the endoplasmic reticulum Ca 2+ pump, creates local Ca 2+ signals that protect lysosomes from rupture by recruiting ALG-2 and ESCRTs without any membrane damage. These findings reveal that Ca 2+ , through ALG-2, helps bring ESCRTs to lysosomes to enhance their resilience and maintain organelle integrity in the face of osmotic stress.SIGNIFICANCE: As the degradative hub of the cell, lysosomes are full of toxic content that can spill into the cytoplasm. There has been much recent interest in how cells sense and repair lysosomal membrane damage using ESCRTs and cholesterol to rapidly fix "nanoscale damage". Here, we extend understanding of how ESCRTs contribute by uncovering a preventative role of the ESCRT machinery. We show that ESCRTs, when recruited by the Ca 2+ -sensor ALG-2, play a critical role in stabilizing the lysosomal membrane against osmotically-induced rupture. This finding suggests that cells have mechanisms not just for repairing but also for actively protecting lysosomes from stress-induced membrane damage.
    DOI:  https://doi.org/10.1101/2024.02.04.578682
  60. Cell Rep. 2024 Feb 12. pii: S2211-1247(24)00066-4. [Epub ahead of print]43(2): 113738
    Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.
    Debanik Choudhury, Na Rong, Hamsa Vardini Senthil Kumar, Sydney Swedick, Ronel Z Samuel, Pihu Mehrotra, John Toftegaard, Nika Rajabian, Ramkumar Thiyagarajan, Ashis K Podder, Yulun Wu, Shahryar Shahini, Kenneth L Seldeen, Bruce Troen, Pedro Lei, Stelios T Andreadis.
      Mitochondrial dysfunction is a hallmark of cellular senescence, with the loss of mitochondrial function identified as a potential causal factor contributing to senescence-associated decline in cellular functions. Our recent findings revealed that ectopic expression of the pluripotency transcription factor NANOG rejuvenates dysfunctional mitochondria of senescent cells by rewiring metabolic pathways. In this study, we report that NANOG restores the expression of key enzymes, PYCR1 and PYCR2, in the proline biosynthesis pathway. Additionally, senescent mesenchymal stem cells manifest severe mitochondrial respiratory impairment, which is alleviated through proline supplementation. Proline induces mitophagy by activating AMP-activated protein kinase α and upregulating Parkin expression, enhancing mitochondrial clearance and ultimately restoring cell metabolism. Notably, proline treatment also mitigates several aging hallmarks, including DNA damage, senescence-associated β-galactosidase, inflammatory cytokine expressions, and impaired myogenic differentiation capacity. Overall, this study highlights the role of proline in mitophagy and its potential in reversing senescence-associated mitochondrial dysfunction and aging hallmarks.
    Keywords:  AMPKα; CP: Cell biology; CP: Metabolism; Parkin; aging; amino acid; autophagy; mitochondria; mitophagy; proline; senescence
    DOI:  https://doi.org/10.1016/j.celrep.2024.113738
  61. Transl Psychiatry. 2024 Feb 13. 14(1): 94
    Autophagy-related gene model as a novel risk factor for schizophrenia.
    Yunfei Tan, Junpeng Zhu, Kenji Hashimoto.
      Autophagy, a cellular process where cells degrade and recycle their own components, has garnered attention for its potential role in psychiatric disorders, including schizophrenia (SCZ). This study aimed to construct and validate a new autophagy-related gene (ARG) risk model for SCZ. First, we analyzed differential expressions in the GSE38484 training set, identifying 4,754 differentially expressed genes (DEGs) between SCZ and control groups. Using the Human Autophagy Database (HADb) database, we cataloged 232 ARGs and pinpointed 80 autophagy-related DEGs (AR-DEGs) after intersecting them with DEGs. Subsequent analyses, including metascape gene annotation, pathway and process enrichment, and protein-protein interaction enrichment, were performed on the 80 AR-DEGs to delve deeper into their biological roles and associated molecular pathways. From this, we identified 34 candidate risk AR-DEGs (RAR-DEGs) and honed this list to final RAR-DEGs via a constructed and optimized logistic regression model. These genes include VAMP7, PTEN, WIPI2, PARP1, DNAJB9, SH3GLB1, ATF4, EIF4G1, EGFR, CDKN1A, CFLAR, FAS, BCL2L1 and BNIP3. Using these findings, we crafted a nomogram to predict SCZ risk for individual samples. In summary, our study offers deeper insights into SCZ's molecular pathogenesis and paves the way for innovative approaches in risk prediction, gene-targeted diagnosis, and community-based SCZ treatments.
    DOI:  https://doi.org/10.1038/s41398-024-02767-5
  62. Front Cell Infect Microbiol. 2024 ;14 1349221
    The host mannose-6-phosphate pathway and viral infection.
    Qincheng Liu, Weiqi Wang, Liwei Xu, Qisheng Zhang, Hongna Wang.
      Viruses, despite their simple structural composition, engage in intricate and complex interactions with their hosts due to their parasitic nature. A notable demonstration of viral behavior lies in their exploitation of lysosomes, specialized organelles responsible for the breakdown of biomolecules and clearance of foreign substances, to bolster their own replication. The man-nose-6-phosphate (M6P) pathway, crucial for facilitating the proper transport of hydrolases into lysosomes and promoting lysosome maturation, is frequently exploited for viral manipulation in support of replication. Recently, the discovery of lysosomal enzyme trafficking factor (LYSET) as a pivotal regulator within the lysosomal M6P pathway has introduced a fresh perspective on the intricate interplay between viral entry and host factors. This groundbreaking revelation illuminates unexplored dimensions of these interactions. In this review, we endeavor to provide a thorough overview of the M6P pathway and its intricate interplay with viral factors during infection. By consolidating the current understanding in this field, our objective is to establish a valuable reference for the development of antiviral drugs that selectively target the M6P pathway.
    Keywords:  GNPT; LYSET; M6P; M6PR; cathepsin; infectious diseases; lysosome; virus
    DOI:  https://doi.org/10.3389/fcimb.2024.1349221
  63. Cell Death Discov. 2024 Feb 15. 10(1): 80
    Restrained Mitf-associated autophagy by Mulberroside A ameliorates osteoclastogenesis and counteracts OVX-Induced osteoporosis in mice.
    Hong Xue, Zhenhua Feng, Putao Yuan, Li Qiao, Qiliang Lou, Xiangde Zhao, Qingliang Ma, Shiyu Wang, Yang Shen, Huali Ye, Jiao Cheng, Jiying Wang, Shuanglin Wan, Boya Zhang, Peihua Shi, Xuewu Sun.
      Bone and mineral metabolism homeostasis accounts for the maintenance of normal skeletal remodeling. However, with aging and changes in hormone levels, over-activated osteoclasts disrupt homeostasis, induce osteoporosis, and even cause osteoporotic fractures, leading to an enormous economic burden. Despite the rapid development of pharmacological therapy for osteoporosis, safer and more effective treatments remain to be explored. Here, we demonstrate that Mulberroside A (Mul-A), a natural component extracted from mulberry bark and branches, effectively suppresses osteoclastogenesis in vitro and counteracts bone loss caused by ovariectomy (OVX). The mechanism underlying this effect involves the repression of autophagic flux during osteoclastogenesis by Mul-A, which can be attributed to the restrained expression of microphthalmia-related transcription factor (Mitf) and its nuclear translocation. Importantly, Mitf overexpression partially reverses the inhibitory effects of Mul-A on autophagy and osteoclastogenesis. Moreover, applying two autophagy agonizts, rapamycin and Torin 1, attenuates the osteoclastogenic regulatory role of Mul-A. Collectively, our study demonstrates that Mul-A damages osteoclast differentiation and ameliorates osteoporosis caused by estrogen deficiency by modulation of Mitf-associated autophagy, indicating its therapeutic potential against osteoporosis.
    DOI:  https://doi.org/10.1038/s41420-024-01847-1
  64. Cell Commun Signal. 2024 Feb 15. 22(1): 124
    Autophagy-modulating biomaterials: multifunctional weapons to promote tissue regeneration.
    Yan Wu, Luxin Li, Zuojun Ning, Changrong Li, Yongkui Yin, Kaiyuan Chen, Lu Li, Fei Xu, Jie Gao.
      Autophagy is a self-renewal mechanism that maintains homeostasis and can promote tissue regeneration by regulating inflammation, reducing oxidative stress and promoting cell differentiation. The interaction between biomaterials and tissue cells significantly affects biomaterial-tissue integration and tissue regeneration. In recent years, it has been found that biomaterials can affect various processes related to tissue regeneration by regulating autophagy. The utilization of biomaterials in a controlled environment has become a prominent approach for enhancing the tissue regeneration capabilities. This involves the regulation of autophagy in diverse cell types implicated in tissue regeneration, encompassing the modulation of inflammatory responses, oxidative stress, cell differentiation, proliferation, migration, apoptosis, and extracellular matrix formation. In addition, biomaterials possess the potential to serve as carriers for drug delivery, enabling the regulation of autophagy by either activating or inhibiting its processes. This review summarizes the relationship between autophagy and tissue regeneration and discusses the role of biomaterial-based autophagy in tissue regeneration. In addition, recent advanced technologies used to design autophagy-modulating biomaterials are summarized, and rational design of biomaterials for providing controlled autophagy regulation via modification of the chemistry and surface of biomaterials and incorporation of cells and molecules is discussed. A better understanding of biomaterial-based autophagy and tissue regeneration, as well as the underlying molecular mechanisms, may lead to new possibilities for promoting tissue regeneration. Video Abstract.
    Keywords:  Anti-apoptosis; Anti-infection; Anti-inflammation; Autophagy; Biomaterials; Proliferation and differentiation; Tissue regeneration
    DOI:  https://doi.org/10.1186/s12964-023-01346-3
  65. PLoS Comput Biol. 2024 Feb 16. 20(2): e1011902
    Linear motifs regulating protein secretion, sorting and autophagy in Leishmania parasites are diverged with respect to their host equivalents.
    Andras Zeke, Toby J Gibson, Laszlo Dobson.
      The pathogenic, tropical Leishmania flagellates belong to an early-branching eukaryotic lineage (Kinetoplastida) with several unique features. Unfortunately, they are poorly understood from a molecular biology perspective, making development of mechanistically novel and selective drugs difficult. Here, we explore three functionally critical targeting short linear motif systems as well as their receptors in depth, using a combination of structural modeling, evolutionary sequence divergence and deep learning. Secretory signal peptides, endoplasmic reticulum (ER) retention motifs (KDEL motifs), and autophagy signals (motifs interacting with ATG8 family members) are ancient and essential components of cellular life. Although expected to be conserved amongst the kinetoplastids, we observe that all three systems show a varying degree of divergence from their better studied equivalents in animals, plants, or fungi. We not only describe their behaviour, but also build models that allow the prediction of localization and potential functions for several uncharacterized Leishmania proteins. The unusually Ala/Val-rich secretory signal peptides, endoplasmic reticulum resident proteins ending in Asp-Leu-COOH and atypical ATG8-like proteins are all unique molecular features of kinetoplastid parasites. Several of their critical protein-protein interactions could serve as targets of selective antimicrobial agents against Leishmaniasis due to their systematic divergence from the host.
    DOI:  https://doi.org/10.1371/journal.pcbi.1011902
  66. FASEB J. 2024 Feb 29. 38(4): e23488
    Amphiregulin improves ventricular remodeling after myocardial infarction by modulating autophagy and apoptosis.
    Nana Li, Ni Xia, Junyi He, Meilin Liu, Muyang Gu, Yuzhi Lu, Haoyi Yang, Zhiheng Hao, Lingfeng Zha, Xuhong Wang, Weimin Wang, Desheng Hu, Jiong Hu, Xiang Cheng.
      Myocardial infarction (MI) is defined as sudden ischemic death of myocardial tissue. Amphiregulin (Areg) regulates cell survival and is crucial for the healing of tissues after damage. However, the functions and mechanisms of Areg after MI remain unclear. Here, we aimed to investigate Areg's impact on myocardial remodeling. Mice model of MI was constructed and Areg-/- mice were used. Expression of Areg was analyzed using western blotting, RT-qPCR, flow cytometry, and immunofluorescence staining. Echocardiographic analysis, Masson's trichrome, and triphenyltetrazolium chloride staining were used to assess cardiac function and structure. RNA sequencing was used for unbiased analysis. Apoptosis and autophagy were determined by western blotting, TUNEL staining, electron microscopy, and mRFP-GFP-LC3 lentivirus. Lysosomal acidity was determined by Lysotracker staining. Areg was elevated in the infarct border zone after MI. It was mostly secreted by macrophages. Areg deficiency aggravated adverse ventricular remodeling, as reflected by worsening cardiac function, a lower survival rate, increased scar size, and interstitial fibrosis. RNA sequencing analyses showed that Areg related to the epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/protein kinase B (PI3K-Akt), mammalian target of rapamycin (mTOR) signaling pathways, V-ATPase and lysosome pathways. Mechanistically, Areg exerts beneficial effects via increasing lysosomal acidity to promote autophagosome clearance, and activating the EGFR/PI3K/Akt/mTOR signaling pathway, subsequently inhibiting excessive autophagosome formation and apoptosis in cardiomyocytes. This study provides a novel evidence for the role of Areg in inhibiting ventricular remodeling after MI by regulating autophagy and apoptosis and identifies Areg as a potential therapeutic target in ventricular remodeling after MI.
    Keywords:  amphiregulin; apoptosis; autophagy; myocardial infarction; ventricular remodeling
    DOI:  https://doi.org/10.1096/fj.202302385R
  67. Biogerontology. 2024 Feb 13.
    Renal aging and mitochondrial quality control.
    Xiuli Guo, Jiao Wang, Yinjie Wu, Xinwang Zhu, Li Xu.
      Mitochondria are dynamic organelles that participate in different cellular process that control metabolism, cell division, and survival, and the kidney is one of the most metabolically active organs that contains abundant mitochondria. Perturbations in mitochondrial homeostasis in the kidney can accelerate kidney aging, and maintaining mitochondrial homeostasis can effectively delay aging in the kidney. Kidney aging is a degenerative process linked to detrimental processes. The significance of aberrant mitochondrial homeostasis in renal aging has received increasing attention. However, the contribution of mitochondrial quality control (MQC) to renal aging has not been reviewed in detail. Here, we generalize the current factors contributing to renal aging, review the alterations in MQC during renal injury and aging, and analyze the relationship between mitochondria and intrinsic renal cells. We also introduce MQC in the context of renal aging, and discuss the study of mitochondria in the intrinsic cells of the kidney, which is the innovation of our paper. In addition, during kidney injury and repair, the specific functions and regulatory mechanisms of MQC systems in resident and circulating cell types remain unclear. Currently, most of the studies we reviewed are based on animal and cellular models, the relationship between renal tissue aging and mitochondria has not been adequately investigated in clinical studies, and there is still a long way to go.
    Keywords:  Aging; Mitochondrial dysfunction; Mitochondrial quality control; Renal intrinsic cells
    DOI:  https://doi.org/10.1007/s10522-023-10091-6
  68. J Immunol. 2024 Feb 16. pii: ji2300599. [Epub ahead of print]
    Fish Uses CTLA-4 Immune Checkpoint to Suppress mTORC1-Controlled T-Cell Glycolysis and Immunity.
    Jiansong Zhang, Xiumei Wei, Qian Zhang, Xinying Jiao, Kang Li, Ming Geng, Yi Cao, Ding Wang, Jie Cheng, Jialong Yang.
      As an immune checkpoint, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) suppresses the activation, proliferation, and effector function of T cells, thus preventing an overexuberant response and maintaining immune homeostasis. However, whether and how this immune checkpoint functions in early vertebrates remains unknown. In the current study, using a Nile tilapia (Oreochromis niloticus) model, we investigated the suppression of T cell response by CTLA-4 in bony fish. Tilapia CTLA-4 is constitutively expressed in lymphoid tissues, and its mRNA and protein expression in lymphocytes are upregulated following PHA stimulation or Edwardsiella piscicida infection. Blockade of CTLA-4 signaling enhanced T cell activation and proliferation but inhibited activation-induced T cell apoptosis, indicating that CTLA-4 negatively regulated T cell activation. In addition, blocking CTLA-4 signaling in vivo increased the differentiation potential and cytotoxicity of T cells, resulting in an enhanced T cell response during E. piscicida infection. Tilapia CTLA-4 competitively bound the B7.2/CD86 molecule with CD28, thus antagonizing the CD28-mediated costimulatory signal of T cell activation. Furthermore, inhibition of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling, c-Myc, or glycolysis markedly impaired the CTLA-4 blockade-enhanced T cell response, suggesting that CTLA-4 suppressed the T cell response of tilapia by inhibiting mTORC1/c-Myc axis-controlled glycolysis. Overall, the findings indicate a detailed mechanism by which CTLA-4 suppresses T cell immunity in tilapia; therefore, we propose that early vertebrates have evolved sophisticated mechanisms coupling immune checkpoints and metabolic reprogramming to avoid an overexuberant T cell response.
    DOI:  https://doi.org/10.4049/jimmunol.2300599
  69. Pharmacol Res. 2024 Feb 13. pii: S1043-6618(24)00041-0. [Epub ahead of print]201 107097
    CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer.
    Zimei Wu, Wenxin Zhang, Lu Chen, Tianxiao Wang, Xinhai Wang, Huanying Shi, Liudi Zhang, Mingkang Zhong, Xiaojin Shi, Xiang Mao, Haifei Chen, Qunyi Li.
      As the world's fourth most deadly cancer, colorectal cancer (CRC) still needed the novel therapeutic drugs and target urgently. Although cyclin-dependent kinase 12 (CDK12) has been shown to be implicated in the malignancy of several types of cancer, its functional role and mechanism in CRC remain largely unknown. Here, we found that suppression of CDK12 inhibited tumor growth in CRC by inducing apoptosis. And CDK12 inhibition triggered autophagy by upregulating autophagy related gene 7 (ATG7) expression. Inhibition of autophagy by ATG7 knockdown and chloroquine (CQ) further decreased cell viability induced by CDK12 inhibition. Further mechanism exploration showed that CDK12 interacted with protein kinase B (AKT) regulated autophagy via AKT/forkhead box O3 (AKT/FOXO3) pathway. FOXO3 transcriptionally upregulated ATG7 expression and autophagy when CDK12 inhibition in CRC. Level of CDK12 and p-FOXO3/FOXO3 ratio were correlated with survival in CRC patients. Moreover, CDK12 inhibition improved the efficacy of anti-programmed cell death 1(PD-1) therapy in CRC murine models by enhancing CD8 + T cells infiltration. Thus, our study founded that CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in CRC. We revealed the roles of CDK12/FOXO3/ATG7 in regulating CRC progression, suggesting potential biomarkers and therapeutic target for CRC.
    Keywords:  Autophagy related gene 7; Chloroquine (PubChem CID: 2719); Colorectal cancer; Cyclin-dependent kinase 12; Programmed cell death 1; SC79 (PubChem CID: 2810830); THZ531 (PubChem CID: 118025540)
    DOI:  https://doi.org/10.1016/j.phrs.2024.107097
  70. Biosens Bioelectron. 2024 Feb 09. pii: S0956-5663(24)00128-3. [Epub ahead of print]251 116123
    Rational design of mitochondria-targeted fluorescent biosensors for in vivo elucidation of the interaction between breast cancer metastasis and mitochondrial autophagy.
    Liangchao Yuan, Yuyao Cao, Qing Zhang, Jiancheng Pan, Changjian Wu, Yaxi Ye, Qingcai Jiao, Hai-Liang Zhu, Zhongchang Wang.
      Breast cancer lung metastases (BCLM) are a major cause of high mortality in patients. The shortage of therapeutic targets and rapid drug screening tools for BCLM is a major challenge at present. Mitochondrial autophagy, which involves the degradation of proteins associated with cancer cell aggressiveness, represents a possible therapeutic approach for the treatment of BCLM. Herein, four fluorescent biosensors with different alkyl chains were designed and synthesized to monitor mitochondrial autophagy. Among them, PMV-12 demonstrated the highest sensitivity to viscosity variance, the least impact on polarity, and the longest imaging time. The introduction of the C12-chain made PMV-12 anchored in the mitochondrial membrane without being disturbed by changes of the mitochondrial membrane potential (MMP), thereby achieving the long-term monitor in situ for mitochondrial autophagy. Mitochondria stained with PMV-12 induced swelling and viscosity increase after treating with apigenin, which indicated that apigenin is a potential mitochondrial autophagy inducer. Apigenin was subsequently verified to inhibit cancer cell invasion by 92%. Furthermore, PMV-12 could monitor the process of BCLM in vivo and evaluate the therapeutic effects of apigenin. This work provides a fluorescent tool for elucidating the role of mitochondrial autophagy in the BCLM process and for anti-metastatic drug development.
    Keywords:  Breast cancer metastasis; Fluorescence imaging; Long-term visualization; Mitochondrial autophagy
    DOI:  https://doi.org/10.1016/j.bios.2024.116123
  71. J Hazard Mater. 2024 Feb 04. pii: S0304-3894(24)00282-6. [Epub ahead of print]467 133703
    Mitochondrial derived vesicle-carrying protein MIGA2 promotes copper-induced autophagosomes-lysosomes fusion by regulating ATG14.
    Quanwei Li, Pan Guo, Shaofeng Wang, Yuanhong Feng, Hui Zhang, Wenlan Yu, Jianzhao Liao, Zhaoxin Tang.
      As an environmental pollution metal, copper (Cu) exposure-induced toxicity is closely related to mitochondrial damage. Mitochondrial-derived vesicles (MDVs) plays an essential role in mitochondrial quality control and cellular metabolism. However, the mechanism by which MDVs are involved in cellular metabolism under Cu exposure remains unclear. Here, the MDV-carrying protein MIGA2 was identified as a crucial molecule involved in the Cu-induced autophagosomes-lysosomes fusion. Furthermore, Cu exposure significantly promoted MDVs secretion, accompanied by a markedly increased MIGA2 expression in MDVs, as well as accelerated the autophagosomes-lysosomes fusion. However, small RNA interference of SNX9 (the MDVs secretion inductor) and MIGA2 blocked autophagic flux induced by Cu, leading to failure of autophagosomes degradation. Co-immunoprecipitation assay further demonstrated that ATG14 was a regulation target protein of MIGA2. Overexpression and knockdown of ATG14 significantly affected the autophagosomes-lysosomes fusion induced by Cu. Meanwhile, knockdown of ATG14 dramatically reversed the effect of MIGA2-overexpression in promoting autophagosomes-lysosomes fusion, while overexpression of ATG14 shows the opposite effect. These results demonstrated that MDVs-carrying MIGA2 protein promoted autophagosomes-lysosomes fusion induced by Cu. This study demonstrated that MDVs is involved in regulating organelles-to-organelles communication, providing a new insight into the toxicity mechanism of Cu exposure on hepatocytes.
    Keywords:  ATG14; Autophagosome-lysosome fusion; Copper; Hepatocytes; MIGA2; Mitochondria-derived vesicles
    DOI:  https://doi.org/10.1016/j.jhazmat.2024.133703
  72. Mol Neurobiol. 2024 Feb 16.
    Autophagy in Multiple Sclerosis: Phagocytosis and Autophagy of Oligodendrocyte Precursor Cells.
    Jia-Qi Wang, Qiang Li, Jia-Yi He, Fang Zhou, Zi-Hao Huang, Li-Bin Wang, Yuan Zhang, Xing Li.
      Multiple sclerosis (MS) is a leading cause of chronic neurological dysfunction in young to middle-aged adults, affecting approximately 2.5 million people worldwide. It is characterized by inflammation, multifocal demyelination, axonal loss, and white and gray matter gliosis. Autophagy is a highly conserved protein degradation pathway. Polymorphisms in autophagy-related genes have been implicated in a variety of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, psoriasis and MS. However, the significance of autophagy in MS remains to be elucidated. This paper aims to explore the potential role of autophagy-related genes in MS diseases by using bioinformatics combined with machine learning methods. Finally, we obtained 9 autophagy genes with the highest correlation with MS, and further changes in these autophagy genes were verified in the experimental autoimmune encephalomyelitis (EAE) model and oligodendrocyte precursor cells (OPCs) engulfed myelin debris (MD). Combined with bioinformatic analysis and experimental data, Becn1 showed obvious expression abnormalities suggesting that this gene has vital functions in autophagy and MD engulfed by OPCs. This work will be of great significance for the further exploration of autophagy-related genes in demyelinating diseases.
    Keywords:  Autophagy; Multiple sclerosis; Oligodendrocyte precursor cells; Myelin debris
    DOI:  https://doi.org/10.1007/s12035-024-03996-x
  73. Nat Neurosci. 2024 Feb 15.
    A neuron-glia lipid metabolic cycle couples daily sleep to mitochondrial homeostasis.
    Paula R Haynes, Elana S Pyfrom, Yongjun Li, Carly Stein, Vishnu Anand Cuddapah, Jack A Jacobs, Zhifeng Yue, Amita Sehgal.
      Sleep is thought to be restorative to brain energy homeostasis, but it is not clear how this is achieved. We show here that Drosophila glia exhibit a daily cycle of glial mitochondrial oxidation and lipid accumulation that is dependent on prior wake and requires the Drosophila APOE orthologs NLaz and GLaz, which mediate neuron-glia lipid transfer. In turn, a full night of sleep is required for glial lipid clearance, mitochondrial oxidative recovery and maximal neuronal mitophagy. Knockdown of neuronal NLaz causes oxidative stress to accumulate in neurons, and the neuronal mitochondrial integrity protein, Drp1, is required for daily glial lipid accumulation. These data suggest that neurons avoid accumulation of oxidative mitochondrial damage during wake by using mitophagy and passing damage to glia in the form of lipids. We propose that a mitochondrial lipid metabolic cycle between neurons and glia reflects a fundamental function of sleep relevant for brain energy homeostasis.
    DOI:  https://doi.org/10.1038/s41593-023-01568-1
  74. Sci Total Environ. 2024 Feb 10. pii: S0048-9697(24)01032-5. [Epub ahead of print]919 170893
    The role of lysosomes in airborne particulate matter-induced pulmonary toxicity.
    Bingxue Nie, Xin Liu, Chengying Lei, Xue Liang, Daoqiang Zhang, Jie Zhang.
      An investigation of the potential role of lysosomes in airborne particulate matter (APM) induced health risks is essential to fully comprehend the pathogenic mechanisms of respiratory diseases. It is commonly accepted that APM-induced lung injury is caused by oxidative stress, inflammatory responses, and DNA damage. In addition, there exists abundant evidence that changes in lysosomal function are essential for cellular adaptation to a variety of particulate stimuli. This review emphasizes that disruption of the lysosomal structure/function is a key step in the cellular metabolic imbalance induced by APMs. After being ingested by cells, most particles are localized within lysosomes. Thus, lysosomes become the primary locus where APMs accumulate, and here they undergo degradation and release toxic components. Recent studies have provided incontrovertible evidence that a wide variety of APMs interfere with the normal function of lysosomes. After being stimulated by APMs, lysosome rupture leads to a loss of lysosomal acidic conditions and the inactivation of proteolytic enzymes, promoting an inflammatory response by activating the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Moreover, APMs interfere with autophagosome production or block autophagic flux, resulting in autophagy dysfunction. Additionally, APMs disrupt the normal function of lysosomes in iron metabolism, leading to disruption on iron homeostasis. Therefore, understanding the impacts of APM exposure from the perspective of lysosomes will provide new insights into the detrimental consequences of air pollution.
    Keywords:  Airborne particulate matters; Disruption; Health risks; Lysosome; Pulmonary toxicity
    DOI:  https://doi.org/10.1016/j.scitotenv.2024.170893
  75. Int J Neuropsychopharmacol. 2024 Feb 14. pii: pyae010. [Epub ahead of print]
    PI3K-AKT/mTOR signalling in psychiatric disorders: a valuable target to stimulate or suppress?
    Yan Chen, Wei Guan, Mei-Lan Wang, Xiao-Yun Lin.
      Economic development and increased stress have considerably increased the prevalence of psychiatric disorders in recent years, which rank as one of the most prevalent diseases globally. Several factors, including chronic social stress, genetic inheritance, and autogenous diseases, lead to the development and progression of psychiatric disorders. Clinical treatments for psychiatric disorders include psychotherapy, chemotherapy, and electric shock therapy. Although various achievements have been made researching psychiatric disorders, the pathogenesis of these diseases has not been fully understood yet, and serious side effects and resistance to antipsychotics are major obstacles to treating patients with psychiatric disorders. Recent studies have shown that the mammalian target of rapamycin (mTOR) is a central signalling hub that functions in nerve growth, synapse formation, and plasticity. The PI3K-AKT/mTOR pathway is a critical target for mediating the rapid antidepressant effects of these pharmacological agents in clinical and preclinical research. Abnormal PI3K-AKT/mTOR signalling is closely associated with the pathogenesis of several neurodevelopmental disorders. In this review, we focused on the role of mTOR signalling and the related aberrant neurogenesis in psychiatric disorders. Elucidating the neurobiology of the PI3K-AKT/mTOR signalling pathway in psychiatric disorders and its actions in response to antidepressants will help us better understand brain development and quickly identify new therapeutic targets for the treatment of these mental illnesses.
    Keywords:  Depression; PI3K-AKT; Psychiatric disorders; Signalling pathway; Targets; mTOR
    DOI:  https://doi.org/10.1093/ijnp/pyae010
  76. Chem Biol Interact. 2024 Feb 13. pii: S0009-2797(24)00050-4. [Epub ahead of print] 110904
    Trifluoperazine activates AMPK / mTOR / ULK1 signaling pathway to induce mitophagy in osteosarcoma cells.
    Wenhui Shen, Xianhui Zeng, Xiangchen Zeng, Baoshan Hu, Chong Ren, Zhiming Lin, Long Zhang, Gang Rui, Miersalijiang Yasen, Xiaohui Chen.
      Osteosarcoma is a prevalent kind of primary bone malignancy. Trifluoperazine, as an antipsychotic drug, has anti-tumor activity against a variety of cancers. Nevertheless, the impact of trifluoperazine on osteosarcoma is unclear. Our investigation aimed to explore the mechanism of trifluoperazine's effect on osteosarcoma. We found that trifluoperazine inhibited 143B and U2-OS osteosarcoma cell proliferation in a method based on the dose. Furthermore, it was shown that trifluoperazine induced the accumulation of reactive oxygen species (ROS) to cause mitochondrial damage and induced mitophagy in osteosarcoma cells. Finally, combined with RNA-seq results, we first demonstrated the AMPK/mTOR/ULK1 signaling pathway as a potential mechanism of trifluoperazine-mediated mitophagy in osteosarcoma cells and can be suppressed by AMPK inhibitor Compound C.
    Keywords:  AMPK; Mitophagy; Osteosarcoma; Trifluoperazine; ULK1; mTOR
    DOI:  https://doi.org/10.1016/j.cbi.2024.110904
  77. Exp Cell Res. 2024 Feb 10. pii: S0014-4827(24)00065-X. [Epub ahead of print] 113974
    Increased extracellular matrix stiffness regulates myofibroblast transformation through induction of autophagy-mediated Kindlin-2 cytoplasmic translocation.
    Zhihan Zhao, Wuyue Han, Guotao Huang, Yong He, Xiaohu Zuo, Li Hong.
      The extracellular matrix (ECM) mechanical properties regulate biological processes, such as fibroblast-myofibroblast transformation (FMT), which is a crucial component in pelvic organ prolapse (POP) development. The 'Kindlin-2' protein, expressed by fibroblasts, plays an important role in the development of the mesoderm, which is responsible for connective tissue formation; however, the role of Kindlin-2 in FMT remains to be explored. In this study, we aimed to explore the role of Kindlin-2 in FMT as it relates to POP. We found that ECM stiffness induces autophagy to translocate Kindlin-2 to the cytoplasm of L929 cells, where it interacts with and degrades MOB1, thereby facilitating Yes-associated protein (YAP) entry into the nucleus and influencing FMT progression. Stiffness-induced autophagy was inhibited when using an autophagy inhibitor, which blocked the translocation of Kindlin-2 to the cytoplasm and partially reversed high-stiffness-induced FMT. In patients with POP, we observed an increase in cytoplasmic Kindlin-2 and nuclear YAP levels. Similar changes in vaginal wall-associated proteins were observed in a mouse model of acute vaginal injury. In conclusion, Kindlin-2 is a key gene affecting ECM stiffness, which regulates FMT by inducing autophagy and may influence the development of POP.
    Keywords:  Autophagy; Extracellular matrix; Kindlin-2; Myofibroblast; Pelvic organ prolapse
    DOI:  https://doi.org/10.1016/j.yexcr.2024.113974
  78. FEBS J. 2024 Feb 16.
    Fusion-fission-mitophagy cycling and metabolic reprogramming coordinate nerve growth factor (NGF)-dependent neuronal differentiation.
    Ilaria Goglia, Ewelina Węglarz-Tomczak, Claudio Gioia, Yanhua Liu, Assunta Virtuoso, Marcella Bonanomi, Daniela Gaglio, Noemi Salmistraro, Ciro De Luca, Michele Papa, Lilia Alberghina, Hans V Westerhoff, Anna Maria Colangelo.
      Neuronal differentiation is regulated by nerve growth factor (NGF) and other neurotrophins. We explored the impact of NGF on mitochondrial dynamics and metabolism through time-lapse imaging, metabolomics profiling, and computer modeling studies. We show that NGF may direct differentiation by stimulating fission, thereby causing selective mitochondrial network fragmentation and mitophagy, ultimately leading to increased mitochondrial quality and respiration. Then, we reconstructed the dynamic fusion-fission-mitophagy cycling of mitochondria in a computer model, integrating these processes into a single network mechanism. Both the computational model and the simulations are able to reproduce the proposed mechanism in terms of mitochondrial dynamics, levels of reactive oxygen species (ROS), mitophagy, and mitochondrial quality, thus providing a computational tool for the interpretation of the experimental data and for future studies aiming to detail further the action of NGF on mitochondrial processes. We also show that changes in these mitochondrial processes are intertwined with a metabolic function of NGF in differentiation: NGF directs a profound metabolic rearrangement involving glycolysis, TCA cycle, and the pentose phosphate pathway, altering the redox balance. This metabolic rewiring may ensure: (a) supply of both energy and building blocks for the anabolic processes needed for morphological reorganization, as well as (b) redox homeostasis.
    Keywords:  NGF differentiation; computational modeling; metabolism; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1111/febs.17083
  79. Biomed Pharmacother. 2024 Feb 12. pii: S0753-3322(24)00139-2. [Epub ahead of print]172 116258
    Roles and mechanisms of optineurin in bone metabolism.
    Junjie Jin, Ruiqi Huang, Yixing Chang, Xuejie Yi.
      Optineurin (OPTN) is a widely expressed multifunctional articulatory protein that participates in cellular or mitochondrial autophagy, vesicular transport, and endoplasmic reticulum (ER) stress via interactions with various proteins. Skeletal development is a complex biological process that requires the participation of various osteoblasts, such as bone marrow mesenchymal stem cells (BMSCs), and osteogenic, osteoclastic, and chondrogenic cells. OPTN was recently found to be involved in the regulation of osteoblast activity, which affects bone metabolism. OPTN inhibits osteoclastogenesis via signaling pathways, including NF-κB, IFN-β, and NRF2. OPTN can promote the differentiation of BMSCs toward osteogenesis and inhibit lipogenic differentiation by delaying BMSC senescence and autophagy. These effects are closely related to the development of bone metabolism disorders, such as Paget's disease of bone, rheumatoid arthritis, and osteoporosis. Therefore, this review aims to explore the role and mechanism of OPTN in the regulation of bone metabolism and related bone metabolic diseases. Our findings will provide new targets and strategies for the prevention and treatment of bone metabolic diseases.
    Keywords:  Bone formation; Bone metabolic disease; Bone resorption; Molecular mechanism; Optineurin
    DOI:  https://doi.org/10.1016/j.biopha.2024.116258
  80. Elife. 2024 Feb 15. pii: RP89854. [Epub ahead of print]12
    Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway.
    Artemis Koumoundourou, Märt Rannap, Elodie De Bruyckere, Sigrun Nestel, Carsten Reissner, Alexei V Egorov, Pengtao Liu, Markus Missler, Bernd Heimrich, Andreas Draguhn, Stefan Britsch.
      The transcription factor Bcl11b has been linked to neurodevelopmental and neuropsychiatric disorders associated with synaptic dysfunction. Bcl11b is highly expressed in dentate gyrus granule neurons and is required for the structural and functional integrity of mossy fiber-CA3 synapses. The underlying molecular mechanisms, however, remained unclear. We show in mice that the synaptic organizer molecule C1ql2 is a direct functional target of Bcl11b that regulates synaptic vesicle recruitment and long-term potentiation at mossy fiber-CA3 synapses in vivo and in vitro. Furthermore, we demonstrate C1ql2 to exert its functions through direct interaction with a specific splice variant of neurexin-3, Nrxn3(25b+). Interruption of C1ql2-Nrxn3(25b+) interaction by expression of a non-binding C1ql2 mutant or by deletion of Nrxn3 in the dentate gyrus granule neurons recapitulates major parts of the Bcl11b as well as C1ql2 mutant phenotype. Together, this study identifies a novel C1ql2-Nrxn3(25b+)-dependent signaling pathway through which Bcl11b controls mossy fiber-CA3 synapse function. Thus, our findings contribute to the mechanistic understanding of neurodevelopmental disorders accompanied by synaptic dysfunction.
    Keywords:  Bcl11b/Ctip2; C1ql2; Neurexin; mossy fiber-CA3 synapse; mouse; neurodevelopmental disorders; neuroscience; transcription factors
    DOI:  https://doi.org/10.7554/eLife.89854
  81. Cancer Cell Int. 2024 Feb 10. 24(1): 69
    AAA237, an SKP2 inhibitor, suppresses glioblastoma by inducing BNIP3-dependent autophagy through the mTOR pathway.
    Yizhi Zhang, Wan Li, Yihui Yang, Sen Zhang, Hong Yang, Yue Hao, Xu Fang, Guanhua Du, Jianyou Shi, Lianqiu Wu, Jinhua Wang.
      BACKGROUND: Glioblastoma (GBM) is the most common brain tumor with the worst prognosis. Temozolomide is the only first-line drug for GBM. Unfortunately, the resistance issue is a classic problem. Therefore, it is essential to develop new drugs to treat GBM. As an oncogene, Skp2 is involved in the pathogenesis of various cancers including GBM. In this study, we investigated the anticancer effect of AAA237 on human glioblastoma cells and its underlying mechanism.METHODS: CCK-8 assay was conducted to evaluate IC50 values of AAA237 at 48, and 72 h, respectively. The Cellular Thermal Shift Assay (CETSA) was employed to ascertain the status of Skp2 as an intrinsic target of AAA237 inside the cellular milieu. The EdU-DNA synthesis test, Soft-Agar assay and Matrigel assay were performed to check the suppressive effects of AAA237 on cell growth. To identify the migration and invasion ability of GBM cells, transwell assay was conducted. RT-qPCR and Western Blot were employed to verify the level of BNIP3. The mRFP-GFP-LC3 indicator system was utilized to assess alterations in autophagy flux and investigate the impact of AAA237 on the dynamic fusion process between autophagosomes and lysosomes. To investigate the effect of compound AAA237 on tumor growth in vivo, LN229 cells were injected into the brains of mice in an orthotopic model.
    RESULTS: AAA237 could inhibit the growth of GBM cells in vitro. AAA237 could bind to Skp2 and inhibit Skp2 expression and the degradation of p21 and p27. In a dose-dependent manner, AAA237 demonstrated the ability to inhibit colony formation, migration, and invasion of GBM cells. AAA237 treatment could upregulate BNIP3 as the hub gene and therefore induce BNIP3-dependent autophagy through the mTOR pathway whereas 3-MA can somewhat reverse this process. In vivo, the administration of AAA237 effectively suppressed the development of glioma tumors with no side effects.
    CONCLUSION: Compound AAA237, a novel Skp2 inhibitor, inhibited colony formation, migration and invasion of GBM cells in a dose-dependent manner and time-dependent manner through upregulating BNIP3 as the hub gene and induced BNIP3-dependent autophagy through the mTOR pathway therefore it might be a viable therapeutic drug for the management of GBM.
    Keywords:  AAA237; Autophagosome–lysosome fusion; BNIP3; Glioblastoma
    DOI:  https://doi.org/10.1186/s12935-023-03191-3
  82. J Cell Mol Med. 2024 Feb;28(4): e18120
    Still water run deep: Therapeutic TP effect of ucMSC-Ex via regulating mTOR to enhance autophagy.
    Zhirong Zhao, Li Han, Mei Xin, Lichen Zhou, Kexin Jiang, Qian Huang, Ruiwu Dai.
      Our previous study confirmed that umbilical cord mesenchymal stem cells-exosomes (ucMSC-Ex) inhibit apoptosis of pancreatic acinar cells to exert protective effects. However, the relationship between apoptosis and autophagy in traumatic pancreatitis (TP) has rarely been reported. We dissected the transcriptomics after pancreatic trauma and ucMSC-Ex therapy by high-throughput sequencing. Additionally, we used rapamycin and MHY1485 to regulate mTOR. HE, inflammatory factors and pancreatic enzymatic assays were used to comprehensively determine the local versus systemic injury level, fluorescence staining and electron microscopy were used to detect the effect of autophagy, and observe the expression levels of autophagy-related markers at the gene and protein levels. High-throughput sequencing identified that autophagy played a crucial role in the pathophysiological process of TP and ucMSC-Ex therapy. The results of electron microscopy, immunofluorescence staining, polymerase chain reaction and western blot suggested that therapeutic effect of ucMSC-Ex was mediated by activation of autophagy in pancreatic acinar cells through inhibition of mTOR. ucMSC-Ex can attenuate pancreas injury by inhibiting mTOR to regulate acinar cell autophagy after TP. Future studies will build on the comprehensive sequencing of RNA carried by ucMSC-Ex to predict and verify specific non-coding RNA.
    Keywords:  autophagy; exosomes; high-throughput sequencing; mTOR; pancreatitis; stem cells
    DOI:  https://doi.org/10.1111/jcmm.18120
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