bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024‒08‒18
fifty-nine papers selected by
Viktor Korolchuk, Newcastle University
  1. Autophagy in Skeletal Muscle.
  2. Optogenetic manipulation of lysosomal physiology and autophagic activity.
  3. mTORC1 phosphorylates and stabilizes LST2 to negatively regulate EGFR.
  4. Recycling the recyclers: lysophagy emerges as a new pharmacological target for retinal degeneration.
  5. Sulfur starvation-induced autophagy in Saccharomyces cerevisiae involves SAM-dependent signaling and transcription activator Met4.
  6. Conjugation of ATG8s to single membranes at a glance.
  7. Deficiency in the mitophagy mediator Parkin accelerates murine skin allograft rejection.
  8. P62-autophagic pathway degrades SLC7A11 to regulate ferroptosis in doxorubicin-induced cardiotoxicity.
  9. Role of canonical and noncanonical autophagy pathways in shaping the life journey of B cells.
  10. Dual perspective on autophagy in glioma: Detangling the dichotomous mechanisms of signaling pathways for therapeutic insights.
  11. Degradation of STIM1 through FAM134B-mediated ER-phagy is potentially involved in cell proliferation.
  12. Neurons Specialize in Presynaptic Autophagy: A Perspective to Ameliorate Neurodegeneration.
  13. PKD regulates mitophagy to prevent oxidative stress and mitochondrial dysfunction during mouse oocyte maturation.
  14. Involvement of Sirt1-FoxO3a-Bnip3 axis and autophagy mediated mitochondrial turnover in according protection to hyperglycemic NRK-52E cells by Berberine.
  15. Importance of Energy, Dietary Protein Sources, and Amino Acid Composition in the Regulation of Metabolism: An Indissoluble Dynamic Combination for Life.
  16. The Role of Endothelial Cell Mitophagy in Age-Related Cardiovascular Diseases.
  17. Application of Nanomaterials and Related Drug Delivery Systems in Autophagy.
  18. Ceramide Ehux-C22 Targets the miR-199a-3p/mTOR Signaling Pathway to Regulate Melanosomal Autophagy in Mouse B16 Cells.
  19. Site-specific photo-crosslinking of Hsc70 with the KFERQ pentapeptide motif in a chaperone-mediated autophagy and microautophagy substrate in mammalian cells.
  20. Autophagy accompanying the developmental process of male germline stem cells.
  21. Cleavage of SQSTM1/p62 by the zika virus protease NS2B3 prevents autophagic degradation of viral NS3 and NS5 proteins.
  22. Benzopyrene represses mitochondrial fission factors and PINK1/Parkin-mediated mitophagy in primary astrocytes.
  23. HDAC2 promotes autophagy-associated HCC malignant progression by transcriptionally activating LAPTM4B.
  24. Sigma-1 receptor recruits LC3 mRNA to ER-associated omegasomes to promote localized LC3 translation enabling functional autophagy.
  25. Benzaldehyde stimulates autophagy via the sonic hedgehog signaling pathway in mouse brain astrocytes after treatment with Angiostrongylus cantonensis excretory-secretory products.
  26. Generation and characterization of human-derived induced pluripotent stem cell line (IGIBi010-A) from a patient with neurodegenerative disease phenotype carrying mutation in SQSTM1/p62 gene.
  27. The role of alternative autophagy in cell viability and response to paclitaxel treatment in v-Ha-ras-transformed NIH 3T3 cells.
  28. Lysosomal iron accumulation and subsequent lysosomes-mitochondria iron transmission mediate PFOS-induced hepatocyte ferroptosis.
  29. GPR50 regulates neuronal development as a mitophagy receptor.
  30. Anticancer Activity of Delta-Tocotrienol in Human Hepatocarcinoma: Involvement of Autophagy Induction.
  31. A PIKfyve modulator combined with an integrated stress response inhibitor to treat lysosomal storage diseases.
  32. Inhibition of autophagy as a novel treatment for neurofibromatosis type 1 tumors.
  33. New insights into the mechanisms and therapeutic strategies of chondrocyte autophagy in osteoarthritis.
  34. JAK2 inhibitor protects the septic heart through enhancing mitophagy in cardiomyocytes.
  35. Bafilomycin 1A Affects p62/SQSTM1 Autophagy Marker Protein Level and Autophagosome Puncta Formation Oppositely under Various Inflammatory Conditions in Cultured Rat Microglial Cells.
  36. MANF facilitates breast cancer cell survival under glucose-starvation conditions via prkn-mediated mitophagy regulation.
  37. CDK4/6 Inhibitors Impede Chemoresistance and Inhibit Tumor Growth of Small Cell Lung Cancer.
  38. Fine-tuning AMPK in physiology and disease using point-mutant mouse models.
  39. Oleanonic acid ameliorates mutant Aβ precursor protein-induced oxidative stress, autophagy deficits, ferroptosis, mitochondrial damage, and ER stress in vitro.
  40. CARD14 SIGNALOSOME FORMATION IS ASSOCIATED WITH ITS ENDOSOMAL RELOCATION AND mTORC1-INDUCED KERATINOCYTE PROLIFERATION.
  41. Characterization of effects of mTOR inhibitors on aging in C. elegans.
  42. Unraveling the AKT/ERK cascade and its role in Parkinson disease.
  43. Calorie restriction and rapamycin distinctly mitigate aging-associated protein phosphorylation changes in mouse muscles.
  44. Inhibition of TFEB deacetylation in proximal tubular epithelial cells (TECs) promotes TFEB activation and alleviates TEC damage in diabetic kidney disease.
  45. Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners.
  46. Role of ATG4 Autophagy-Related Protein Family in the Lower Airways of Patients with Stable COPD.
  47. Decoding the decline: unveiling drivers of sarcopenia.
  48. Progranulin inhibits autophagy to facilitate intracellular colonization of Helicobacter pylori through the PGRN/mTOR/DCN axis in gastric epithelial cells.
  49. Dysregulation of mitochondria, apoptosis and mitophagy in Leber's hereditary optic neuropathy with MT-ND1 3635G>A mutation.
  50. Tetrahydrocurcumin ameliorates hepatic steatosis by restoring hepatocytes lipophagy through mTORC1-TFEB pathway in nonalcoholic steatohepatitis.
  51. The degradation of α--synuclein is limited by dynein to drive the AALP pathway through HDAC6 upon paraquat exposure.
  52. Emerging role of natural lipophagy modulators in metabolic dysfunction-associated steatotic liver disease.
  53. Inflammation, mitochondrial and lysosomal dysfunction as key players in rheumatoid arthritis?
  54. Mitochondrial Probe for Glutathione Depletion Reveals NME3 Essentiality for Mitochondrial Redox Response.
  55. Alteration of cGAS-STING signaling pathway components in the mouse cortex and hippocampus during healthy brain aging.
  56. Rapamycin increases murine lifespan but does not reduce mineral volume in the Matrix GLA Protein (MGP) knockout mouse model of medial arterial calcification.
  57. Ginsenoside Rg1 ameliorates cerebral ischemia-reperfusion injury by regulating Pink1/ Parkin-mediated mitochondrial autophagy and inhibiting microglia NLRP3 activation.
  58. ER-phagy drives age-onset remodeling of endoplasmic reticulum structure-function and lifespan.
  59. Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation.
  1. Cold Spring Harb Perspect Biol. 2024 Aug 12. pii: a041565. [Epub ahead of print]
    Autophagy in Skeletal Muscle.
    Anais Franco-Romero, Marco Sandri, Stefano Schiaffino.
      Skeletal muscle fibers possess, like all cells of our body, an evolutionary conserved autophagy machinery, which allows them to segregate unfolded proteins and damaged organelles within autophagosomes, and to induce fusion of autophagosomes with lysosomes, leading to degradation of those altered cell constituents. This process may be selective for specific cell components, as in the case of glycogen (glycophagy) or organelles, as with mitochondria (mitophagy). The autophagic flux is activated by fasting, and contributes with the proteasome to provide the organism with amino acids required for survival. Autophagy is also essential for the normal turnover of muscle proteins and organelles, as shown by the degenerative changes induced by genetic block of the autophagic mechanism, and in several myopathies. Autophagy is enhanced in muscle by exercise and impaired during aging, suggesting that aging-dependent muscle dysfunction could be delayed by boosting autophagy.
    DOI:  https://doi.org/10.1101/cshperspect.a041565
  2. Autophagy. 2024 Aug 15.
    Optogenetic manipulation of lysosomal physiology and autophagic activity.
    Wenping Zeng, Canjun Li, Lili Qu, Chunlei Cang.
      Lysosomes are essential degradative organelles and signaling hubs within cells, playing a crucial role in the regulation of macroautophagy/autophagy. Dysfunction of lysosomes and impaired autophagy are closely associated with the development of various neurodegenerative diseases. Enhancing lysosomal activity and boosting autophagy levels holds great promise as effective strategies for treating these diseases. However, there remains a lack of methods to dynamically regulate lysosomal activity and autophagy levels in living cells or animals. In our recent work, we applied optogenetics to manipulate lysosomal physiology and function, developing three lysosome-targeted optogenetic tools: lyso-NpHR3.0, lyso-ArchT, and lyso-ChR2. These new actuators enable light-dependent regulation of key aspects such as lysosomal membrane potential, lumenal pH, hydrolase activity, degradation processes, and Ca2+ dynamics in living cells. Notably, lyso-ChR2 activation induces autophagy via the MTOR pathway while it promotes Aβ clearance through autophagy induction in cellular models of Alzheimer disease. Furthermore, lyso-ChR2 activation reduces Aβ deposition and alleviates Aβ-induced paralysis in Caenorhabditis elegans models of Alzheimer disease. Our lysosomal optogenetic actuators offer a novel method for dynamically regulating lysosomal physiology and autophagic activity in living cells and animals.
    Keywords:  Alzheimer disease; MTOR; autophagy; lysosome; optogenetics
    DOI:  https://doi.org/10.1080/15548627.2024.2392464
  3. Proc Natl Acad Sci U S A. 2024 Aug 20. 121(34): e2405959121
    mTORC1 phosphorylates and stabilizes LST2 to negatively regulate EGFR.
    Stefania Battaglioni, Louise-Marie Craigie, Sofia Filippini, Timm Maier, Michael N Hall.
      TORC1 (target of rapamycin complex 1) is a highly conserved protein kinase that plays a central role in regulating cell growth. Given the role of mammalian TORC1 (mTORC1) in metabolism and disease, understanding mTORC1 downstream signaling and feedback loops is important. mTORC1 recognizes some of its substrates via a five amino acid binding sequence called the TOR signaling (TOS) motif. mTORC1 binding to a TOS motif facilitates phosphorylation of a distinct, distal site. Here, we show that LST2, also known as ZFYVE28, contains a TOS motif (amino acids 401 to 405) and is directly phosphorylated by mTORC1 at serine 670 (S670). mTORC1-mediated S670 phosphorylation promotes LST2 monoubiquitination on lysine 87 (K87). Monoubiquitinated LST2 is stable and displays a broad reticular distribution. When mTORC1 is inactive, unphosphorylated LST2 is degraded by the proteasome. The absence of LST2 enhances EGFR (epidermal growth factor receptor) signaling. We propose that mTORC1 negatively feeds back on its upstream receptor EGFR via LST2.
    Keywords:  LST2; TOS motif; mTOR signaling; negative feedback; phosphorylation substrate
    DOI:  https://doi.org/10.1073/pnas.2405959121
  4. Autophagy. 2024 Aug 12.
    Recycling the recyclers: lysophagy emerges as a new pharmacological target for retinal degeneration.
    Juan Ignacio Jiménez-Loygorri, Patricia Boya.
      Dysregulated macroautophagy/autophagy is one of the hallmarks of aging and has also been linked to higher incidence of several age-associated diseases such as age-related macular degeneration (AMD). The main cell type affected in AMD is the retinal pigment epithelium (RPE), and this disease can lead to central vision loss. Despite affecting around 8.7% of the population between 45-85 years, its etiopathogenesis remains unknown. In our recent manuscript using the pharmacological sodium iodate (SI) model of AMD we identified severe lysosomal membrane permeabilization (LMP) in the RPE, that leads to autophagy flux blockage and proteostasis defects. Treatment with the natural compound urolithin A (UA) reduces RPE cell death and alleviates vision loss, concurrent with full autophagy restoration. While UA was initially described as a specific mitophagy inducer, we now show that it is also able to promote SQSTM1/p62-dependent lysophagy in the context of lysosomal damage and LMP. Genetic downregulation of SQSTM1/p62 fully abolishes the effect of UA on lysophagy while mitophagy stimulation remains unaffected. In summary, these findings highlight the wide range of pathways modulated by UA and its potential implementation in the management of AMD and other diseases involving lysosomal damage.
    Keywords:  AMD; RPE; autophagy; lysosomal membrane permeabilization; lysosome
    DOI:  https://doi.org/10.1080/15548627.2024.2391726
  5. Nat Commun. 2024 Aug 13. 15(1): 6927
    Sulfur starvation-induced autophagy in Saccharomyces cerevisiae involves SAM-dependent signaling and transcription activator Met4.
    Magali Prigent, Hélène Jean-Jacques, Delphine Naquin, Stéphane Chédin, Marie-Hélène Cuif, Renaud Legouis, Laurent Kuras.
      Autophagy is a key lysosomal degradative mechanism allowing a prosurvival response to stresses, especially nutrient starvation. Here we investigate the mechanism of autophagy induction in response to sulfur starvation in Saccharomyces cerevisiae. We found that sulfur deprivation leads to rapid and widespread transcriptional induction of autophagy-related (ATG) genes in ways not seen under nitrogen starvation. This distinctive response depends mainly on the transcription activator of sulfur metabolism Met4. Consistently, Met4 is essential for autophagy under sulfur starvation. Depletion of either cysteine, methionine or SAM induces autophagy flux. However, only SAM depletion can trigger strong transcriptional induction of ATG genes and a fully functional autophagic response. Furthermore, combined inactivation of Met4 and Atg1 causes a dramatic decrease in cell survival under sulfur starvation, highlighting the interplay between sulfur metabolism and autophagy to maintain cell viability. Thus, we describe a pathway of sulfur starvation-induced autophagy depending on Met4 and involving SAM as signaling sulfur metabolite.
    DOI:  https://doi.org/10.1038/s41467-024-51309-6
  6. J Cell Sci. 2024 Aug 01. pii: jcs261031. [Epub ahead of print]137(15):
    Conjugation of ATG8s to single membranes at a glance.
    Carmen Figueras-Novoa, Lewis Timimi, Elena Marcassa, Rachel Ulferts, Rupert Beale.
      Autophagy refers to a set of degradative mechanisms whereby cytoplasmic contents are targeted to the lysosome. This is best described for macroautophagy, where a double-membrane compartment (autophagosome) is generated to engulf cytoplasmic contents. Autophagosomes are decorated with ubiquitin-like ATG8 molecules (ATG8s), which are recruited through covalent lipidation, catalysed by the E3-ligase-like ATG16L1 complex. LC3 proteins are ATG8 family members that are often used as a marker for autophagosomes. In contrast to canonical macroautophagy, conjugation of ATG8s to single membranes (CASM) describes a group of non-canonical autophagy processes in which ATG8s are targeted to pre-existing single-membrane compartments. CASM occurs in response to disrupted intracellular pH gradients, when the V-ATPase proton pump recruits ATG16L1 in a process called V-ATPase-ATG16L1-induced LC3 lipidation (VAIL). Recent work has demonstrated a parallel, alternative axis for CASM induction, triggered when the membrane recruitment factor TECPR1 recognises sphingomyelin exposed on the cytosolic face of a membrane and forms an alternative E3-ligase-like complex. This sphingomyelin-TECPR1-induced LC3 lipidation (STIL) is independent of the V-ATPase and ATG16L1. In light of these discoveries, this Cell Science at a Glance article summarises these two mechanisms of CASM to highlight how they differ from canonical macroautophagy, and from each other.
    Keywords:  ATG8ylation; Autophagy; CASM; STIL; TECPR1; V-ATPase; VAIL
    DOI:  https://doi.org/10.1242/jcs.261031
  7. Am J Transplant. 2024 Aug 12. pii: S1600-6135(24)00491-X. [Epub ahead of print]
    Deficiency in the mitophagy mediator Parkin accelerates murine skin allograft rejection.
    Kathleen M Wragg, Matthew J Worley, Jane C Deng, Morgan Salmon, Daniel R Goldstein.
      Alterations in mitochondrial function and associated quality control programs, including mitochondrial-specific autophagy, termed mitophagy, are gaining increasing recognition in the context of disease. However, the role of mitophagy in organ transplant rejection remains poorly understood. Using mice deficient in Parkin, a ubiquitin-ligase which tags damaged or dysfunctional mitochondria for autophagic clearance, we assessed the impact of Parkin-dependent mitophagy on skin-graft rejection. We observed accelerated graft loss in Parkin-deficient mice across multiple-skin graft models. Immune cell distributions post-transplantation were largely unperturbed compared to wild-type; however, the CD8+ T cells of Parkin-deficient mice expressed more T-bet, IFNγ and Ki67, indicating greater priming towards effector function. This was accompanied by increased circulating levels of IL-12p70 in Parkin-deficient mice. Using a mixed leukocyte reaction, we demonstrated that naïve Parkin-deficient CD4+ and CD8+ T cells exhibit enhanced activation marker expression and proliferative responses to alloantigen, which were attenuated with administration of a pharmacological mitophagy inducer (p62-mediated mitophagy inducer), known to increase mitophagy in the absence of a functional PINK1-Parkin pathway. These findings indicate a role for Parkin-dependent mitophagy in curtailing skin-graft rejection.
    DOI:  https://doi.org/10.1016/j.ajt.2024.08.005
  8. Life Sci. 2024 Aug 13. pii: S0024-3205(24)00571-X. [Epub ahead of print] 122981
    P62-autophagic pathway degrades SLC7A11 to regulate ferroptosis in doxorubicin-induced cardiotoxicity.
    Jihong Wang, Hong Yi, Juxiang Li, Yuting Yang, Guofang Sun, Yumei Xue, Ling He.
      Doxorubicin-induced cardiotoxicity (DIC) poses a significant challenge, impeding its widespread application. Emerging evidence suggests the involvement of ferroptosis in the DIC. While the downregulation of SLC7A11 expression has been linked to the promotion of ferroptosis, the precise regulatory mechanism remains unclear. Recent studies, including our own, have highlighted abnormal levels of autophagy adapter protein P62 and autophagy in DIC development. Thus, our study aimed to further investigate the role of autophagy and ferroptosis in DIC, elucidating underlying molecular mechanisms across molecular, cellular, and whole-organ levels utilizing gene knockdown, immunoprecipitation, and mass spectrometry techniques. The results of our findings unveiled cardiomyocyte damage, heightened autophagy levels, and ferroptosis in DOX-treated mouse hearts. Notably, inhibition of autophagy levels attenuated DOX-induced ferroptosis. Mechanistically, we discovered that the autophagy adaptor protein P62 mediates the entry of SLC7A11 into the autophagic pathway for degradation. Furthermore, the addition of autophagy inhibitors (CQ or BAF) could elevate SLC7A11 and GPX4 protein expression, reduce the accumulation of Fe2+ and ROS in cardiomyocytes, and thus mitigate DOX-induced ferroptosis. In summary, our findings underscore the pivotal role of the P62-autophagy pathway in SLC7A11 degradation, modulating ferroptosis to exacerbate DIC. This finding offers significant insights into the underlying molecular mechanisms of DOX-induced ferroptosis and identifies new targets for reversing DIC.
    Keywords:  Autophagy; Ferroptosis; P62; SLC7A11
    DOI:  https://doi.org/10.1016/j.lfs.2024.122981
  9. Front Immunol. 2024 ;15 1426204
    Role of canonical and noncanonical autophagy pathways in shaping the life journey of B cells.
    Yiwen Wang, Lan Wu, Luc Van Kaer.
      Autophagy is a regulated intracellular catabolic process by which invading pathogens, damaged organelles, aggregated proteins, and other macromolecules are degraded in lysosomes. It has been widely appreciated that autophagic activity plays an important role in regulating the development, fate determination, and function of cells in the immune system, including B lymphocytes. Autophagy encompasses several distinct pathways that have been linked to B cell homeostasis and function. While B cell presentation of major histocompatibility complex (MHC) class II-restricted cytosolic antigens to T cells involves both macroautophagy and chaperone-mediated autophagy (CMA), plasma cells and memory B cells mainly rely on macroautophagy for their survival. Emerging evidence indicates that core autophagy factors also participate in processes related to yet clearly distinct from classical autophagy. These autophagy-related pathways, referred to as noncanonical autophagy or conjugation of ATG8 to single membranes (CASM), contribute to B cell homeostasis and functions, including MHC class II-restricted antigen presentation to T cells, germinal center formation, plasma cell differentiation, and recall responses. Dysregulation of B cell autophagy has been identified in several autoimmune and autoinflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. In this review, we discuss recent advances in understanding the role of canonical and noncanonical autophagy in B cells, including B cell development and maturation, antigen processing and presentation, pathogen-specific antibody responses, cytokine secretion, and autoimmunity. Unraveling the molecular mechanisms of canonical and noncanonical autophagy in B cells will improve our understanding of B cell biology, with implications for the development of autophagy-based immunotherapies.
    Keywords:  B cell biology; B lymphocytes; antibodies; autophagy; canonical autophagy; humoral immunity; noncanonical autophagy
    DOI:  https://doi.org/10.3389/fimmu.2024.1426204
  10. Biochim Biophys Acta Rev Cancer. 2024 Aug 08. pii: S0304-419X(24)00099-4. [Epub ahead of print]1879(5): 189168
    Dual perspective on autophagy in glioma: Detangling the dichotomous mechanisms of signaling pathways for therapeutic insights.
    Moumita Kundu, Subhayan Das, Ankita Dey, Mahitosh Mandal.
      Autophagy is a normal physiological process that aids the recycling of cellular nutrients, assisting the cells to cope with stressed conditions. However, autophagy's effect on cancer, including glioma, is uncertain and involves complicated molecular mechanisms. Several contradictory reports indicate that autophagy may promote or suppress glioma growth and progression. Autophagy inhibitors potentiate the efficacy of chemotherapy or radiation therapy in glioma. Numerous compounds stimulate autophagy to cause glioma cell death. Autophagy is also involved in the therapeutic resistance of glioma. This review article aims to detangle the complicated molecular mechanism of autophagy to provide a better perception of the two-sided role of autophagy in glioma and its therapeutic implications. The protein and epigenetic modulators of the cytoprotective and cytotoxic role of autophagy are described in this article. Moreover, several signaling pathways are associated with autophagy and its effects on glioma. We have reviewed the molecular pathways and highlighted the signaling axis involved in cytoprotective and cytotoxic autophagy. Additionally, this article discusses the role of autophagy in therapeutic resistance, including glioma stem cell maintenance and tumor microenvironment regulation. It also summarizes several investigations on the anti-glioma effects of autophagy modulators to understand the associated mechanisms and provide insights regarding its therapeutic implications.
    Keywords:  Autophagy; Cytoprotective; Cytotoxic; Glioma; Resistance
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189168
  11. J Biol Chem. 2024 Aug 09. pii: S0021-9258(24)02175-6. [Epub ahead of print] 107674
    Degradation of STIM1 through FAM134B-mediated ER-phagy is potentially involved in cell proliferation.
    Hiroaki Kajiho, Toshiaki Sakisaka.
      Autophagy is classified as non-selective or selective depending on the types of degrading substrates. Endoplasmic reticulum (ER)-phagy is a form of selective autophagy for transporting the ER-resident proteins to autolysosomes. FAM134B, a member of the family with sequence similarity 134, is a well-known ER-phagy receptor. Dysfunction of FAM134B results in several diseases including viral infection, inflammation, neurodegenerative disorder and cancer, indicating that FAM134B has crucial roles in various kinds of intracellular functions. However, how FAM134B-mediated ER-phagy regulates intracellular functions is not well understood. In this study, we found that FAM134B knockdown in mammalian cells accelerated cell proliferation. FAM134B knockdown increased the protein amount of STIM1, an ER Ca2+ sensor protein mediating the store-operated Ca2+ entry (SOCE) involved in G1 to S phase transition. FAM134B bound to STIM1 through its C-terminal cytosolic region. FAM134B knockdown reduced transport of STIM1 from the ER to autolysosomes. Finally, FAM134B knockdown accelerated G1 to S phase transition. These results suggest that FAM134B is involved in cell proliferation possibly through degradation of STIM1 via ER-phagy.
    Keywords:  ER-phagy; FAM134B; STIM1; autophagy; cell cycle; cell proliferation; endoplasmic reticulum (ER); protein degradation
    DOI:  https://doi.org/10.1016/j.jbc.2024.107674
  12. Mol Neurobiol. 2024 Aug 14.
    Neurons Specialize in Presynaptic Autophagy: A Perspective to Ameliorate Neurodegeneration.
    Abhishek Kumar Mishra, Manish Kumar Tripathi, Dipak Kumar, Satya Prakash Gupta.
      The efficient and prolonged neurotransmission is reliant on the coordinated action of numerous synaptic proteins in the presynaptic compartment that remodels synaptic vesicles for neurotransmitter packaging and facilitates their exocytosis. Once a cycle of neurotransmission is completed, membranes and associated proteins are endocytosed into the cytoplasm for recycling or degradation. Both exocytosis and endocytosis are closely regulated in a timely and spatially constrained manner. Recent research demonstrated the impact of dysfunctional synaptic vesicle retrieval in causing retrograde degeneration of midbrain neurons and has highlighted the importance of such endocytic proteins, including auxilin, synaptojanin1 (SJ1), and endophilin A (EndoA) in neurodegenerative diseases. Additionally, the role of other associated proteins, including leucine-rich repeat kinase 2 (LRRK2), adaptor proteins, and retromer proteins, is being investigated for their roles in regulating synaptic vesicle recycling. Research suggests that the degradation of defective vesicles via presynaptic autophagy, followed by their recycling, not only revitalizes them in the active zone but also contributes to strengthening synaptic plasticity. The presynaptic autophagy rejuvenating terminals and maintaining neuroplasticity is unique in autophagosome formation. It involves several synaptic proteins to support autophagosome construction in tiny compartments and their retrograde trafficking toward the cell bodies. Despite having a comprehensive understanding of ATG proteins in autophagy, we still lack a framework to explain how autophagy is triggered and potentiated in compact presynaptic compartments. Here, we reviewed synaptic proteins' involvement in forming presynaptic autophagosomes and in retrograde trafficking of terminal cargos. The review also discusses the status of endocytic proteins and endocytosis-regulating proteins in neurodegenerative diseases and strategies to combat neurodegeneration.
    Keywords:  Autophagy; Endocytic proteins; Neurodegenerative diseases; Presynaptic autophagy; Synaptic dysfunction; Synaptic proteins
    DOI:  https://doi.org/10.1007/s12035-024-04399-8
  13. Mitochondrion. 2024 Aug 13. pii: S1567-7249(24)00104-1. [Epub ahead of print] 101946
    PKD regulates mitophagy to prevent oxidative stress and mitochondrial dysfunction during mouse oocyte maturation.
    Ya-Ping Liu, Bing He, Wen-Xin Wang, Wen-Lin Pan, Le Jiao, Jing-Jing Yan, Shao-Chen Sun, Yu Zhang.
      Mitochondria play dominant roles in various cellular processes such as energy production, apoptosis, calcium homeostasis, and oxidation-reduction balance. Maintaining mitochondrial quality through mitophagy is essential, especially as its impairment leads to the accumulation of dysfunctional mitochondria in aging oocytes. Our previous research revealed that PKD expression decreases in aging oocytes, and its inhibition negatively impacts oocyte quality. Given PKD's role in autophagy mechanisms, this study investigates whether PKD regulates mitophagy to maintain mitochondrial function and support oocyte maturation. When fully grown oocytes were treated with CID755673, a potent PKD inhibitor, we observed meiosis arrest at the metaphase I stage, along with decreased spindle stability. Our results demonstrate an association with mitochondrial dysfunction, including reduced ATP production and fluctuations in Ca2+ homeostasis, which ultimately lead to increased ROS accumulation, stimulating oxidative stress-induced apoptosis and DNA damage. Further research has revealed that these phenomena result from PKD inhibition, which affects the phosphorylation of ULK, thereby reducing autophagy levels. Additionally, PKD inhibition leads to decreased Parkin expression, which directly and negatively affects mitophagy. These defects result in the accumulation of damaged mitochondria in oocytes, which is the primary cause of mitochondrial dysfunction. Taken together, these findings suggest that PKD regulates mitophagy to support mitochondrial function and mouse oocyte maturation, offering insights into potential targets for improving oocyte quality and addressing mitochondrial-related diseases in aging females.
    Keywords:  Mitochondria; Mitophagy; Oocyte maturation; PKD; Parkin; ULK
    DOI:  https://doi.org/10.1016/j.mito.2024.101946
  14. Toxicol In Vitro. 2024 Aug 08. pii: S0887-2333(24)00146-2. [Epub ahead of print] 105916
    Involvement of Sirt1-FoxO3a-Bnip3 axis and autophagy mediated mitochondrial turnover in according protection to hyperglycemic NRK-52E cells by Berberine.
    Sugandh Saxena, Sumit Kumar Anand, Ankita Sharma, Poonam Kakkar.
      Aberrant accumulation of dysfunctional mitochondria in renal cells during hyperglycemia signifies perturbed autophagy and mitochondrial turnover. This study aims to focus on the underlying mechanism involved in autophagy and mitophagy inducing efficacy of Berberine (isoquinoline alkaloid) in hyperglycemic NRK-52E cells. Berberine mediated protection to hyperglycemic cells prevented alteration in mitochondrial structure and function. Treatment with SRT-1720 (Sirt1 activator) enhanced autophagy, decreased apoptosis, upregulated expression of downstream moieties (FoxO3a and Bnip3) and ameliorated mitochondria related anomalies while nicotinamide (Sirt1 inhibitor) treatment exhibited reversal of the same. GFP reporter assay ascertained enhanced transcriptional activity of FoxO in Berberine treated hyperglycemic cells, which was found to be correlated to increased expression of downstream protein Bnip3. Knocking down FoxO3a disrupted autophagy and stimulated apoptosis. N-acetyl-L-cysteine pre-treatment confirmed that generation of ROS intervened high glucose induced toxicity in NRK-52E cells. Berberine co-treatment resulted in differential expressions of key proteins involved in autophagy and mitophagy like LC3B, ATGs, Beclin1, Sirt1, Bnip3, FoxO3a and Parkin. Further, enhanced mitophagy in Berberine treated cells was confirmed by transmission electron microscopy. Thus, our findings give evidence that the protection accorded by Berberine against hyperglycemia in renal proximal tubular cells (NRK-52E) involves instigation of Sirt1-FoxO3a-Bnip3 axis and autophagy mediated mitophagy induction.
    Keywords:  Autophagy; Berberine; Diabetic nephropathy; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.tiv.2024.105916
  15. Nutrients. 2024 Jul 25. pii: 2417. [Epub ahead of print]16(15):
    Importance of Energy, Dietary Protein Sources, and Amino Acid Composition in the Regulation of Metabolism: An Indissoluble Dynamic Combination for Life.
    Giovanni Corsetti, Evasio Pasini, Tiziano M Scarabelli, Claudia Romano, Arashpreet Singh, Carol C Scarabelli, Francesco S Dioguardi.
      PURPOSE: This paper aims to present a unique perspective that emphasizes the intricate interplay between energy, dietary proteins, and amino acid composition, underscoring their mutual dependence for health-related considerations. Energy and protein synthesis are fundamental to biological processes, crucial for the sustenance of life and the growth of organisms.METHODS AND RESULTS: We explore the intricate relationship between energy metabolism, protein synthesis, regulatory mechanisms, protein sources, amino acid availability, and autophagy in order to elucidate how these elements collectively maintain cellular homeostasis. We underscore the vital role this dynamic interplay has in preserving cell life.
    CONCLUSIONS: A deeper understanding of the link between energy and protein synthesis is essential to comprehend fundamental cellular processes. This insight could have a wide-ranging impact in several medical fields, such as nutrition, metabolism, and disease management.
    Keywords:  AMPK; amino acids; autophagy; energy; entropy; mTOR; protein synthesis
    DOI:  https://doi.org/10.3390/nu16152417
  16. Aging Dis. 2024 Jul 29.
    The Role of Endothelial Cell Mitophagy in Age-Related Cardiovascular Diseases.
    Quancheng Han, Yiding Yu, Xiujuan Liu, Yonghong Guo, Jingle Shi, Yitao Xue, Yan Li.
      Aging is a major risk factor for cardiovascular diseases (CVD), and mitochondrial autophagy impairment is considered a significant physiological change associated with aging. Endothelial cells play a crucial role in maintaining vascular homeostasis and function, participating in various physiological processes such as regulating vascular tone, coagulation, angiogenesis, and inflammatory responses. As aging progresses, mitochondrial autophagy impairment in endothelial cells worsens, leading to the development of numerous cardiovascular diseases. Therefore, regulating mitochondrial autophagy in endothelial cells is vital for preventing and treating age-related cardiovascular diseases. However, there is currently a lack of systematic reviews in this area. To address this gap, we have written this review to provide new research and therapeutic strategies for managing aging and age-related cardiovascular diseases.
    DOI:  https://doi.org/10.14336/AD.2024.0788
  17. Molecules. 2024 Jul 26. pii: 3513. [Epub ahead of print]29(15):
    Application of Nanomaterials and Related Drug Delivery Systems in Autophagy.
    Ling Mei, Kai Liao, Haiyan Chen, Yifan Zhang, Zihan Zhang, Qiangwei Li, Man Li.
      Autophagy, a lysosomal self-degradation pathway, plays a critical role in cellular homeostasis by degrading endogenous damaged organelles and protein aggregates into recyclable biological molecules. Additionally, it detoxifies extracellular toxic substances, including drugs and toxic materials, thereby preserving the stability of the intracellular environment. The swift progression of nanotechnology has led to an increased focus on understanding the relationship between nanomaterials and autophagy. The effects of various nanomaterials and nano drug delivery systems on autophagy and their biological functions have been preliminarily assessed, revealing that modulation of intracellular autophagy levels by these agents represents a novel cellular response mechanism. Notably, autophagy regulation based on nanomaterials or nano drug delivery systems for a range of diseases is currently the subject of extensive research. Given the close association between autophagy levels and tumors, the regulation of autophagy has emerged as a highly active area of research in the development of innovative tumor therapies. This review synthesizes the current understanding of the application of nanomaterials or nano drug delivery systems on autophagy and their potential biological functions, suggesting a new avenue for nanomaterial-based autophagy regulation.
    Keywords:  autophagy; drug delivery; nanomaterials; nanoparticle; tumor targeted
    DOI:  https://doi.org/10.3390/molecules29153513
  18. Int J Mol Sci. 2024 Jul 24. pii: 8061. [Epub ahead of print]25(15):
    Ceramide Ehux-C22 Targets the miR-199a-3p/mTOR Signaling Pathway to Regulate Melanosomal Autophagy in Mouse B16 Cells.
    Jiyue Wan, Shumiao Zhang, Guiling Li, Shiying Huang, Jian Li, Zhengxiao Zhang, Jingwen Liu.
      Melanosomes are specialized membrane-bound organelles where melanin is synthesized and stored. The levels of melanin can be effectively reduced by inhibiting melanin synthesis or promoting melanosome degradation via autophagy. Ceramide, a key component in the metabolism of sphingolipids, is crucial for preserving the skin barrier, keeping it hydrated, and warding off the signs of aging. Our preliminary study indicated that a long-chain C22-ceramide compound (Ehux-C22) isolated from the marine microalga Emiliania huxleyi, reduced melanin levels via melanosomal autophagy in B16 cells. Recently, microRNAs (miRNAs) were shown to act as melanogenesis-regulating molecules in melanocytes. However, whether the ceramide Ehux-C22 can induce melanosome autophagy at the post-transcriptional level, and which potential autophagy-dependent mechanisms are involved, remains unknown. Here, miR-199a-3p was screened and identified as a novel upregulated miRNA in Ehux-C22-treated B16 cells. An in vitro high melanin expression model in cultured mouse melanoma cells (B16 cells) was established by using 0.2 μM alpha-melanocyte-stimulating hormone(α-MSH) and used for subsequent analyses. miR-199a-3p overexpression significantly enhanced melanin degradation, as indicated by a reduction in the melanin level and an increase in melanosome autophagy. Further investigation demonstrated that in B16 cells, Ehux-C22 activated miR-199a-3p and inhibited mammalian target of rapamycin(mTOR) level, thus activating the mTOR-ULK1 signaling pathway by promoting the expression of unc-51-like autophagy activating kinase 1 (ULK1), B-cell lymphoma-2 (Bcl-2), Beclin-1, autophagy-related gene 5 (ATG5), and microtubule-associated protein light chain 3 (LC3-II) and degrading p62. Therefore, the roles of Ehux-C22-regulated miR-199a-3p and the mTOR pathway in melanosomal autophagy were elucidated. This research may provide novel perspectives on the post-translational regulation of melanin metabolism, which involves the coordinated control of melanosomes.
    Keywords:  Ehux-C22; mTOR-ULK1 signaling pathway; melanosomal autophagy; miR-199a-3p; mouse B16 melanoma cells
    DOI:  https://doi.org/10.3390/ijms25158061
  19. Biochem Biophys Res Commun. 2024 Aug 08. pii: S0006-291X(24)01051-9. [Epub ahead of print]736 150515
    Site-specific photo-crosslinking of Hsc70 with the KFERQ pentapeptide motif in a chaperone-mediated autophagy and microautophagy substrate in mammalian cells.
    Tatsuro Seike, Kazue Terasawa, Takanori Iwata, Jun-Lin Guan, Tetsuro Watabe, Shigeyuki Yokoyama, Miki Hara-Yokoyama.
      Heat shock cognate protein 70 (Hsc70/HSPA8) belongs to the Hsp70 family of molecular chaperones. The fundamental functions of Hsp70 family molecular chaperones depend on ATP-dependent allosteric regulation of binding and release of hydrophobic polypeptide substrates. Hsc70 is also involved in various other cellular functions including selective pathways of protein degradation: chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI), in which Hsc70 recruits substrate proteins containing a KFERQ-like pentapeptide motif from the cytosol to lysosomes and late endosomes, respectively. However, whether the interaction between Hsc70 and the pentapeptide motif is direct or mediated by other molecules has remained unknown. In the present study, we introduced a photo-crosslinker near the KFERQ motif in a CMA/eMI model substrate and successfully detected its crosslinking with Hsc70, revealing the direct interaction between Hsc70 and the KFERQ motif for the first time. In addition, we demonstrated that the loss of the Hsc70 ATPase activity by the D10 N mutation appreciably reduced the crosslinking efficiency. Our present results suggested that the ATP allostery of Hsc70 is involved in the direct interaction of Hsc70 with the KFERQ-like pentapeptide.
    Keywords:  Chaperone; Chaperone-mediated autophagy; Hsc70; Microautophagy; Site-specific photo-crosslinking; The KFERQ motif
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150515
  20. Cell Tissue Res. 2024 Aug 14.
    Autophagy accompanying the developmental process of male germline stem cells.
    Zhuofei Jiang, Liji Chen, Tao Wang, Jie Zhao, Shuxian Liu, Yating He, Liyun Wang, Hongfu Wu.
      Germline stem cells are a crucial type of stem cell that can stably pass on genetic information to the next generation, providing the necessary foundation for the reproduction and survival of organisms. Male mammalian germline stem cells are unique cell types that include primordial germ cells and spermatogonial stem cells. They can differentiate into germ cells, such as sperm and eggs, thereby facilitating offspring reproduction. In addition, they continuously generate stem cells through self-renewal mechanisms to support the normal function of the reproductive system. Autophagy involves the use of lysosomes to degrade proteins and organelles that are regulated by relevant genes. This process plays an important role in maintaining the homeostasis of germline stem cells and the synthesis, degradation, and recycling of germline stem cell products. Recently, the developmental regulatory mechanism of germline stem cells has been further elucidated, and autophagy has been shown to be involved in the regulation of self-renewal and differentiation of germline stem cells. In this review, we introduce autophagy accompanying the development of germline stem cells, focusing on the autophagy process accompanying the development of male spermatogonial stem cells and the roles of related genes and proteins. We also briefly outline the effects of autophagy dysfunction on germline stem cells and reproduction.
    Keywords:  Autophagy; Differentiation; Germline stem cells; Self-renewal; Spermatogonial stem cells
    DOI:  https://doi.org/10.1007/s00441-024-03910-w
  21. Autophagy. 2024 Aug 11.
    Cleavage of SQSTM1/p62 by the zika virus protease NS2B3 prevents autophagic degradation of viral NS3 and NS5 proteins.
    Peng Zhou, Qingxiang Zhang, Yueshan Yang, Wanrong Wu, Dong Chen, Zhenhua Zheng, Anan Jongkaewwattana, Hui Jin, Hongbo Zhou, Rui Luo.
      Macroautophagy/autophagy plays a crucial role in inhibiting viral replication and regulating the host's immune response. The autophagy receptor SQSTM1/p62 (sequestosome 1) restricts viral replication by directing specific viral proteins to phagophores for degradation. In this study, we investigate the reciprocal relationship between Zika virus (ZIKV) and selective autophagy mediated by SQSTM1/p62. We show that NS2B3 protease encoded by ZIKV cleaves human SQSTM1/p62 at arginine 265 (R265). This cleavage also occurs with endogenous SQSTM1 in ZIKV-infected cells. Furthermore, overexpression of SQSTM1 inhibits ZIKV replication in A549 cells, while its absence increases viral titer. We have also shown that SQSTM1 impedes ZIKV replication by interacting with NS3 and NS5 and directing them to autophagic degradation, and that NS2B3-mediated cleavage could potentially alter this antiviral function of SQSTM1. Taken together, our study highlights the role of SQSTM1-mediated selective autophagy in the host's antiviral defense against ZIKV and uncovers potential viral evasion strategies that exploit the host's autophagic machinery to ensure successful infection.
    Keywords:  Cleavage; NS2B3 protease; SQSTM1; Zika virus; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2390810
  22. Toxicology. 2024 Aug 13. pii: S0300-483X(24)00207-5. [Epub ahead of print] 153926
    Benzopyrene represses mitochondrial fission factors and PINK1/Parkin-mediated mitophagy in primary astrocytes.
    Yunn Me Me Paing, Yunkyung Eom, Sung Hoon Lee.
      Mitochondria are essential for various physiological functions in astrocytes in the brain, such as maintaining ion and pH homeostasis, regulating neurotransmission, and modulating neuroinflammation. Mitophagy, a form of autophagy specific to mitochondria, is essential for ensuring mitochondrial quality and function. Benzo[a]pyrene (BaP) accumulates in the brain, and exposure to it is recognized as an environmental risk factor for neurodegenerative diseases. However, while the toxic mechanisms of BaP have been investigated in neurons, their effects on astrocytes-the most prevalent glial cells in the brain-are not clearly understood. Therefore, this study aims to investigate the toxic effects of exposure to BaP on mitochondria in primary astrocytes. Fluorescent probes and genetically encoded indicators were utilized to visualize mitochondrial morphology and physiology, and regulatory factors involved in mitochondrial morphology and mitophagy were assessed. Additionally, the mitochondrial respiration rate was measured in BaP-exposed astrocytes. BaP exposure resulted in mitochondrial enlargement owing to the suppression of mitochondrial fission factors. Furthermore, BaP-exposed astrocytes demonstrated reduced mitophagy and exhibited aberrant mitochondrial function and physiology, such as altered mitochondrial respiration rates, increased mitochondrial superoxide, disrupted mitochondrial membrane potential, and dysregulated mitochondrial Ca2+. These findings offer insights into the underlying toxic mechanisms of BaP exposure in neurodegenerative diseases by inducing aberrant mitophagy and mitochondrial dysfunction in astrocytes.
    Keywords:  astrocytes; benzo[a]pyrene; fission factor; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.tox.2024.153926
  23. Cell Death Dis. 2024 Aug 15. 15(8): 593
    HDAC2 promotes autophagy-associated HCC malignant progression by transcriptionally activating LAPTM4B.
    Meifeng Wang, Jianping Liao, Jie Wang, Meifang Xu, Ye Cheng, Lixin Wei, Aimin Huang.
      Hepatocellular carcinoma (HCC) is a significant global health challenge. The activation of autophagy plays an essential role in promoting the proliferation and survival of cancer cells. However, the upstream regulatory network and mechanisms governing autophagy in HCC remain unclear. This study demonstrated that histone deacetylase 2 (HDAC2) regulates autophagy in HCC. Its expression was elevated in HCC tissues, and high HDAC2 expression was strongly associated with poor prognosis in individuals with HCC. Integrated in vitro and in vivo investigations confirmed that HDAC2 promotes autophagy and autophagy-related malignant progression in HCC. Mechanistically, HDAC2 bound specifically to the lysosome-associated protein transmembrane 4-β (LAPTM4B) promoter at four distinct binding sites, enhancing its transcriptional activation and driving autophagy-related malignant progression in HCC. These findings establish LAPTM4B as a direct target gene of HDAC2. Furthermore, the selective inhibitor of HDAC2 effectively alleviated the malignant development of HCC. In addition, multivariate Cox regression analysis of 105 human HCC samples revealed that HDAC2 expression is an independent predictor of HCC prognosis. This study underscores the crucial role of the HDAC2-LAPTM4B axis in regulating autophagy in the malignant evolution of HCC and highlights the potential of targeting HDAC2 to prevent and halt the malignant progression of HCC.
    DOI:  https://doi.org/10.1038/s41419-024-06981-3
  24. Cell Rep. 2024 Aug 10. pii: S2211-1247(24)00969-0. [Epub ahead of print]43(8): 114619
    Sigma-1 receptor recruits LC3 mRNA to ER-associated omegasomes to promote localized LC3 translation enabling functional autophagy.
    Jeffrey Knupp, Yu-Jie Chen, Emily Wang, Peter Arvan, Billy Tsai.
      Autophagosome formation initiated on the endoplasmic reticulum (ER)-associated omegasome requires LC3. Translational regulation of LC3 biosynthesis is unexplored. Here we demonstrate that LC3 mRNA is recruited to omegasomes by directly binding to the ER transmembrane Sigma-1 receptor (S1R). Cell-based and in vitro reconstitution experiments show that S1R interacts with the 3' UTR of LC3 mRNA and ribosomes to promote LC3 translation. Strikingly, the 3' UTR of LC3 is also required for LC3 protein lipidation, thereby linking the mRNA-3' UTR to LC3 function. An autophagy-defective S1R mutant responsible for amyotrophic lateral sclerosis cannot bind LC3 mRNA or induce LC3 translation. We propose a model wherein S1R de-represses LC3 mRNA via its 3' UTR at the ER, enabling LC3 biosynthesis and lipidation. Because several other LC3-related proteins use the same mechanism, our data reveal a conserved pathway for localized translation essential for autophagosome biogenesis with insights illuminating the molecular basis of a neurodegenerative disease.
    Keywords:  ALS; CP: Cell biology; CP: Molecular biology; LC3; autophagy; lipidation; omegasome
    DOI:  https://doi.org/10.1016/j.celrep.2024.114619
  25. Int J Parasitol Drugs Drug Resist. 2024 Aug 12. pii: S2211-3207(24)00041-1. [Epub ahead of print]26 100560
    Benzaldehyde stimulates autophagy via the sonic hedgehog signaling pathway in mouse brain astrocytes after treatment with Angiostrongylus cantonensis excretory-secretory products.
    Kuang-Yao Chen, Chien-Ju Cheng, Yuan-Ting Chang, Yi-Hsuan Lin, Yi-Hao Huang, Sheng-Yu Lin, Lian-Chen Wang, Kai-Yuan Jhan, Cheng-Hsun Chiu.
      Autophagy is a vital cellular process responsible for digesting various cytoplasmic organelles. This process plays a crucial role in maintaining cell survival and homeostasis, especially under conditions that cause nutrient deficiency, cellular damage, and oxidative stress. Neuroangiostrongyliasis is an infection caused by the parasitic nematode Angiostrongylus cantonensis and is considered as an emerging disease in many parts of the world. However, effective therapeutic strategies for neuroangiostrongyliasis still need to be further developed. In this study, we investigated the effects of benzaldehyde treatment on autophagy and sonic hedgehog (Shh) signaling in A. cantonensis-infected mice and its mechanisms. First, we found autophagosome generation in the central nervous system after A. cantonensis infection. Next, benzaldehyde combined with albendazole treatment reduced eosinophilic meningitis and upregulated the expression of Shh signaling- and autophagy-related molecules in A. cantonensis-infected mouse brains. In vitro experiments demonstrated that benzaldehyde could induce autophagy via the Shh signaling pathway in A. cantonensis excretory-secretory products (ESPs)-treated mouse astrocytes. Finally, benzaldehyde treatment also decreased lipid droplet accumulation and increased cholesterol production by activating the Shh pathway after ESPs treatment. In conclusion, these findings suggested that benzaldehyde treatment could alleviate brain damage by stimulating autophagy generation through the Shh signaling pathway.
    Keywords:  Angiostrongylus cantonensis; Autophagy; Benzaldehyde; Excretory-secretory products; Sonic hedgehog
    DOI:  https://doi.org/10.1016/j.ijpddr.2024.100560
  26. Stem Cell Res. 2024 Aug 05. pii: S1873-5061(24)00218-6. [Epub ahead of print]80 103520
    Generation and characterization of human-derived induced pluripotent stem cell line (IGIBi010-A) from a patient with neurodegenerative disease phenotype carrying mutation in SQSTM1/p62 gene.
    Istaq Ahmad, Himanshi Kapoor, Achal Kumar Srivastava, Mohammed Faruq.
      SQSTM1 (Sequestosome 1) also known as p62, plays several important physiological roles in the cell. It regulates autophagy and mitochondrial homeostasis and can further lead to metabolic reprogramming. Pathogenic variants in SQSTM1 gene are known to cause Neurodegeneration with ataxia, dystonia, and gaze palsy in autosomal recessive inheritance fashion. We report here, the generation of induced pluripotent stem cell (iPSC) line (IGIBi010-A) carrying a novel homozygous frameshift variant in SQSTM1 i.e. p.Leu251SerfsTer4. In future, this iPSC line will be used as a resource to elucidate the molecular pathway, targeting strategies for disease biology derived by variation in SQSTM1 gene.
    DOI:  https://doi.org/10.1016/j.scr.2024.103520
  27. Biochem Biophys Res Commun. 2024 Aug 06. pii: S0006-291X(24)01042-8. [Epub ahead of print]736 150506
    The role of alternative autophagy in cell viability and response to paclitaxel treatment in v-Ha-ras-transformed NIH 3T3 cells.
    Hye-Gyo Kim, Myeng-Han Ro, Michael Lee.
      In confluent v-Ha-ras-transformed NIH 3T3 fibroblasts (Ras-NIH 3T3), LC3 downregulation may precede a decrease in canonical autophagy, thus contributing to cell survival. Herein, we aimed to investigate the role of alternative autophagy in the viability of long-term cultures of Ras-NIH 3T3 cells and their parental NIH 3T3 cells. As cell confluence increased with the culture period, the level of alternative autophagy, as assessed through Lamp2-Rab9 co-localization, gradually decreased in both cell lines. However, Ras-NIH 3T3 cells maintained higher levels of alternative autophagy than the parental cells did. Rab9 knockdown minimally affected NIH 3T3 cells while drastically reducing the viability of Ras-NIH 3T3 cells, which suggested that alternative autophagy plays a critical role in Ras-NIH 3T3 cells. In contrast, reactive oxygen species (ROS) production in Ras-NIH 3T3 cells was higher than that in NIH 3T3 cells during long-term culture. Moreover, NIH 3T3 cells exhibited a continual decrease in mitochondrial mass, whereas Ras-NIH 3T3 cells maintained high mitochondrial mass. Immunofluorescence analysis of mitochondrial membrane marker proteins and mitochondrial membrane potential (MMP) also demonstrated a temporal pattern of changes similar to those of mitochondrial mass. This finding could be attributed to the relatively higher level of alternative autophagy in Ras-NIH 3T3 cells facilitating the removal of damaged mitochondria. Paclitaxel treatment in Ras-NIH 3T3 cells induced an increase in canonical autophagy rates along with suppression of alternative autophagy. Ras-NIH 3T3 cells showed high sensitivity to paclitaxel at the early stage of culture, but as cell confluence increased, resistance to paclitaxel increased, showing a similar level of cell viability to the vehicle control group. The study findings suggest that alternative autophagy is more important than canonical autophagy for maintaining cell survival in response to an unfavorable environment, such as during high cell confluence and exposure to anticancer agents.
    Keywords:  Atg5; Rab9; Ras-transformed; Reactive oxygen species (ROS); alternative autophagy; mitochondria
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150506
  28. Ecotoxicol Environ Saf. 2024 Aug 14. pii: S0147-6513(24)00966-7. [Epub ahead of print]284 116890
    Lysosomal iron accumulation and subsequent lysosomes-mitochondria iron transmission mediate PFOS-induced hepatocyte ferroptosis.
    Jixun Li, Ruzhen Feng, Wei Yang, Peiyao Liang, Tianming Qiu, Jingyuan Zhang, Xiance Sun, Qiujuan Li, Guang Yang, Xiaofeng Yao.
      Perfluorooctane sulfonate (PFOS) is known as a persistent organic pollutant. A significant correlation between PFOS and liver ferroptosis has been unveiled, but the precise mechanism needs to be elucidated. In prior research, we found that PFOS treatment provoked mitochondrial iron overload. In this study, we observed a gradual increase in lysosomal iron in L-O2 cells after exposure to PFOS for 0.5-24 h. In PFOS-exposed L-O2 cells, suppressing autophagy relieved the lysosomal iron overload. Inhibiting transient receptor potential mucolipin 1 (TRPML1), a calcium efflux channel on the lysosomal membrane, led to a further rise in lysosomal iron levels and decreased mitochondrial iron overload during PFOS treatment. Suppressing VDAC1, a subtype of voltage-dependent anion-selective channels (VDACs) on the outer mitochondrial membrane, had no impact on PFOS-triggered mitochondrial iron overload, whereas restraining VDAC2/3 relieved this condition. Although silencing VDAC2 relieved PFOS-induced mitochondrial iron overload, it had no effect on PFOS-triggered lysosomal iron overload. Silencing VDAC3 alleviated PFOS-mediated mitochondrial iron overload and led to an additional increase in lysosomal iron. Therefore, we regarded VDAC3 as the specific VDACs subtype that mediated the lysosomes-mitochondria iron transfer. Additionally, in the presence of PFOS, an enhanced association between TRPML1 and VDAC3 was found in mice liver tissue and L-O2 cells. Our research unveils a novel regulatory mechanism of autophagy on the iron homeostasis and the effect of TRPML1-VDAC3 interaction on lysosomes-mitochondria iron transfer, giving an explanation of PFOS-induced ferroptosis and shedding some light on the role of classic calcium channels in iron transmission.
    Keywords:  Ferroptosis; Lysosomal iron; Mitochondrial iron; PFOS; Transient receptor potential mucolipin 1; Voltage-dependent anion-selective channel 3
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.116890
  29. Cell Death Dis. 2024 Aug 15. 15(8): 591
    GPR50 regulates neuronal development as a mitophagy receptor.
    Ji-Chuan Liu, Xiu-Yun Zhao, Ming-Lei Wu, Yi-Fan Shi, Ze-Ping Huang, Li-Pao Fang, Chao Zhu, Xuan Peng, Zi-Ling Shi, Li-Jun Lan, Wen-Li Ji, Li Luo, Lei Feng, Zeng-Li Zhang, De-En Xu, Shao Li, Zheng-Hong Qin, Yan-Yun Sun, Melitta Schachner, Quan-Hong Ma.
      Neurons rely heavily on high mitochondrial metabolism to provide sufficient energy for proper development. However, it remains unclear how neurons maintain high oxidative phosphorylation (OXPHOS) during development. Mitophagy plays a pivotal role in maintaining mitochondrial quality and quantity. We herein describe that G protein-coupled receptor 50 (GPR50) is a novel mitophagy receptor, which harbors the LC3-interacting region (LIR) and is required in mitophagy under stress conditions. Although it does not localize in mitochondria under normal culturing conditions, GPR50 is recruited to the depolarized mitochondrial membrane upon mitophagy stress, which marks the mitochondrial portion and recruits the assembling autophagosomes, eventually facilitating the mitochondrial fragments to be engulfed by the autophagosomes. Mutations Δ502-505 and T532A attenuate GPR50-mediated mitophagy by disrupting the binding of GPR50 to LC3 and the mitochondrial recruitment of GPR50. Deficiency of GPR50 causes the accumulation of damaged mitochondria and disrupts OXPHOS, resulting in insufficient ATP production and excessive ROS generation, eventually impairing neuronal development. GPR50-deficient mice exhibit impaired social recognition, which is rescued by prenatal treatment with mitoQ, a mitochondrially antioxidant. The present study identifies GPR50 as a novel mitophagy receptor that is required to maintain mitochondrial OXPHOS in developing neurons.
    DOI:  https://doi.org/10.1038/s41419-024-06978-y
  30. Cancers (Basel). 2024 Jul 26. pii: 2654. [Epub ahead of print]16(15):
    Anticancer Activity of Delta-Tocotrienol in Human Hepatocarcinoma: Involvement of Autophagy Induction.
    Marina Montagnani Marelli, Chiara Macchi, Massimiliano Ruscica, Patrizia Sartori, Roberta Manuela Moretti.
      (1) Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Surgical resection, tumor ablation, and liver transplantation are curative treatments indicated for early-stage HCC. The management of intermediate and advanced stages of pathology is based on the use of systemic therapies which often show important side effects. Vitamin E-derivative tocotrienols (TTs) play antitumoral properties in different tumors. Here, we analyzed the activity of delta-TT (δ-TT) on HCC human cell lines. (2) We analyzed the ability of δ-TT to trigger apoptosis, to induce oxidative stress, autophagy, and mitophagy in HepG2 cell line. We evaluated the correlation between the activation of autophagy with the ability of δ-TT to induce cell death. (3) The data obtained demonstrate that δ-TT exerts an antiproliferative and proapoptotic effect in HCC cells. Furthermore, δ-TT induces the release of mitochondrial ROS and causes a structural and functional alteration of the mitochondria compatible with a fission process. Finally, δ-TT triggers selective autophagy process removing dysfunctional mitochondria. Inhibition of autophagy reversed the cytotoxic action of δ-TT. (4) Our results demonstrate that δ-TT through the activation of autophagy could represent a potential new approach in the treatment of advanced HCC.
    Keywords:  apoptosis; autophagy; delta-tocotrienol; hepatocarcinoma; mitochondria
    DOI:  https://doi.org/10.3390/cancers16152654
  31. Proc Natl Acad Sci U S A. 2024 Aug 20. 121(34): e2320257121
    A PIKfyve modulator combined with an integrated stress response inhibitor to treat lysosomal storage diseases.
    William C Hou, Lynée A Massey, Derek Rhoades, Yin Wu, Wen Ren, Chiara Frank, Herman S Overkleeft, Jeffrey W Kelly.
      Lysosomal degradation pathways coordinate the clearance of superfluous and damaged cellular components. Compromised lysosomal degradation is a hallmark of many degenerative diseases, including lysosomal storage diseases (LSDs), which are caused by loss-of-function mutations within both alleles of a lysosomal hydrolase, leading to lysosomal substrate accumulation. Gaucher's disease, characterized by <15% of normal glucocerebrosidase function, is the most common LSD and is a prominent risk factor for developing Parkinson's disease. Here, we show that either of two structurally distinct small molecules that modulate PIKfyve activity, identified in a high-throughput cellular lipid droplet clearance screen, can improve glucocerebrosidase function in Gaucher patient-derived fibroblasts through an MiT/TFE transcription factor that promotes lysosomal gene translation. An integrated stress response (ISR) antagonist used in combination with a PIKfyve modulator further improves cellular glucocerebrosidase activity, likely because ISR signaling appears to also be slightly activated by treatment by either small molecule at the higher doses employed. This strategy of combining a PIKfyve modulator with an ISR inhibitor improves mutant lysosomal hydrolase function in cellular models of additional LSD.
    Keywords:  Gaucher’s disease; PIKfyve; Parkinson’s disease; integrated stress response; lysosomal storage disease
    DOI:  https://doi.org/10.1073/pnas.2320257121
  32. Mol Oncol. 2024 Aug 11.
    Inhibition of autophagy as a novel treatment for neurofibromatosis type 1 tumors.
    Megan Stevens, Yuanli Wang, Stephanie J Bouley, Torrey R Mandigo, Aditi Sharma, Sonali Sengupta, Amy Housden, Norbert Perrimon, James A Walker, Benjamin E Housden.
      Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutation of the NF1 gene that is associated with various symptoms, including the formation of benign tumors, called neurofibromas, within nerves. Drug treatments are currently limited. The mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib is used for a subset of plexiform neurofibromas (PNs) but is not always effective and can cause side effects. Therefore, there is a clear need to discover new drugs to target NF1-deficient tumor cells. Using a Drosophila cell model of NF1, we performed synthetic lethal screens to identify novel drug targets. We identified 54 gene candidates, which were validated with variable dose analysis as a secondary screen. Pathways associated with five candidates could be targeted using existing drugs. Among these, chloroquine (CQ) and bafilomycin A1, known to target the autophagy pathway, showed the greatest potential for selectively killing NF1-deficient Drosophila cells. When further investigating autophagy-related genes, we found that 14 out of 30 genes tested had a synthetic lethal interaction with NF1. These 14 genes are involved in multiple aspects of the autophagy pathway and can be targeted with additional drugs that mediate the autophagy pathway, although CQ was the most effective. The lethal effect of autophagy inhibitors was conserved in a panel of human NF1-deficient Schwann cell lines, highlighting their translational potential. The effect of CQ was also conserved in a Drosophila NF1 in vivo model and in a xenografted NF1-deficient tumor cell line grown in mice, with CQ treatment resulting in a more significant reduction in tumor growth than selumetinib treatment. Furthermore, combined treatment with CQ and selumetinib resulted in a further reduction in NF1-deficient cell viability. In conclusion, NF1-deficient cells are vulnerable to disruption of the autophagy pathway. This pathway represents a promising target for the treatment of NF1-associated tumors, and we identified CQ as a candidate drug for the treatment of NF1 tumors.
    Keywords:  Drosophila; autophagy; drug repurposing; neurofibromatosis type 1; synthetic lethality
    DOI:  https://doi.org/10.1002/1878-0261.13704
  33. J Mol Med (Berl). 2024 Aug 15.
    New insights into the mechanisms and therapeutic strategies of chondrocyte autophagy in osteoarthritis.
    Lujia Tang, Jiatong Ding, Kangping Yang, Zhen Zong, Rui Wu, Hui Li.
      Osteoarthritis (OA) is a chronic joint disease with an unclear cause characterized by secondary osteophytes and degenerative changes in the articular cartilage. More than 250 million people are expected to be affected by it by 2050, putting a tremendous socioeconomic strain on the entire world. OA cannot currently be treated with any effective medications that change the illness. Over time, chondrocytes undergo gradual metabolic, structural, and functional changes as a result of aging or abuse. The degenerative progression of osteoarthritis is significantly influenced by the imbalance of chondrocyte homeostasis. By continuously recycling and rebuilding macromolecules or organelles, autophagy functions as a crucial regulatory system to maintain homeostasis during an individual's growth and development. This review uses chondrocytes as its starting point and establishes a strong connection between autophagy and osteoarthritis in order to thoroughly examine the mechanisms behind chondrocyte autophagy in osteoarthritis. Biomarkers of chondrocyte autophagy will be identified, and prospective targeted medications and novel treatment approaches for slowing or preventing the course of OA will be developed based on chondrocyte senescence, autophagy, and apoptosis in OA. KEY MESSAGES: Currently, OA has not been treated with any drugs that can effectively cure it. We hope that by exploring specific targets in the course of osteoarthritis, we can promote the progress of treatment strategies. The degenerative progression of osteoarthritis is significantly influenced by the imbalance of chondrocyte balance. Through the continuous recovery and reconstruction of macromolecules or organelles, autophagy is an important regulatory system for maintaining homeostasis during individual growth and development. In this paper, the close relationship between autophagy and osteoarthritis was established with chondrocytes as the starting point, in order to further explore the mechanism of chondrocyte autophagy in osteoarthritis. The development process of osteoarthritis was studied from the perspective of chondrocytes, and the change of autophagy level had a significant impact on osteoarthritis. Chondrocyte autophagy is mainly determined by intracellular mitochondrial autophagy, so we are committed to finding relevant molecules. Through PI3K/AKT- and MAPK-related pathways, the biomarkers of chondrocyte autophagy were identified, and chondrocyte senescence, autophagy, and apoptosis based on osteoarthritis provided a constructive idea for the development of prospective targeted drugs and new therapies to slow down or prevent the progression of osteoarthritis.
    Keywords:  Autophagy; Chondrocyte; Osteoarthritis
    DOI:  https://doi.org/10.1007/s00109-024-02473-1
  34. Biomed Pharmacother. 2024 Aug 08. pii: S0753-3322(24)01163-6. [Epub ahead of print]178 117279
    JAK2 inhibitor protects the septic heart through enhancing mitophagy in cardiomyocytes.
    Dafei Han, Tiantian Su, Mingzhu Wang, Renhao Zhang, Huihui Xu, Rui Chu, Zhenduo Zhu, Yawei Shen, Nan Wang, Shufang He, Yongsheng Wang, Yongsheng Han, Qingtong Wang.
      Sepsis-induced myocardial dysfunction (SIMD) is a severe complication in sepsis, manifested as myocardial systolic dysfunction, which is associated with poor prognosis and higher mortality. Mitophagy, a self-protective mechanism maintaining cellular homeostasis, plays an indispensable role in cardioprotection. This study aimed to unveil the cardioprotective effects of Baricitinib on LPS-induced myocardial dysfunction and its effect on mitophagy. Herein, we demonstrated that LPS induced severe myocardial dysfunction and initiated mitophagy in septic mice hearts. Despite the initiation of mitophagy, a significant number of apoptotic cells and damaged mitochondria persisted in the myocardium, and myocardial energy metabolism remained impaired, indicating that the limited mitophagy was insufficient to mitigate LPS-induced damage. The JAK2-AKT-mTOR signaling pathway is activated in LPS-induced cardiomyocytes and in the hearts of septic mice. Baricitinib administration remarkably improved cardiac function, suppressed systemic inflammatory response, attenuated histopathological changes, inhibited cardiac cell apoptosis and alleviated myocardial damage in septic mice. Furthermore, Baricitinib treatment significantly enhanced PINK1-Parkin-mediated mitophagy, increased autophagosomes, decreased impaired mitochondria, and restored myocardial energy metabolism. Mechanically, the limited mitophagy in septic myocardium was associated with increased p-ULK1 (Ser757), which was regulated by p-mTOR. Baricitinib reduced p-ULK1 (Ser757) and enhanced mitophagy by inhibiting the JAK2-AKT-mTOR signaling pathway. Inhibition of mitophagy with Mdivi-1 reversed the cardiac protective and anti-inflammatory effects of Baricitinib in septic mice. These findings suggest that Baricitinib attenuates SIMD by enhancing mitophagy in cardiomyocytes via the JAK2-AKT-mTOR signaling pathway, providing a novel mechanistic and therapeutic insight into the SIMD.
    Keywords:  Baricitinib; JAK2-AKT-mTOR signaling pathway; Mitophagy; Sepsis-induced myocardial dysfunction
    DOI:  https://doi.org/10.1016/j.biopha.2024.117279
  35. Int J Mol Sci. 2024 Jul 29. pii: 8265. [Epub ahead of print]25(15):
    Bafilomycin 1A Affects p62/SQSTM1 Autophagy Marker Protein Level and Autophagosome Puncta Formation Oppositely under Various Inflammatory Conditions in Cultured Rat Microglial Cells.
    István Pesti, Gábor Barczánfalvi, Karolina Dulka, Diana Kata, Eszter Farkas, Karoly Gulya.
      Regulation of autophagy through the 62 kDa ubiquitin-binding protein/autophagosome cargo protein sequestosome 1 (p62/SQSTM1), whose level is generally inversely proportional to autophagy, is crucial in microglial functions. Since autophagy is involved in inflammatory mechanisms, we investigated the actions of pro-inflammatory lipopolysaccharide (LPS) and anti-inflammatory rosuvastatin (RST) in secondary microglial cultures with or without bafilomycin A1 (BAF) pretreatment, an antibiotic that potently inhibits autophagosome fusion with lysosomes. The levels of the microglia marker protein Iba1 and the autophagosome marker protein p62/SQSTM1 were quantified by Western blots, while the number of p62/SQSTM1 immunoreactive puncta was quantitatively analyzed using fluorescent immunocytochemistry. BAF pretreatment hampered microglial survival and decreased Iba1 protein level under all culturing conditions. Cytoplasmic p62/SQSTM1 level was increased in cultures treated with LPS+RST but reversed markedly when BAF+LPS+RST were applied together. Furthermore, the number of p62/SQSTM1 immunoreactive autophagosome puncta was significantly reduced when RST was used but increased significantly in BAF+RST-treated cultures, indicating a modulation of autophagic flux through reduction in p62/SQSTM1 degradation. These findings collectively indicate that the cytoplasmic level of p62/SQSTM1 protein and autophagocytotic flux are differentially regulated, regardless of pro- or anti-inflammatory state, and provide context for understanding the role of autophagy in microglial function in various inflammatory settings.
    Keywords:  autophagosome; autophagy; bafilomycin A1; inflammation; lipopolysaccharide; microglia; p62/SQSTM1; rosuvastatin
    DOI:  https://doi.org/10.3390/ijms25158265
  36. Autophagy. 2024 Aug 15.
    MANF facilitates breast cancer cell survival under glucose-starvation conditions via prkn-mediated mitophagy regulation.
    Zhenchong Xiong, Lin Yang, Chao Zhang, Weiling Huang, Wenjing Zhong, Jiarong Yi, Jikun Feng, Xiazi Zouxu, Libing Song, Xi Wang.
      During tumor expansion, breast cancer (BC) cells often experience reactive oxygen species accumulation and mitochondrial damage because of glucose shortage. However, the mechanism by which BC cells deal with the glucose-shortage-induced oxidative stress remains unclear. Here, we showed that MANF (mesencephalic astrocyte derived neurotrophic factor)-mediated mitophagy facilitates BC cell survival under glucose-starvation conditions. MANF-mediated mitophagy also promotes fatty acid oxidation in glucose-starved BC cells. Moreover, during glucose starvation, SENP1-mediated de-SUMOylation of MANF increases cytoplasmic MANF expression through the inhibition of MANF's nuclear translocation and hence renders mitochondrial distribution of MANF. MANF mediates mitophagy by binding to PRKN (parkin RBR E3 ubiquitin protein ligase), a key mitophagy regulator, in the mitochondria. Under conditions of glucose starvation, protein oxidation inhibits PRKN activity; nevertheless, the CXXC motif of MANF alleviates protein oxidation in RING II-domain of PRKN and restores its E3 ligase activity. Furthermore, MANF-PRKN interactions are essential for BC tumor growth and metastasis. High MANF expression predicts poor outcomes in patients with BC. Our results highlight the prosurvival role of MANF-mediated mitophagy in BC cells during glucose starvation, suggesting MANF as a potential therapeutic target.
    Keywords:  Breast cancer; MANF; PRKN; ROS; glucose starvation; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2392415
  37. Adv Sci (Weinh). 2024 Aug 13. e2400666
    CDK4/6 Inhibitors Impede Chemoresistance and Inhibit Tumor Growth of Small Cell Lung Cancer.
    Yang Wen, Xue Sun, Lingge Zeng, Shumei Liang, Deyu Li, Xiangtian Chen, Fanrui Zeng, Chao Zhang, Qiongyao Wang, Qinsong Zhong, Ling Deng, Linlang Guo.
      Small cell lung cancer (SCLC) is characterized by rapid development of chemoresistance and poor outcomes. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are widely used in breast cancer and other cancer types. However, the molecular mechanisms of CDK4/6 in SCLC chemoresistance remain poorly understood. Here, Rb1flox/flox, Trp53flox/flox, Ptenflox/flox (RTP) and Rb1flox/flox, Trp53flox/flox, MycLSL/LSL (RPM) spontaneous SCLC mouse models, SCLC cell line-derived xenograft (CDX) models, and SCLC patient-derived xenograft (PDX) models are established to reveal the potential effects of CDK4/6is on SCLC chemoresistance. In this study, it is found that CDK4/6is palbociclib (PD) or ribociclib (LEE) combined with chemotherapeutic drugs significantly inhibit SCLC tumor growth. Mechanistically, CDK4/6is do not function through the classic Retionblastoma1 (RB) dependent axis in SCLC. CDK4/6is induce impair autophagy through the AMBRA1-lysosome signaling pathway. The upregulated AMBRA1 protein expression leads to CDK6 degradation via autophagy,  and the following TFEB and TFE3 nuclear translocation inhibition leading to the lysosome-related genes levels downregulation. Moreover, it is found that the expression of CDK6 is higher in SCLC tumors than in normal tissue and it is associated with the survival and prognosis of SCLC patients. Finally, these findings demonstrate that combining CDK4/6is with chemotherapy treatment may serve as a potential therapeutic option for SCLC patients.
    Keywords:  AMBRA1; CDK6; SCLC; autophagic flux; chemoresistance; lysosomal depletion
    DOI:  https://doi.org/10.1002/advs.202400666
  38. Dis Model Mech. 2024 Aug 01. pii: dmm050798. [Epub ahead of print]17(8):
    Fine-tuning AMPK in physiology and disease using point-mutant mouse models.
    Naghmana Ashraf, Jeanine L Van Nostrand.
      AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that monitors the cellular energy status to adapt it to the fluctuating nutritional and environmental conditions in an organism. AMPK plays an integral part in a wide array of physiological processes, such as cell growth, autophagy and mitochondrial function, and is implicated in diverse diseases, including cancer, metabolic disorders, cardiovascular diseases and neurodegenerative diseases. AMPK orchestrates many different physiological outcomes by phosphorylating a broad range of downstream substrates. However, the importance of AMPK-mediated regulation of these substrates in vivo remains an ongoing area of investigation to better understand its precise role in cellular and metabolic homeostasis. Here, we provide a comprehensive overview of our understanding of the kinase function of AMPK in vivo, as uncovered from mouse models that harbor phosphorylation mutations in AMPK substrates. We discuss some of the inherent limitations of these mouse models, highlight the broader implications of these studies for understanding human health and disease, and explore the valuable insights gained that could inform future therapeutic strategies for the treatment of metabolic and non-metabolic disorders.
    Keywords:  AMPK; Cell signaling; Mouse models
    DOI:  https://doi.org/10.1242/dmm.050798
  39. Biochim Biophys Acta Mol Basis Dis. 2024 Aug 10. pii: S0925-4439(24)00452-6. [Epub ahead of print]1870(8): 167459
    Oleanonic acid ameliorates mutant Aβ precursor protein-induced oxidative stress, autophagy deficits, ferroptosis, mitochondrial damage, and ER stress in vitro.
    Liqing Tao, Zewang Liu, Xinying Li, Hongyan Wang, Yicheng Wang, Dongming Zhou, Heng Zhang.
      Accumulation in the brain of amyloid-β (Aβ), derived from cleavage of Aβ precursor protein (APP), is a hallmark of Alzheimer's disease (AD). Oleanonic acid (OA), a phytochemical from several plants, has proven anti-inflammatory effects, but its role in AD remains unknown. Here we found that OA reduced APP expression and inhibited oxidative stress via Nrf2/HO-1 signaling in SH-SY5Y neuroblastoma cells stably overexpressing APP. OA suppressed phosphorylated mTOR but increased autophagy markers ATG5 and LC3-II. Moreover, OA rescued ferroptosis-related factors GPX4, NCOA, and COX2 and ER stress markers GRP78, CHOP, and three main induction pathways of ER stress including IRE1/XBP1s, PERK/EIF2α, and ATF6. OA alleviated mitochondrial damage through MFN1, MFN2, OPA1, FIS1, and DRP1. Furthermore, OA upregulated GDF11 expression and downregulated phosphorylation of ErbB4 and TrkB without affecting BDNF levels. Thus, OA might protect neurons from APP-induced neurotoxicity by inhibiting oxidative stress, autophagy deficits, ferroptosis, mitochondrial damage, and ER stress in AD, providing a new promising therapeutic strategy in patients with AD.
    Keywords:  Autophagy; Aβ precursor protein-induced neurotoxicity; Ferroptosis and ER stress; Mitochondrial damage; Oleanonic acid; Oxidative stress
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167459
  40. Biochem J. 2024 08 15. pii: BCJ20240058. [Epub ahead of print]
    CARD14 SIGNALOSOME FORMATION IS ASSOCIATED WITH ITS ENDOSOMAL RELOCATION AND mTORC1-INDUCED KERATINOCYTE PROLIFERATION.
    Paul A O'Sullivan, Aigerim Aidarova, Inna Afonina, Joan Manils, Teresa L M Thurston, Rachel Instrell, Michael Howell, Stefan Boeing, Sashini Ranawana, Melanie Herpels, Riwia Chetien, Matilda Bassa, Helen R Flynn, David Frith, Ambrosius Snijders, Ashleigh Howes, Rudi Beyaert, Anne Bowcock, Steve C Ley.
      Rare mutations in CARD14 promote psoriasis by inducing CARD14-BCL10-MALT1 complexes that activate NF-kB and MAP kinases. Here, the downstream signalling mechanism of the highly penetrant CARD14E138Aalteration is described. In addition to BCL10 and MALT1, CARD14E138A associated with several proteins important in innate immune signalling. Interactions with M1-specific ubiquitin E3 ligase HOIP, and K63-specific ubiquitin E3 ligase TRAF6 promoted BCL10 ubiquitination and were essential for NF-kB and MAP kinase activation. In contrast, the ubiquitin binding proteins A20 and ABIN1, both genetically associated with psoriasis development, negatively regulated signalling by inducing CARD14E138A turnover. CARD14E138A localized to early endosomes and was associated with the AP2 adaptor complex. AP2 function was required for CARD14E138A activation of mTOR complex 1, which stimulated keratinocyte metabolism, but not for NF-kB nor MAP kinase activation. Furthermore, rapamycin ameliorated CARD14E138A-induced keratinocyte proliferation and epidermal acanthosis in mice, suggesting that blocking mTORC1 may be therapeutically beneficial in CARD14-dependent psoriasis.
    Keywords:  AP2 complex; CARD14; keratinocytes; mTORC1; psoriasis; signalling
    DOI:  https://doi.org/10.1042/BCJ20240058
  41. J Gerontol A Biol Sci Med Sci. 2024 Aug 16. pii: glae196. [Epub ahead of print]
    Characterization of effects of mTOR inhibitors on aging in C. elegans.
    Aihan Zhang, Gadea Meecham Garcia, Chiminh Nguyen Hong, Peiyun Xie, Carina C Kern, Bruce Zhang, Hannah Chapman, David Gems.
      Pharmacological inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway with rapamycin can extend lifespan in several organisms. Although this includes the nematode Caenorhabditis elegans, effects in this species are relatively weak and sometimes difficult to reproduce. Here we test effects of drug dosage and timing of delivery to establish the upper limits of its capacity to extend life, and investigate drug effects on age-related pathology and causes of mortality. Liposome-mediated rapamycin treatment throughout adulthood showed a dose-dependent effect, causing a maximal 21.9% increase in mean lifespan, but shortening of lifespan at the highest dose, suggesting drug toxicity. Rapamycin treatment of larvae delayed development, weakly reduced fertility and modestly extended lifespan. By contrast, treatment initiated later in life robustly increased lifespan, even from day 16 (or ~70 yr in human terms). The rapalog temsirolimus extended lifespan similarly to rapamycin, but effects of everolimus were weaker. As in mouse, rapamycin had mixed effects on age-related pathologies, inhibiting one (uterine tumor growth) but not several others, suggesting a segmental antigeroid effect. These findings should usefully inform future experimental studies with rapamycin and rapalogs in C. elegans.
    Keywords:  Age-related pathology; Lifespan; Rapalog; Rapamycin; mTOR
    DOI:  https://doi.org/10.1093/gerona/glae196
  42. Arch Toxicol. 2024 Aug 13.
    Unraveling the AKT/ERK cascade and its role in Parkinson disease.
    Priyanka Kumari Keshri, Surya Pratap Singh.
      Parkinson disease represents a significant and growing burden on global healthcare systems, necessitating a deeper understanding of their underlying molecular mechanisms for the development of effective treatments. The AKT and ERK pathways play crucial roles in the disease, influencing multiple cellular pathways that support neuronal survival. Researchers have made notable progress in uncovering how these pathways are controlled by upstream kinases and how their downstream effects contribute to cell signalling. However, as we delve deeper into their intricacies, we encounter increasing complexity, compounded by the convergence of multiple signalling pathways. Many of their targets overlap with those of other kinases, and they not only affect specific substrates but also influence entire signalling networks. This review explores the intricate interplay of the AKT/ERK pathways with several other signalling cascades, including oxidative stress, endoplasmic reticulum stress, calcium homeostasis, inflammation, and autophagy, in the context of Parkinson disease. We discuss how dysregulation of these pathways contributes to disease progression and neuronal dysfunction, highlighting potential therapeutic targets for intervention. By elucidating the complex network of interactions between the AKT/ERK pathways and other signalling cascades, this review aims to provide insights into the pathogenesis of Parkinson disease and describe the development of novel therapeutic strategies.
    Keywords:  AKT/ERK pathways; Autophagy; Endoplasmic reticulum (ER) stress; Neuroinflammation; Neurotrophins; Oxidative stress; Parkinson disease
    DOI:  https://doi.org/10.1007/s00204-024-03829-9
  43. Commun Biol. 2024 Aug 10. 7(1): 974
    Calorie restriction and rapamycin distinctly mitigate aging-associated protein phosphorylation changes in mouse muscles.
    Meric Ataman, Nitish Mittal, Lionel Tintignac, Alexander Schmidt, Daniel J Ham, Asier González, Markus A Ruegg, Mihaela Zavolan.
      Calorie restriction (CR) and treatment with rapamycin (RM), an inhibitor of the mTORC1 growth-promoting signaling pathway, are known to slow aging and promote health from worms to humans. At the transcriptome and proteome levels, long-term CR and RM treatments have partially overlapping effects, while their impact on protein phosphorylation within cellular signaling pathways have not been compared. Here we measured the phosphoproteomes of soleus, tibialis anterior, triceps brachii and gastrocnemius muscles from adult (10 months) and 30-month-old (aged) mice receiving either a control, a calorie restricted or an RM containing diet from 15 months of age. We reproducibly detected and extensively analyzed a total of 6960 phosphosites, 1415 of which are not represented in standard repositories. We reveal the effect of these interventions on known mTORC1 pathway substrates, with CR displaying greater between-muscle variation than RM. Overall, CR and RM have largely consistent, but quantitatively distinct long-term effects on the phosphoproteome, mitigating age-related changes to different degrees. Our data expands the catalog of protein phosphorylation sites in the mouse, providing important information regarding their tissue-specificity, and revealing the impact of long-term nutrient-sensing pathway inhibition on mouse skeletal muscle.
    DOI:  https://doi.org/10.1038/s42003-024-06679-4
  44. FASEB J. 2024 Aug 31. 38(16): e23884
    Inhibition of TFEB deacetylation in proximal tubular epithelial cells (TECs) promotes TFEB activation and alleviates TEC damage in diabetic kidney disease.
    Xiaoyu Li, Yaozhi Zhang, Huixia Chen, Yang Wu, Yongming Chen, Siqiao Gong, Yonghan Liu, Huafeng Liu.
      The inhibition of the autophagolysosomal pathway mediated by transcription factor EB (TFEB) inactivation in proximal tubular epithelial cells (TECs) is a key mechanism of TEC injury in diabetic kidney disease (DKD). Acetylation is a novel mechanism that regulates TFEB activity. However, there are currently no studies on whether the adjustment of the acetylation level of TFEB can reduce the damage of diabetic TECs. In this study, we investigated the effect of Trichostatin A (TSA), a typical deacetylase inhibitor, on TFEB activity and damage to TECs in both in vivo and in vitro models of DKD. Here, we show that TSA treatment can alleviate the pathological damage of glomeruli and renal tubules and delay the DKD progression in db/db mice, which is associated with the increased expression of TFEB and its downstream genes. In vitro studies further confirmed that TSA treatment can upregulate the acetylation level of TFEB, promote its nuclear translocation, and activate the expression of its downstream genes, thereby reducing the apoptosis level of TECs. TFEB deletion or HDAC6 knockdown in TECs can counteract the activation effect of TSA on autophagolysosomal pathway. We also found that TFEB enhances the transcription of Tfeb through binding to its promoter and promotes its own expression. Our results, thus, provide a novel therapeutic mechanism for DKD that the alleviation of TEC damage by activating the autophagic lysosomal pathway through upregulating TFEB acetylation can, thus, delay DKD progression.
    Keywords:  Trichostatin A; acetylation; diabetic kidney disease; transcription factor EB; tubular epithelial cells
    DOI:  https://doi.org/10.1096/fj.202302634R
  45. bioRxiv. 2024 Aug 07. pii: 2024.08.06.606926. [Epub ahead of print]
    Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners.
    Katie C Coate, Chunhua Dai, Ajay Singh, Jade Stanley, Brittney A Covington, Amber Bradley, Favour Oladipupo, Yulong Gong, Scott Wisniewski, Erick Spears, Greg Poffenberger, Alexandria Bustabad, Tyler Rodgers, Nandita Dey, Leonard D Shultz, Dale L Greiner, Hai Yan, Alvin C Powers, Wenbiao Chen, E Danielle Dean.
      Objective: Dysregulated glucagon secretion and inadequate functional beta cell mass are hallmark features of diabetes. While glucagon receptor (GCGR) antagonism ameliorates hyperglycemia and elicits beta cell regeneration in pre-clinical models of diabetes, it also promotes alpha and delta cell hyperplasia. We sought to investigate the mechanism by which loss of glucagon action impacts pancreatic islet non-alpha cells, and the relevance of these observations in a human islet context.Methods: We used zebrafish, rodents, and transplanted human islets comprising six different models of interrupted glucagon signaling to examine their impact on delta and beta cell proliferation and mass. We also used models with global deficiency of the cationic amino acid transporter, SLC7A2, and mTORC1 inhibition via rapamycin, to determine whether amino acid-dependent nutrient sensing was required for islet non-alpha cell growth.
    Results: Inhibition of glucagon signaling stimulated delta cell proliferation in mouse and transplanted human islets, and in mouse islets. This was rapamycin-sensitive and required SLC7A2. Likewise, gcgr deficiency augmented beta cell proliferation via SLC7A2- and mTORC1-dependent mechanisms in zebrafish and promoted cell cycle engagement in rodent beta cells but was insufficient to drive a significant increase in beta cell mass in mice.
    Conclusion: Our findings demonstrate that interruption of glucagon signaling augments islet non-alpha cell proliferation in zebrafish, rodents, and transplanted human islets in a manner requiring SLC7A2 and mTORC1 activation. An increase in delta cell mass may be leveraged for future beta cell regeneration therapies relying upon delta cell reprogramming.
    DOI:  https://doi.org/10.1101/2024.08.06.606926
  46. Int J Mol Sci. 2024 Jul 26. pii: 8182. [Epub ahead of print]25(15):
    Role of ATG4 Autophagy-Related Protein Family in the Lower Airways of Patients with Stable COPD.
    Francesco Nucera, Antonino Di Stefano, Fabio Luigi Massimo Ricciardolo, Isabella Gnemmi, Cristina Pizzimenti, Francesco Monaco, Giovanni Tuccari, Gaetano Caramori, Antonio Ieni.
      Autophagy is a complex physiological pathway mediating homeostasis and survival of cells degrading damaged organelles and regulating their recycling. Physiologic autophagy can maintain normal lung function, decrease lung cellular senescence, and inhibit myofibroblast differentiation. It is well known that autophagy is activated in several chronic inflammatory diseases; however, its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and the expression of autophagy-related genes (ATGs) in lower airways of COPD patients is still controversial. The expression and localization of all ATG proteins that represented key components of the autophagic machinery modulating elongation, closure, and maturation of autophagosome membranes were retrospectively measured in peripheral lungs of patients with stable COPD (n = 10), control smokers with normal lung function (n = 10), and control nonsmoking subjects (n = 8) using immunohistochemical analysis. These results show an increased expression of ATG4 protein in alveolar septa and bronchiolar epithelium of stable COPD patients compared to smokers with normal lung function and non-smoker subjects. In particular, the genes in the ATG4 protein family (including ATG4A, ATG4B, ATG4C, and ATG4D) that have a key role in the modulation of the physiological autophagic machinery are the most important ATGs increased in the compartment of lower airways of stable COPD patients, suggesting that the alteration shown in COPD patients can be also correlated to impaired modulation of autophagic machinery modulating elongation, closure, and maturation of autophagosomes membranes. Statistical analysis was performed by the Kruskal-Wallis test and the Mann-Whitney U test for comparison between groups. A statistically significant increased expression of ATG4A (p = 0.0047), ATG4D (p = 0.018), and ATG5 (p = 0.019) was documented in the bronchiolar epithelium as well in alveolar lining for ATG4A (p = 0.0036), ATG4B (p = 0.0054), ATG4C (p = 0.0064), ATG4D (p = 0.0084), ATG5 (p = 0.0088), and ATG7 (p = 0.018) in patients with stable COPD compared to control groups. The ATG4 isoforms may be considered as additional potential targets for the development of new drugs in COPD.
    Keywords:  ATG4; autophagy; chronic obstructive pulmonary disease; lung disease; treatment
    DOI:  https://doi.org/10.3390/ijms25158182
  47. J Clin Invest. 2024 Aug 15. pii: e183302. [Epub ahead of print]134(16):
    Decoding the decline: unveiling drivers of sarcopenia.
    Allison M Owen, Christopher S Fry.
      There remains a critical need to define molecular pathways underlying sarcopenia to identify putative therapeutic targets. Research in the mechanisms of aging and sarcopenia relies heavily on preclinical rodent models. In this issue of the JCI, Kerr et al. implemented a clinically-relevant sarcopenia classification system of aged C57BL/6J mice, capturing sarcopenia prevalence across both sexes. The authors performed detailed physiological, molecular, and energetic analyses and demonstrated that mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in male mice. Sarcopenia was less prevalent in female mice with fewer alterations compared with the male-affected processes. The findings highlight factors beyond age as necessary for classifying the sarcopenic phenotype in rodent models, reveal sexual dimorphism across the trajectory of age-related declines in muscle mass and function in a commonly used rodent model, and provide insight into sex-dependent molecular alterations associated with sarcopenia progression.
    DOI:  https://doi.org/10.1172/JCI183302
  48. Front Cell Infect Microbiol. 2024 ;14 1425367
    Progranulin inhibits autophagy to facilitate intracellular colonization of Helicobacter pylori through the PGRN/mTOR/DCN axis in gastric epithelial cells.
    Linlin Liu, Miao Xiang, Jiaqi Zhou, Zongjiao Ren, Wenjing Shi, Xianhong Du, Xiaoyan Fu, Panpan Li, Hongyan Wang.
      Helicobacter pylori (H. pylori) infection is the primary risk factor for the progress of gastric diseases. The persistent stomach colonization of H. pylori is closely associated with the development of gastritis and malignancies. Although the involvement of progranulin (PGRN) in various cancer types has been well-documented, its functional role and underlying mechanisms in gastric cancer (GC) associated with H. pylori infection remain largely unknown. This report demonstrated that PGRN was up-regulated in GC and associated with poor prognosis, as determined through local and public database analysis. Additionally, H. pylori induced the up-regulation of PGRN in gastric epithelial cells both in vitro and in vivo. Functional studies have shown that PGRN promoted the intracellular colonization of H. pylori. Mechanistically, H. pylori infection induced autophagy, while PGRN inhibited autophagy to promote the intracellular colonization of H. pylori. Furthermore, PGRN suppressed H. pylori-induced autophagy by down-regulating decorin (DCN) through the mTOR pathway. In general, PGRN inhibited autophagy to facilitate intracellular colonization of H. pylori via the PGRN/mTOR/DCN axis. This study provides new insights into the molecular mechanisms underlying the progression of gastric diseases, suggesting PGRN as a potential therapeutic target and prognostic predictor for these disorders.
    Keywords:  DCN; Helicobacter pylori; PGRN; autophagy; intracellular colonization
    DOI:  https://doi.org/10.3389/fcimb.2024.1425367
  49. Gene. 2024 Aug 13. pii: S0378-1119(24)00734-0. [Epub ahead of print] 148853
    Dysregulation of mitochondria, apoptosis and mitophagy in Leber's hereditary optic neuropathy with MT-ND1 3635G>A mutation.
    Yingqi Chen, Xiaoyang Wei, Xiaorui Ci, Yanchun Ji, Juanjuan Zhang.
      Leber's hereditary optic neuropathy (LHON) is a maternal inherited disorder, primarily due to mitochondrial DNA (mtDNA) mutations. This investigation aimed to assess the pathogenicity of m.3635G>A alteration known to confer susceptibility to LHON. The disruption of electrostatic interactions among S110 of the MT-ND1 and the side chain of E4, along with the carbonyl backbone of M1 in the NDUFA1, was observed in complex I of cybrids with m.3635G>A. This disturbance affected the complex I assembly activity by changing the mitochondrial respiratory chain composition and function. In addition, the affected cybrids exhibited notable deficiencies in complex I activities, including impaired mitochondrial respiration and depolarization of its membrane potential. Apoptosis was also stimulated in the mutant group, as witnessed by the secretion of cytochrome c and activation of PARP, caspase 3, 7, and 9 compared to the control. Furthermore, the mutant group exhibited decreased levels of autophagy protein light chain 3, accumulation of autophagic substrate P62, and impaired PINK1/Parkin-dependent mitophagy. Overall, the current study has confirmed the crucial involvement of the alteration of the m.3635G>A gene in the development of LHON. These findings contribute to a deeper comprehension of the pathophysiological mechanisms underlying LHON, providing a fundamental basis for further research.
    Keywords:  Apoptosis; Leber’s hereditary optic neuropathy (LHON); MT-ND1 mutation; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.gene.2024.148853
  50. Biomed Pharmacother. 2024 Aug 12. pii: S0753-3322(24)01181-8. [Epub ahead of print]178 117297
    Tetrahydrocurcumin ameliorates hepatic steatosis by restoring hepatocytes lipophagy through mTORC1-TFEB pathway in nonalcoholic steatohepatitis.
    Jiazhen Wu, Fengkun Guan, Haipiao Huang, Hanbin Chen, Yuhong Liu, Shangbin Zhang, Muxia Li, Jianping Chen.
      PURPOSE: To investigate the therapeutic effect and underlying mechanism of tetrahydrocurcumin (THC) on nonalcoholic steatohepatitis (NASH) induced by high-fat diet (HFD).METHODS: NASH rat model was established through long-term feeding HFD, and the steatosis cell model was stimulated via palmitate acid (PA). The therapeutic effect of THC was evaluated in terms of liver function, lipid metabolism, liver pathophysiology, inflammation and oxidative stress in vivo, and lipid accumulation in vitro. The alteration in lipophagy was identified by using western blot and immunofluorescence. mTORC1-TFEB signaling pathway was measured by qRT-PCR, western blot and protein-ligand docking. In addition, chloroquine and MHY1485 were further introduced to validate the effect of THC on lipophagy and mTORC1-TFEB signaling pathway, respectively.
    RESULTS: THC effectively improved hepatic steatosis, inflammation and oxidative stress in NASH rats, and reduced lipid accumulation in steatosis L02 cells and Hep G2 cells. THC promoted lipophagy with increasing LC3B-II as well as decreasing P62 expression via lysosomal biogenesis upregulation, which was greatly weakened after chloroquine intervention. mTORC1-TFEB is a critical pathway for regulating lysosome in autophagy, THC treatment induced TFEB nucleus translocation via inhibiting mTORC1 to upregulate lysosomal biogenesis. However, these effects were partly eliminated by mTORC1 activator MHY1485.
    CONCLUSION: THC restored lipophagy to reduce lipid accumulation by regulating mTORC1-TFEB pathway in NASH rats and steatosis hepatocytes. These findings suggested that THC represents a therapeutic candidate for NASH treatment.
    Keywords:  Lipophagy; NASH; TFEB; Tetrahydrocurcumin; mTORC1
    DOI:  https://doi.org/10.1016/j.biopha.2024.117297
  51. Ecotoxicol Environ Saf. 2024 Aug 10. pii: S0147-6513(24)00917-5. [Epub ahead of print]283 116841
    The degradation of α--synuclein is limited by dynein to drive the AALP pathway through HDAC6 upon paraquat exposure.
    Ai Qi, Kaidong Wang, Yujing Li, Rong Hu, Guiling Hu, Yang Li, Ge Shi, Min Huang.
      Lewy body disease (LBD), one of the most common neurodegenerative diseases (NDDs), is characterized by excessive accumulation of α-synuclein (α-syn) in neurons. In recent years, environmental factors such as exposure to herbicides and pesticides have been attributed to the development of this condition. While majority of the studies on neurotoxic effects of paraquat (PQ) have focused on α-syn-mediated neuronal damage in the early stages of α-syn accumulation in neurons, efforts to explore the key target for α-syn degradation are limited. Recent research has suggested that histone deacetylase 6 (HDAC6) might possibly regulate amyloid clearance, and that the metabolism of compounds in neurons is also directly affected by axonal transport in neurons. Dynein predominantly mediates reverse transportation of metabolites and uptake of signal molecules and other compounds at the end of axons, which is conducive to the reuse of cell components. However, the role of interaction of dynein with HDAC6 in metabolites transport is still unclear. Therefore, this study aimed to investigate the role of HDAC6 in α-syn accumulation/clearance in neurons and the associated possible influencing factors. The results revealed that HDAC6 could transport ubiquitinated α-syn, bind to dynein, form an aggresome, and relocate to the center of the microtubule tissue, ultimately reducing abnormal accumulation of α-syn. However, PQ treatment resulted in HDAC6 upregulation, causing abnormal aggregation of α-syn. Taken together, these findings indicated that PQ exposure caused abnormal accumulation of α-syn and decreased effective degradation of α-syn by HDAC6-mediated aggresome-autophagy-lysosome pathway.
    Keywords:  Aggresome; Autophagy; Dynein; Histone deacetylase 6; Paraquat; α-Synuclein
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.116841
  52. Nutrition. 2024 Jun 11. pii: S0899-9007(24)00166-7. [Epub ahead of print]126 112517
    Emerging role of natural lipophagy modulators in metabolic dysfunction-associated steatotic liver disease.
    Nahla E El-Ashmawy, Eman G Khedr, Ghada M Al-Ashmawy, Asmaa A Kamel.
      Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a seriously increasing liver disorder affecting nearly 32% of adults globally. Hepatic triglycerides (TG) accumulation is the hallmark of MASLD, which results from dysregulated lipid and fatty acid uptake, increased de novo lipogenesis (DNL), and decreased lipid removal. More recently, selective autophagy of lipid droplets (LDs), termed lipophagy, has emerged to be closely associated with disrupted hepatic lipid homeostasis. Recent studies have indicated that a series of natural products have shown promise as an alternative approach in attenuating MASLD via regulating lipophagy in vivo and in vitro. Therefore, lipophagy could be a new approach for natural products to be used to improve MASLD. This article aims to provide a comprehensive overview on the interrelationship between dysregulated lipid metabolism, lipophagy, and MASLD pathogenesis. In addition, the role of some natural products as lipophagy modulators and their impact on MASLD will be discussed.
    Keywords:  Autophagy; Lipid droplets; Lipophagy; MASLD; NAFLD; Natural products
    DOI:  https://doi.org/10.1016/j.nut.2024.112517
  53. Int Immunopharmacol. 2024 Aug 14. pii: S1567-5769(24)01440-1. [Epub ahead of print]141 112919
    Inflammation, mitochondrial and lysosomal dysfunction as key players in rheumatoid arthritis?
    Valentina Mihaylova, Rositsa Karalilova, Zguro Batalov, Maria Kazakova, Anastas Batalov, Victoria Sarafian.
      Rheumatoid arthritis (RA) is an inflammatory joint disease characterized by persistent synovitis and inflammation. The exact mechanism of mitochondrial function in the presence of inflammation and dysregulation of autophagic processes in the pathogenesis of RA is still unclear. The aim of our study is to determine mitochondrial function, gene and protein levels of biomolecules related to inflammation (YKL-40) and autophagy (LAMPs) and to search a connection between them in the RA context. Twenty newly diagnosed RA patients and ten healthy individuals were included in the study. Disease severity was assessed by ultrasonography. Conventional clinico-laboratory parameters, immunological markers and protein levels of LAMPs and YKL-40 were examined in plasma. Gene expression analysis for the quantitative measurement of LAMPs and YKL-40 were conducted in white blood cells (WBC). A real-time metabolic analysis was performed to assess mitochondrial function and cell metabolism in peripheral blood mononuclear cells (PBMCs). Increase in spare respiratory capacity in PBMCs of RA patients was detected. Decreased LAMPs plasma protein levels and increased protein levels of YKL-40 in RA patients compared to healthy individuals were measured. No significant differences were found in gene expressions. Correlations between mitochondrial, ultrasonographic and protein levels of the biomarkers related with inflammation and autophagy were established. New data on mitochondrial dysfunction in RA patients and links to inflammation and mitophagy are reported. The relationship between dysregulation of mitophagy and joint diseases deserves to be thoroughly investigated as it would be a promising therapeutic approach.
    Keywords:  Autophagy; Inflammation; Mitochondrial function; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.intimp.2024.112919
  54. ACS Chem Biol. 2024 Aug 12.
    Mitochondrial Probe for Glutathione Depletion Reveals NME3 Essentiality for Mitochondrial Redox Response.
    Piriththiv Dhavarasa, Tanja Sack, Carmine P Cerrato, Ashley P Cheng, Yi Y Zhang, Kangfu Chen, Shana O Kelley.
      Maintenance of the mitochondrial thiol redox state is essential for cell survival. However, we lack a comprehensive understanding of the redox response to mitochondrial glutathione depletion. We developed a mitochondria-penetrating peptide, mtCDNB, to specifically deplete mitochondrial glutathione. A genome-wide CRISPR/Cas9 screen in tandem with mtCDNB treatment was employed to uncover regulators of the redox response to mitochondrial glutathione depletion. We identified nucleoside diphosphate kinase 3 (NME3) as a regulator of mitochondrial dynamics. We show that NME3 is recruited to the mitochondrial outer membrane when under redox stress. In the absence of NME3, there is impaired mitophagy, which leads to the accumulation of dysfunctional mitochondria. NME3 knockouts depleted of mitochondrial glutathione have increased mitochondrial ROS production, accumulate mtDNA lesions, and present a senescence-associated secretory phenotype. Our findings suggest a novel role for NME3 in selecting mitochondria for degradation through mitophagy under conditions of mitochondrial redox stress.
    DOI:  https://doi.org/10.1021/acschembio.4c00287
  55. Front Aging Neurosci. 2024 ;16 1429005
    Alteration of cGAS-STING signaling pathway components in the mouse cortex and hippocampus during healthy brain aging.
    Sergio Passarella, Shananthan Kethiswaran, Karina Brandes, I-Chin Tsai, Kristin Cebulski, Andrea Kröger, Daniela C Dieterich, Peter Landgraf.
      The cGAS-STING pathway is a pivotal element of the innate immune system, recognizing cytosolic DNA to initiate the production of type I interferons and pro-inflammatory cytokines. This study investigates the alterations of the cGAS-STING signaling components in the cortex and hippocampus of mice aged 24 and 108 weeks. In the cortex of old mice, an increase in the dsDNA sensor protein cGAS and its product 2'3'-cGAMP was observed, without corresponding activation of downstream signaling, suggesting an uncoupling of cGAS activity from STING activation. This phenomenon may be attributed to increased dsDNA concentrations in the EC neurons, potentially arising from nuclear DNA damage. Contrastingly, the hippocampus did not exhibit increased cGAS activity with aging, but there was a notable elevation in STING levels, particularly in microglia, neurons and astrocytes. This increase in STING did not correlate with enhanced IRF3 activation, indicating that brain inflammation induced by the cGAS-STING pathway may manifest extremely late in the aging process. Furthermore, we highlight the role of autophagy and its interplay with the cGAS-STING pathway, with evidence of autophagy dysfunction in aged hippocampal neurons leading to STING accumulation. These findings underscore the complexity of the cGAS-STING pathway's involvement in brain aging, with regional variations in activity and potential implications for neurodegenerative diseases.
    Keywords:  autophagy; brain aging; cGAS-STING pathway; cortex; hippocampus; senescence
    DOI:  https://doi.org/10.3389/fnagi.2024.1429005
  56. bioRxiv. 2024 Aug 05. pii: 2024.08.01.606196. [Epub ahead of print]
    Rapamycin increases murine lifespan but does not reduce mineral volume in the Matrix GLA Protein (MGP) knockout mouse model of medial arterial calcification.
    Parya Behzadi, Rolando A Cuevas, Alex Crane, Andrew A Wendling, Claire C Chu, William J Moorhead, Ryan Wong, Mark Brown, Joshua Tamakloe, Swathi Suresh, Payam Salehi, Iris Z Jaffe, Allison L Kuipers, Lyudmila Lukashova, Konstantinos Verdelis, Cynthia St Hilaire.
      Peripheral artery disease (PAD) is the narrowing of the arteries that carry blood to the lower extremities. PAD has been traditionally associated with atherosclerosis. However, recent studies have found that medial arterial calcification (MAC) is the primary cause of chronic limb ischemia below the knee. MAC involves calcification of the elastin fibers surrounding smooth muscle cells (SMCs) in arteries. Matrix GLA Protein (MGP) binds circulating calcium and inhibits vascular calcification. Mgp -/- mice develop severe MAC and die within 8 weeks of birth due to aortic rupture or heart failure. We previously discovered a rare genetic disease Arterial Calcification due to Deficiency in CD73 (ACDC) in which patients present with extensive MAC in their lower extremity arteries. Using a patient-specific induced pluripotent stem cell model we found that rapamycin inhibited calcification. Here we investigated whether rapamycin could reduce MAC in vivo using Mgp -/- mice as a model. Mgp +/+ and Mgp -/- mice received 5mg/kg rapamycin or vehicle. Calcification content was assessed via microCT, and vascular morphology and extracellular matrix content assessed histologically. Immunostaining and western blot analysis were used to examine SMC phenotypes and cellular functions. Rapamycin prolonged Mgp -/- mice lifespan, decreased mineral density in the arteries, and increased smooth muscle actin protein levels, however, calcification volume, vessel morphology, SMC proliferation, and autophagy flux were all unchanged. These findings suggest that rapamycin's effects in the Mgp -/- mouse are independent of the vascular phenotype.
    DOI:  https://doi.org/10.1101/2024.08.01.606196
  57. Brain Res Bull. 2024 Aug 10. pii: S0361-9230(24)00176-X. [Epub ahead of print]216 111043
    Ginsenoside Rg1 ameliorates cerebral ischemia-reperfusion injury by regulating Pink1/ Parkin-mediated mitochondrial autophagy and inhibiting microglia NLRP3 activation.
    Changbai Sui, Ying Liu, Jun Jiang, Jianhua Tang, Ling Yu, Guoying Lv.
      OBJECTIVE: This study aimed to further elucidate the mechanism of ginsenoside Rg1 in the treatment of cerebral ischemia-reperfusion.METHODS: In this study, we observed the apoptosis of RM cells (microglia) after oxygen-glucose deprivation/reoxygenation (OGD/R) modeling before and after Rg1 administration, changes in mitochondrial membrane potential, changes in the content of Reactive oxygen species (ROS) and inflammatory vesicles NLR Family Pyrin Domain Containing 3 (NLRP3), and the expression levels of autophagy-related proteins, inflammatory factors, and apoptosis proteins. We further examined the pathomorphological changes in brain tissue, neuronal damage, changes in mitochondrial morphology and mitochondrial structure, and the autophagy-related proteins, inflammatory factors, and apoptosis proteins expression levels in CI/RI rats before and after administration of Rg1 in vivo experiments.
    RESULTS: In vitro experiments showed that Rg1 induced mitochondrial autophagy, decreased mitochondrial membrane potential, and reduced ROS content thereby inhibiting NLRP3 activation, decreasing secretion of inflammatory factors and RM cell apoptosis by regulating the PTEN induced putative kinase 1(Pink1) /Parkin signaling pathway. In vivo experiments showed that Rg1 induced mitochondrial autophagy, inhibited NLRP3 activation, improved inflammatory response, and reduced apoptosis by regulating the Pink1/Parkin signaling pathway, and Rg1 significantly reduced the area of cerebral infarcts, improved the pathological state of brain tissue, and attenuated the neuronal damage, thus improving cerebral ischemia/reperfusion injury in rats.
    CONCLUSION: Our results suggest that ginsenoside Rg1 can ameliorate cerebral ischemia-reperfusion injury by modulating Pink1/ Parkin-mediated mitochondrial autophagy in microglia and inhibiting microglial NLRP3 activation.
    Keywords:  Cerebral ischemia/reperfusion injury; Ginsenoside Rg1; Microglia; Mitochondrial autophagy; Pink1/Parkin
    DOI:  https://doi.org/10.1016/j.brainresbull.2024.111043
  58. bioRxiv. 2024 Aug 08. pii: 2024.08.07.607085. [Epub ahead of print]
    ER-phagy drives age-onset remodeling of endoplasmic reticulum structure-function and lifespan.
    Ekf Donahue, N L Hepowit, B Keuchel, A G Mulligan, D J Johnson, M Ellisman, R Arrojo E Drigo, J MacGurn, K Burkewitz.
      The endoplasmic reticulum (ER) comprises an array of structurally distinct subdomains, each with characteristic functions. While altered ER-associated processes are linked to age-onset pathogenesis, whether shifts in ER morphology underlie these functional changes is unclear. We report that ER remodeling is a conserved feature of the aging process in models ranging from yeast to C. elegans and mammals. Focusing on C. elegans as an exemplar of metazoan aging, we find that as animals age, ER mass declines in virtually all tissues and ER morphology shifts from rough sheets to tubular ER. The accompanying large-scale shifts in proteomic composition correspond to the ER turning from protein synthesis to lipid metabolism. To drive this substantial remodeling, ER-phagy is activated early in adulthood, promoting turnover of rough ER in response to rises in luminal protein-folding burden and reduced global protein synthesis. Surprisingly, ER remodeling is a pro-active and protective response during aging, as ER-phagy impairment limits lifespan in yeast and diverse lifespan-extending paradigms promote profound remodeling of ER morphology even in young animals. Altogether our results reveal ER-phagy and ER morphological dynamics as pronounced, underappreciated mechanisms of both normal aging and enhanced longevity.
    DOI:  https://doi.org/10.1101/2024.08.07.607085
  59. Biochem J. 2024 Aug 13. pii: BCJ20240255. [Epub ahead of print]
    Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation.
    Sarah E Garnish, Christopher R Horne, Yanxiang Meng, Samuel N Young, Annette V Jacobsen, Joanne Hildebrand, James M Murphy.
      Necroptosis is a lytic and pro-inflammatory form of programmed cell death executed by the terminal effector, the MLKL (Mixed Lineage Kinase Domain-like) pseudokinase. Downstream of death and Toll-like receptor stimulation, MLKL is trafficked to the plasma membrane via the Golgi-, actin- and microtubule- machinery, where activated MLKL accumulates until a critical lytic threshold is exceeded and cell death ensues. Mechanistically, MLKL's lytic function relies on disengagement of the N-terminal membrane-permeabilising four-helix bundle (4HB) domain from the central autoinhibitory brace helix: a process that can be experimentally mimicked by introducing the R30E MLKL mutation to induce stimulus-independent cell death. Here, we screened a library of 429 kinase inhibitors for their capacity to block R30E MLKL-mediated cell death, to identify co-effectors in the terminal steps of necroptotic signaling. We identified 13 compounds - ABT-578, AR-A014418, AZD1480, AZD5363, Idelalisib,  Ipatasertib, LJ1308, PHA-793887, Rapamycin, Ridaforolimus, SMI-4a,  Temsirolimus and Tideglusib - each of which inhibits mTOR signalling or regulators thereof, and blocked constitutive cell death executed by R30E MLKL. Our study implicates mTOR signalling as an auxiliary factor in promoting transport of activated MLKL oligomers to the plasma membrane, where they accumulate into hotspots that permeabilise the lipid bilayer to cause cell death.
    Keywords:  mechanistic target of rapamycinr; necroptosis; protein kinase; pseudokinase; signalling
    DOI:  https://doi.org/10.1042/BCJ20240255
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