bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023‒10‒01
fifty-four papers selected by
Viktor Korolchuk, Newcastle University
  1. Chlorpromazine affects autophagy in association with altered Rag GTPase-mTORC1-TFEB signaling.
  2. Autophagy Receptor-Inspired Antibody-Fusion Proteins for Targeted Intracellular Degradation.
  3. Nutrient-dependent signaling pathways that control autophagy in yeast.
  4. Structural view on autophagosome formation.
  5. Model Organisms to Study Autophagy.
  6. Direct regulation of FNIP1 and FNIP2 by MEF2 sustains MTORC1 activation and tumor progression in pancreatic cancer.
  7. Roles of Stress Response in Autophagy Processes and Aging-Related Diseases.
  8. Role of mTORC1 Signaling in Regulating the Immune Function of Granulocytes in Teleost Fish.
  9. Ubiquitin Ligase Nrdp1 Controls Autophagy-Associated Acrosome Biogenesis and Mitochondrial Arrangement during Spermiogenesis.
  10. The Current State of Research on Sirtuin-Mediated Autophagy in Cardiovascular Diseases.
  11. mTORC1 Regulates the Metabolic Switch of Postnatal Cardiomyocytes During Regeneration.
  12. Autophagy Modulation as a Potential Therapeutic Strategy in Osteosarcoma: Current Insights and Future Perspectives.
  13. The Dual Role of Autophagy in Postischemic Brain Neurodegeneration of Alzheimer's Disease Proteinopathy.
  14. Lost in translation: a neglected mTOR target for lymphangioleiomyomatosis.
  15. Sirtuins and autophagy in lipid metabolism.
  16. Stressed Hippo kinase turns to autophagy.
  17. ULK1 forms distinct oligomeric states and nanoscopic structures during autophagy initiation.
  18. Blocking glycosphingolipid production alters autophagy in osteoclasts and improves myeloma bone disease.
  19. Vacuolar proteases and autophagy in phytopathogenic fungi: A review.
  20. Long Noncoding RNA Gpr137b-ps Promotes Advanced Atherosclerosis via the Regulation of Autophagy in Macrophages.
  21. NLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85α to drive tumorigenesis.
  22. Identification of a muscle-specific isoform of VMA21 as a potent actor in X-linked myopathy with excessive autophagy pathogenesis.
  23. Redox-mediated activation of ATG3 promotes ATG8 lipidation and autophagy progression in Chlamydomonas reinhardtii.
  24. Regulation of Tomato Fruit Autophagic Flux and Promotion of Fruit Ripening by the Autophagy-Related Gene SlATG8f.
  25. FCS-like zinc finger proteins maintain energy homeostasis during stresses.
  26. Inhibition of Dipeptidyl Peptidase-4 Activates Autophagy to Promote Survival of Breast Cancer Cells via the mTOR/HIF-1α Pathway.
  27. Nitric Oxide Induces Autophagy in Triticum aestivum Roots.
  28. Review of PINK1-Parkin-mediated mitochondrial autophagy in Alzheimer's disease.
  29. Interaction between Autophagy and Senescence in Pancreatic Beta Cells.
  30. Proteome census upon nutrient stress reveals Golgiphagy membrane receptors.
  31. Syringin Prevents 6-Hydroxydopamine Neurotoxicity by Mediating the MiR-34a/SIRT1/Beclin-1 Pathway and Activating Autophagy in SH-SY5Y Cells and the Caenorhabditis elegans Model.
  32. Autophagy and Biomaterials: A Brief Overview of the Impact of Autophagy in Biomaterial Applications.
  33. Regulation of Phosphoinositide Signaling by Scaffolds at Cytoplasmic Membranes.
  34. Protein interaction network analysis of mTOR signaling reveals modular organization.
  35. Lipopolysaccharide promotes NLRP3 inflammasome activation by inhibiting TFEB-mediated autophagy in NRK-52E cells.
  36. p38MAPK/MK2 signaling stimulates host cells autophagy pathways to restrict Salmonella infection.
  37. PP2C phosphatases Ptc1 and Ptc2 dephosphorylate PGK1 to regulate autophagy and aflatoxin synthesis in the pathogenic fungus Aspergillus flavus.
  38. Obatoclax Rescues FUS-ALS Phenotypes in iPSC-Derived Neurons by Inducing Autophagy.
  39. mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia.
  40. Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly.
  41. Lysosomal cyst(e)ine storage potentiates tolerance to oxidative stress in cancer cells.
  42. DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.
  43. Cardiac glycosides restore autophagy flux in an iPSC-derived neuronal model of WDR45 deficiency.
  44. Nucleocapsid Protein (N) of Peste des petits ruminants Virus (PPRV) Interacts with Cellular Phosphatidylinositol-3-Kinase (PI3K) Complex-I and Induces Autophagy.
  45. ATG14 plays a critical role in hepatic lipid droplet homeostasis.
  46. Transcriptional pausing factor M1BP regulates cellular homeostasis by suppressing autophagy and apoptosis in Drosophila eye.
  47. Selective removal of misfolded SOD1 delays disease onset in a mouse model of amyotrophic lateral sclerosis.
  48. Role of Fyn and the interleukin-6-STAT-3-autophagy axis in sarcopenia.
  49. An mTORC1-Dependent Mouse Model for Cardiac Sarcoidosis.
  50. Glutamine regulates the cellular proliferation and cell cycle progression by modulating the mTOR mediated protein levels of β-TrCP.
  51. Mechanistic insights into the interactions of Arl8b with the RUN domains of PLEKHM1 and SKIP.
  52. The lipid basis of cell death and autophagy.
  53. Cathepsin D mediates prenatal caffeine exposure-caused NAFLD susceptibility in male rat offspring by regulating autophagy.
  54. Irisin ameliorates diabetic kidney disease by restoring autophagy in podocytes.
  1. Front Cell Dev Biol. 2023 ;11 1266198
    Chlorpromazine affects autophagy in association with altered Rag GTPase-mTORC1-TFEB signaling.
    Ningning Li, Lingling Rao, Xueqing Zhao, Junwen Shen, Dan Su, Guoqiang Ma, Shan Sun, Qilian Ma, Li Zhang, Chunsheng Dong, Kin Yip Tam, Jochen H M Prehn, Hongfeng Wang, Zheng Ying.
      Autophagy is a critical protein and organelle quality control system, which regulates cellular homeostasis and survival. Growing pieces of evidence suggest that autophagic dysfunction is strongly associated with many human diseases, including neurological diseases and cancer. Among various autophagic regulators, microphthalmia (MiT)/TFE transcription factors, including transcription factor EB (TFEB), have been shown to act as the master regulators of autophagosome and lysosome biogenesis in both physiological and pathological conditions. According to the previous studies, chlorpromazine (CPZ), an FDA-approved antipsychotic drug, affects autophagy in diverse cell lines, but the underlying mechanism remains elusive. In our present study, we find that CPZ treatment induces TFEB nuclear translocation through Rag GTPases, the upstream regulators of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Meanwhile, CPZ treatment also blocks autophagosome-lysosome fusion. Notably, we find a significant accumulation of immature autophagosome vesicles in CPZ-treated cells, which may impede cellular homeostasis due to the dysfunction of the autophagy-lysosome pathway. Interestingly and importantly, our data suggest that the expression of the active form of Rag GTPase heterodimers helps in reducing the accumulation of autophagosomes in CPZ-treated cells, further suggesting a major contribution of the Rag GTPase-mTORC1-TFEB signaling axis in CPZ-induced autophagic impairment.
    Keywords:  CPZ; Rag GTPases; TFEB; autophagy; mTORC1
    DOI:  https://doi.org/10.3389/fcell.2023.1266198
  2. J Am Chem Soc. 2023 Sep 25.
    Autophagy Receptor-Inspired Antibody-Fusion Proteins for Targeted Intracellular Degradation.
    Ziwen Jiang, Yu-Hsuan Kuo, Michelle R Arkin.
      Autophagy is responsible for the degradation of large intracellular contents, such as unwanted protein aggregates and organelles. Impaired autophagy can therefore lead to the accumulation of pathological aggregates, correlating with aging and neurodegenerative diseases. However, a broadly applicable methodology is not available for the targeted degradation of protein aggregates or organelles in mammalian cells. Herein, we developed a series of autophagy receptor-inspired targeting chimeras (AceTACs) that can induce the targeted degradation of aggregation-prone proteins and protein aggregates (e.g., huntingtin, TDP-43, and FUS mutants), as well as organelles (e.g., mitochondria, peroxisomes, and endoplasmic reticulum). These antibody-fusion-based AceTAC degraders were designed to mimic the function of autophagy receptors, simultaneously binding with the cellular targets and the LC3 proteins on the autophagosomal membrane, eventually transporting the target to the autophagy-lysosomal process for degradation. The AceTAC degradation system provides design principles for antibody-based degradation through autophagy, largely expanding the scope of intracellular targeted degradation technologies.
    DOI:  https://doi.org/10.1021/jacs.3c05199
  3. FEBS Lett. 2023 Sep 27.
    Nutrient-dependent signaling pathways that control autophagy in yeast.
    Shree Padma Metur, Daniel J Klionsky.
      Macroautophagy/autophagy is a highly conserved catabolic process vital for cellular stress responses and maintaining equilibrium within the cell. Malfunctioning autophagy has been implicated in the pathogenesis of various diseases, including certain neurodegenerative disorders, diabetes, metabolic diseases and cancer. Cells face diverse metabolic challenges, such as limitations in nitrogen, carbon, and minerals such as phosphate and iron, necessitating the integration of complex metabolic information. Cells utilize a signal transduction network of sensors, transducers, and effectors to coordinate the execution of the autophagic response, concomitant with the severity of the nutrient-starvation condition. This review presents the current mechanistic understanding of how cells regulate the initiation of autophagy through various nutrient-dependent signaling pathways. Emphasizing findings from studies in yeast, we explore the emerging principles that underlie the nutrient-dependent regulation of autophagy, significantly shaping stress-induced autophagy responses under various metabolic stress conditions.
    Keywords:  AMPK; PKA; TOR; autophagy regulation; nutrient homeostasis; signaling
    DOI:  https://doi.org/10.1002/1873-3468.14741
  4. FEBS Lett. 2023 Sep 27.
    Structural view on autophagosome formation.
    Nobuo N Noda.
      Autophagy is a conserved intracellular degradation system in eukaryotes, involving the sequestration of degradation targets into autophagosomes, which are subsequently delivered to lysosomes (or vacuoles in yeasts and plants) for degradation. In budding yeast, starvation-induced autophagosome formation relies on approximately 20 core Atg proteins, grouped into six functional categories: the Atg1/ULK complex, the phosphatidylinositol-3 kinase complex, the Atg9 transmembrane protein, the Atg2-Atg18/WIPI complex, the Atg8 lipidation system, and the Atg12-Atg5 conjugation system. Additionally, selective autophagy requires cargo receptors and other factors, including a fission factor, for specific sequestration. This review covers the 30-year history of structural studies on core Atg proteins and factors involved in selective autophagy, examining X-ray crystallography, NMR, and cryo-EM techniques. The molecular mechanisms of autophagy are explored based on protein structures, and future directions in the structural biology of autophagy are discussed, considering the advancements in the era of AlphaFold.
    Keywords:  AlphaFold; autophagy; core Atg proteins; selective autophagy; structural studies
    DOI:  https://doi.org/10.1002/1873-3468.14742
  5. Cells. 2023 Sep 05. pii: 2212. [Epub ahead of print]12(18):
    Model Organisms to Study Autophagy.
    Qiuhong Xiong, Ludwig Eichinger.
      Autophagy is the major lysosomal pathway for the clearance of proteins, organelles and microbes in eukaryotic cells. Therefore, autophagic dysfunction can lead to numerous human diseases, like cancer or neurodegeneration, and may facilitate infections by pathogens. However, despite tremendous advances in the understanding of autophagy over the past decades, the functions and regulations of autophagy-related proteins in canonical and non-canonical autophagy are still not fully resolved. The Special Issue "Model Organisms to Study Autophagy" organized by Cells includes six original articles and one review that show the latest achievements in autophagy research using different model organisms. The Special Issue summarizes and discusses different aspects of autophagy that open new avenues in understanding autophagy functions and mechanisms.
    Keywords:  autophagy; function; model organism; non-canonical autophagy
    DOI:  https://doi.org/10.3390/cells12182212
  6. Autophagy. 2023 Sep 29. 1-20
    Direct regulation of FNIP1 and FNIP2 by MEF2 sustains MTORC1 activation and tumor progression in pancreatic cancer.
    Li Xia, Tiejian Nie, Fangfang Lu, Lu Huang, Xiaolong Shi, Dongni Ren, Jianjun Lu, Xiaobin Li, Tuo Xu, Bozhou Cui, Qing Wang, Guodong Gao, Qian Yang.
      MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) orchestrates diverse environmental signals to facilitate cell growth and is frequently activated in cancer. Translocation of MTORC1 from the cytosol to the lysosomal surface by the RRAG GTPases is the key step in MTORC1 activation. Here, we demonstrated that transcription factors MEF2A and MEF2D synergistically regulated MTORC1 activation via modulating its cyto-lysosome shutting. Mechanically, MEF2A and MEF2D controlled the transcription of FNIP1 and FNIP2, the components of the FLCN-FNIP1 or FNIP2 complex that acts as a RRAGC-RRAGD GTPase-activating element to promote the recruitment of MTORC1 to lysosome and its activation. Furthermore, we determined that the pro-oncogenic protein kinase SRC/c-Src directly phosphorylated MEF2D at three conserved tyrosine residues. The tyrosine phosphorylation enhanced MEF2D transcriptional activity and was indispensable for MTORC1 activation. Finally, both the protein and tyrosine phosphorylation levels of MEF2D are elevated in human pancreatic cancers, positively correlating with MTORC1 activity. Depletion of both MEF2A and MEF2D or expressing the unphosphorylatable MEF2D mutant suppressed tumor cell growth. Thus, our study revealed a transcriptional regulatory mechanism of MTORC1 that promoted cell anabolism and proliferation and uncovered its critical role in pancreatic cancer progression.Abbreviation: ACTB: actin beta; ChIP: chromatin immunoprecipitation; EGF: epidermal growth factor; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; FLCN: folliculin; FNIP1: folliculin interacting protein 1; FNIP2: folliculin interacting protein 2; GAP: GTPase activator protein; GEF: guanine nucleotide exchange factors; GTPase: guanosine triphosphatase; LAMP2: lysosomal associated membrane protein 2; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEF2: myocyte enhancer factor 2; MEF2A: myocyte enhancer factor 2A; MEF2D: myocyte enhancer factor 2D; MEF2D-3YF: Y131F, Y333F, Y337F mutant; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NR4A1: nuclear receptor subfamily 4 group A member 1; RPTOR: regulatory associated protein of MTOR complex 1; RHEB: Ras homolog, mTORC1 binding; RPS6KB1: ribosomal protein S6 kinase B1; RRAG: Ras related GTP binding; RT-qPCR: real time-quantitative PCR; SRC: SRC proto-oncogene, non-receptor tyrosine kinase; TMEM192: transmembrane protein 192; WT: wild-type.
    Keywords:  Autophagy; cell metabolism; oncogenesis; protein kinase; transcription factor
    DOI:  https://doi.org/10.1080/15548627.2023.2259735
  7. Int J Mol Sci. 2023 Sep 07. pii: 13804. [Epub ahead of print]24(18):
    Roles of Stress Response in Autophagy Processes and Aging-Related Diseases.
    Yoshihisa Watanabe, Katsutoshi Taguchi, Masaki Tanaka.
      The heat shock factor 1 (HSF1)-mediated stress response pathway and autophagy processes play important roles in the maintenance of proteostasis. Autophagy processes are subdivided into three subtypes: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. Recently, molecular chaperones and co-factors were shown to be involved in the selective degradation of substrates by these three autophagy processes. This evidence suggests that autophagy processes are regulated in a coordinated manner by the HSF1-mediated stress response pathway. Recently, various studies have demonstrated that proteostasis pathways including HSF1 and autophagy are implicated in longevity. Furthermore, they serve as therapeutic targets for aging-related diseases such as cancer and neurodegenerative diseases. In the future, these studies will underpin the development of therapies against various diseases.
    Keywords:  aging; chaperone-mediated autophagy; macroautophagy; microautophagy; proteostasis network; stress response
    DOI:  https://doi.org/10.3390/ijms241813804
  8. Int J Mol Sci. 2023 Sep 06. pii: 13745. [Epub ahead of print]24(18):
    Role of mTORC1 Signaling in Regulating the Immune Function of Granulocytes in Teleost Fish.
    Jiafeng Cao, Weiguang Kong, Gaofeng Cheng, Zhen Xu.
      Granulocytes are crucial innate immune cells that have been extensively studied in teleost fish. Studies in mammals have revealed that mechanistic target of rapamycin complex 1 (mTORC1) signaling acts as a significant immune regulatory hub, influencing granulocyte immune function. To investigate whether mTORC1 signaling also regulates the immune function of granulocytes in teleost fish, we established a model of RAPA inhibition of the mTORC1 signaling pathway using granulocytes from largemouth bass (Micropterus salmoides). Our results demonstrated that inhibition of mTORC1 signaling promoted autophagy and apoptosis of granulocytes while inhibiting cell proliferation. Moreover, inhibition of the mTORC1 signaling pathway enhanced the phagocytosis capacity of granulocytes. Collectively, our findings revealed the evolutionarily conserved role of the mTORC1 signaling pathway in regulating granulocyte responses, thus providing novel insights into the function of granulocytes in teleost fish.
    Keywords:  RNA-Seq; granulocytes; immunity; largemouth bass; mechanistic target of rapamycin complex 1 (mTORC1)
    DOI:  https://doi.org/10.3390/ijms241813745
  9. Cells. 2023 Sep 05. pii: 2211. [Epub ahead of print]12(18):
    Ubiquitin Ligase Nrdp1 Controls Autophagy-Associated Acrosome Biogenesis and Mitochondrial Arrangement during Spermiogenesis.
    Zi-Yu Luo, Tian-Xia Jiang, Tao Zhang, Ping Xu, Xiao-Bo Qiu.
      Autophagy is critical to acrosome biogenesis and mitochondrial quality control, but the underlying mechanisms remain unclear. The ubiquitin ligase Nrdp1/RNF41 promotes ubiquitination of the mitophagy-associated Parkin and interacts with the pro-autophagic protein SIP/CacyBP. Here, we report that global deletion of Nrdp1 leads to formation of the round-headed sperm and male infertility by disrupting autophagy. Quantitative proteome analyses demonstrated that the expression of many proteins associated with mitochondria, lysosomes, and acrosomes was dysregulated in either spermatids or sperm of the Nrdp1-deficient mice. Deletion of Nrdp1 increased the levels of Parkin but decreased the levels of SIP, the mitochondrial fission protein Drp1 and the mitochondrial protein Tim23 in sperm, accompanied by the inhibition of autophagy, the impairment of acrosome biogenesis and the disruption of mitochondrial arrangement in sperm. Thus, our results uncover an essential role of Nrdp1 in spermiogenesis and male fertility by promoting autophagy, providing important clues to cope with the related male reproductive diseases.
    Keywords:  Nrdp1; Parkin; SIP/CacyBP; acrosome; autophagy; mitochondrium; mitophagy; spermiogenesis; ubiquitin ligase
    DOI:  https://doi.org/10.3390/cells12182211
  10. J Cardiovasc Dev Dis. 2023 Sep 06. pii: 382. [Epub ahead of print]10(9):
    The Current State of Research on Sirtuin-Mediated Autophagy in Cardiovascular Diseases.
    Yuqin Wang, Yongnan Li, Hong Ding, Dan Li, Wanxi Shen, Xiaowei Zhang.
      Sirtuins belong to the class III histone deacetylases and possess nicotinamide adenine dinucleotide-dependent deacetylase activity. They are involved in the regulation of multiple signaling pathways implicated in cardiovascular diseases. Autophagy is a crucial adaptive cellular response to stress stimuli. Mounting evidence suggests a strong correlation between Sirtuins and autophagy, potentially involving cross-regulation and crosstalk. Sirtuin-mediated autophagy plays a crucial regulatory role in some cardiovascular diseases, including atherosclerosis, ischemia/reperfusion injury, hypertension, heart failure, diabetic cardiomyopathy, and drug-induced myocardial damage. In this context, we summarize the research advancements pertaining to various Sirtuins involved in autophagy and the molecular mechanisms regulating autophagy. We also elucidate the biological function of Sirtuins across diverse cardiovascular diseases and further discuss the development of novel drugs that regulate Sirtuin-mediated autophagy.
    Keywords:  AMPK; FOXOs; Sirtuins; Sirtuins-based therapies; autophagy; cardiovascular diseases; mTOR
    DOI:  https://doi.org/10.3390/jcdd10090382
  11. bioRxiv. 2023 Sep 13. pii: 2023.09.12.557400. [Epub ahead of print]
    mTORC1 Regulates the Metabolic Switch of Postnatal Cardiomyocytes During Regeneration.
    Wyatt G Paltzer, Timothy J Aballo, Jiyoung Bae, Katharine A Hubert, Dakota J Nuttall, Cassidy Perry, Kayla N Wanless, Raya Nahlawi, Ying Ge, Ahmed I Mahmoud.
      The metabolic switch from glycolysis to fatty acid oxidation in postnatal cardiomyocytes contributes to the loss of the cardiac regenerative potential of the mammalian heart. However, the mechanisms that regulate this metabolic switch remain unclear. The protein kinase complex mechanistic target of rapamycin complex 1 (mTORC1) is a central signaling hub that regulates cellular metabolism and protein synthesis, yet its role during mammalian heart regeneration and postnatal metabolic maturation is undefined. Here, we use immunoblotting, rapamycin treatment, myocardial infarction, and global proteomics to define the role of mTORC1 in postnatal heart development and regeneration. Our results demonstrate that the activity of mTORC1 is dynamically regulated between the regenerating and the non-regenerating hearts. Acute inhibition of mTORC1 by rapamycin or everolimus reduces cardiomyocyte proliferation and inhibits neonatal heart regeneration following injury. Our quantitative proteomic analysis demonstrates that transient inhibition of mTORC1 during neonatal heart injury did not reduce protein synthesis, but rather shifts the cardiac proteome of the neonatal injured heart from glycolysis towards fatty acid oxidation. This indicates that mTORC1 inhibition following injury accelerates the postnatal metabolic switch, which promotes metabolic maturation and impedes cardiomyocyte proliferation and heart regeneration. Taken together, our results define an important role for mTORC1 in regulating postnatal cardiac metabolism and may represent a novel target to modulate cardiac metabolism and promote heart regeneration.
    DOI:  https://doi.org/10.1101/2023.09.12.557400
  12. Int J Mol Sci. 2023 Sep 07. pii: 13827. [Epub ahead of print]24(18):
    Autophagy Modulation as a Potential Therapeutic Strategy in Osteosarcoma: Current Insights and Future Perspectives.
    Sergio Almansa-Gómez, Francisco Prieto-Ruiz, José Cansado, Marisa Madrid.
      Autophagy, the process that enables the recycling and degradation of cellular components, is essential for homeostasis, which occurs in response to various types of stress. Autophagy plays an important role in the genesis and evolution of osteosarcoma (OS). The conventional treatment of OS has limitations and is not always effective at controlling the disease. Therefore, numerous researchers have analyzed how controlling autophagy could be used as a treatment or strategy to reverse resistance to therapy in OS. They highlight how the inhibition of autophagy improves the efficacy of chemotherapeutic treatments and how the promotion of autophagy could prove positive in OS therapy. The modulation of autophagy can also be directed against OS stem cells, improving treatment efficacy and preventing cancer recurrence. Despite promising findings, future studies are needed to elucidate the molecular mechanisms of autophagy and its relationship to OS, as well as the mechanisms underlying the functioning of autophagic modulators. Careful evaluation is required as autophagy modulation may have adverse effects on normal cells, and the optimization of autophagic modulators for use as drugs in OS is imperative.
    Keywords:  autophagy; cancer; chemoresistance; modulation; osteosarcoma; radioresistance; treatment
    DOI:  https://doi.org/10.3390/ijms241813827
  13. Int J Mol Sci. 2023 Sep 07. pii: 13793. [Epub ahead of print]24(18):
    The Dual Role of Autophagy in Postischemic Brain Neurodegeneration of Alzheimer's Disease Proteinopathy.
    Ryszard Pluta.
      Autophagy is a self-defense and self-degrading intracellular system involved in the recycling and elimination of the payload of cytoplasmic redundant components, aggregated or misfolded proteins and intracellular pathogens to maintain cell homeostasis and physiological function. Autophagy is activated in response to metabolic stress or starvation to maintain homeostasis in cells by updating organelles and dysfunctional proteins. In neurodegenerative diseases, such as cerebral ischemia, autophagy is disturbed, e.g., as a result of the pathological accumulation of proteins associated with Alzheimer's disease and their structural changes. Postischemic brain neurodegeneration, such as Alzheimer's disease, is characterized by the accumulation of amyloid and tau protein. After cerebral ischemia, autophagy was found to be activated in neuronal, glial and vascular cells. Some studies have shown the protective properties of autophagy in postischemic brain, while other studies have shown completely opposite properties. Thus, autophagy is now presented as a double-edged sword with possible therapeutic potential in brain ischemia. The exact role and regulatory pathways of autophagy that are involved in cerebral ischemia have not been conclusively elucidated. This review aims to provide a comprehensive look at the advances in the study of autophagy behavior in neuronal, glial and vascular cells for ischemic brain injury. In addition, the importance of autophagy in neurodegeneration after cerebral ischemia has been highlighted. The review also presents the possibility of modulating the autophagy machinery through various compounds on the development of neurodegeneration after cerebral ischemia.
    Keywords:  Alzheimer’s disease proteinopathy; apoptosis; autophagy; brain ischemia; endothelial cells; glial cells; necrosis; neurodegeneration; neurons; recirculation; reperfusion
    DOI:  https://doi.org/10.3390/ijms241813793
  14. Eur Respir Rev. 2023 Sep 30. pii: 230100. [Epub ahead of print]32(169):
    Lost in translation: a neglected mTOR target for lymphangioleiomyomatosis.
    Jilly F Evans, Francis X McCormack, Nahum Sonenberg, Vera P Krymskaya.
      Lymphangioleiomyomatosis (LAM) is a cystic lung disease of women resulting from mutations in tuberous sclerosis complex (TSC) genes that suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway. mTORC1 activation enhances a plethora of anabolic cellular functions, mainly via the activation of mRNA translation through stimulation of ribosomal protein S6 kinase (S6K1)/ribosomal protein S6 (S6) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1)/eukaryotic translation initiation factor 4E (eIF4E). Rapamycin (sirolimus), an allosteric inhibitor of mTORC1, stabilises lung function in many but not all LAM patients and, upon cessation of the drug, disease progression resumes. At clinically tolerable concentrations, rapamycin potently inhibits the ribosomal S6K1/S6 translation ribosome biogenesis and elongation axis, but not the translation 4E-BP1/eIF4E initiation axis. In this mini-review, we propose that inhibition of mTORC1-driven translation initiation is an obvious but underappreciated therapeutic strategy in LAM, TSC and other mTORC1-driven diseases.
    DOI:  https://doi.org/10.1183/16000617.0100-2023
  15. Cell Biochem Funct. 2023 Sep 27.
    Sirtuins and autophagy in lipid metabolism.
    Xuan Sun, Xiaoting Yang, Wanfei Gui, Songling Liu, Qingjun Gui.
      Sirtuins are a family of NAD+ -dependent deacetylases that regulate some important biological processes, including lipid metabolism and autophagy, through their deacetylase function. Autophagy is a new discovery in the field of lipid metabolism, which may provide a new idea for the regulation of lipid metabolism. There are many tandem parts in the regulation process of lipid metabolism and autophagy of sirtuins protein family. This paper summarized these tandem parts and proposed the possibility of sirtuins regulating lipid autophagy, as well as the interaction and synergy between sirtuins protein family. Currently, some natural drugs have been reported to affect metabolism by regulating sirtuins, some of which regulate autophagy by targeting sirtuins.
    Keywords:  Sirtuins; autophagy; lipid metabolism; metabolic disease; natural drugs
    DOI:  https://doi.org/10.1002/cbf.3860
  16. Sci Signal. 2023 Sep 26. 16(804): eadk9489
    Stressed Hippo kinase turns to autophagy.
    Leslie K Ferrarelli.
      The Hippo kinase MAP4K2 takes a YAP-independent path to tolerating energy stress.
    DOI:  https://doi.org/10.1126/scisignal.adk9489
  17. Sci Adv. 2023 Sep 29. 9(39): eadh4094
    ULK1 forms distinct oligomeric states and nanoscopic structures during autophagy initiation.
    Chiranjib Banerjee, Dushyant Mehra, Daihyun Song, Angel Mancebo, Ji-Man Park, Do-Hyung Kim, Elias M Puchner.
      Autophagy induction involves extensive molecular and membrane reorganization. Despite substantial progress, the mechanism underlying autophagy initiation remains poorly understood. Here, we used quantitative photoactivated localization microscopy with single-molecule sensitivity to analyze the nanoscopic distribution of endogenous ULK1, the kinase that triggers autophagy. Under amino acid starvation, ULK1 formed large clusters containing up to 161 molecules at the endoplasmic reticulum. Cross-correlation analysis revealed that ULK1 clusters engaging in autophagosome formation require 30 or more molecules. The ULK1 structures with more than the threshold number contained varying levels of Atg13, Atg14, Atg16, LC3B, GEC1, and WIPI2. We found that ULK1 activity is dispensable for the initial clustering of ULK1, but necessary for the subsequent expansion of the clusters, which involves interaction with Atg14, Atg16, and LC3B and relies on Vps34 activity. This quantitative analysis at the single-molecule level has provided unprecedented insights into the behavior of ULK1 during autophagy initiation.
    DOI:  https://doi.org/10.1126/sciadv.adh4094
  18. Autophagy. 2023 Sep 29. 1-3
    Blocking glycosphingolipid production alters autophagy in osteoclasts and improves myeloma bone disease.
    Houfu Leng, Anna Katharina Simon, Nicole J Horwood.
      Glycosphingolipids (GSLs) are key constituents of membrane bilayers playing a role in structural integrity, cell signalling in microdomains, endosomes and lysosomes, and cell death pathways. Conversion of ceramide into GSLs is controlled by GCS (glucosylceramide synthase) and inhibitors of this enzyme for the treatment of lipid storage disorders and specific cancers. With a diverse range of functions attributed to GSLs, the ability of the GSC inhibitor, eliglustat, to reduce myeloma bone disease was investigated. In pre-clinical models of multiple myeloma, osteoclast-driven bone loss was reduced by eliglustat in a mechanistically separate manner to zoledronic acid, a bisphosphonate that prevents osteoclast-mediated bone destruction. Autophagic degradation of TNF receptor-associated factor 3 (TRAF3), a key step for osteoclast differentiation, was inhibited by eliglustat as evidenced by TRAF3 lysosomal and cytoplasmic accumulation. By altering GSL composition, eliglustat prevented lysosomal degradation whilst exogenous addition of missing GSLs rescued TRAF3 degradation to restore osteoclast formation in bone marrow cells from myeloma patients. This work highlights the clinical potential of eliglustat as a therapy for myeloma bone disease. Furthermore, using eliglustat as a lysosomal inhibitor in osteoclasts may widen its therapeutic uses to other bone disorders such as bone metastasis, osteoporosis and inflammatory bone loss.
    Keywords:  Autophagy; TRAF3; glycosphingolipid; multiple myeloma; osteoclast
    DOI:  https://doi.org/10.1080/15548627.2023.2208931
  19. Front Fungal Biol. 2022 ;3 948477
    Vacuolar proteases and autophagy in phytopathogenic fungi: A review.
    Margarita Juárez-Montiel, Daniel Clark-Flores, Pedro Tesillo-Moreno, Esaú de la Vega-Camarillo, Dulce Andrade-Pavón, Juan Alfredo Hernández-García, César Hernández-Rodríguez, Lourdes Villa-Tanaca.
      Autophagy (macroautophagy) is a survival and virulence mechanism of different eukaryotic pathogens. Autophagosomes sequester cytosolic material and organelles, then fuse with or enter into the vacuole or lysosome (the lytic compartment of most fungal/plant cells and many animal cells, respectively). Subsequent degradation of cargoes delivered to the vacuole via autophagy and endocytosis maintains cellular homeostasis and survival in conditions of stress, cellular differentiation, and development. PrA and PrB are vacuolar aspartyl and serine endoproteases, respectively, that participate in the autophagy of fungi and contribute to the pathogenicity of phytopathogens. Whereas the levels of vacuolar proteases are regulated by the expression of the genes encoding them (e.g., PEP4 for PrA and PRB1 for PrB), their activity is governed by endogenous inhibitors. The aim of the current contribution is to review the main characteristics, regulation, and role of vacuolar soluble endoproteases and Atg proteins in the process of autophagy and the pathogenesis of three fungal phytopathogens: Ustilago maydis, Magnaporthe oryzae, and Alternaria alternata. Aspartyl and serine proteases are known to participate in autophagy in these fungi by degrading autophagic bodies. However, the gene responsible for encoding the vacuolar serine protease of U. maydis has yet to be identified. Based on in silico analysis, this U. maydis gene is proposed to be orthologous to the Saccharomyces cerevisiae genes PRB1 and PBI2, known to encode the principal protease involved in the degradation of autophagic bodies and its inhibitor, respectively. In fungi that interact with plants, whether phytopathogenic or mycorrhizal, autophagy is a conserved cellular degradation process regulated through the TOR, PKA, and SNF1 pathways by ATG proteins and vacuolar proteases. Autophagy plays a preponderant role in the recycling of cell components as well as in the fungus-plant interaction.
    Keywords:  ATG8 and TOR; autophagic body degradation; autophagy; phytopathogenic fungus; vacuolar proteases PrA and PrB
    DOI:  https://doi.org/10.3389/ffunb.2022.948477
  20. Arterioscler Thromb Vasc Biol. 2023 Sep 28.
    Long Noncoding RNA Gpr137b-ps Promotes Advanced Atherosclerosis via the Regulation of Autophagy in Macrophages.
    Wenbo Qu, Xin Zhou, Xinjian Jiang, Xianwei Xie, Kaijian Xu, Xia Gu, Ruisi Na, Minghui Piao, Xiangwen Xi, Na Sun, Xueyu Wang, Xiang Peng, Junyan Xu, Jiangtian Tian, Jian Zhang, Junli Guo, Maomao Zhang, Yao Zhang, Zhenwei Pan, Kun Wang, Bo Yu, Bin Sun, Shuijie Li, Jinwei Tian.
      BACKGROUND: Current therapies cannot completely reverse advanced atherosclerosis. High levels of amino acids, induced by Western diet, stimulate mTORC1 (mammalian target of rapamycin complex 1)-autophagy defects in macrophages, accelerating atherosclerotic plaque progression. In addition, autophagy-lysosomal dysfunction contributes to plaque necrotic core enlargement and lipid accumulation. Therefore, it is essential to investigate the novel mechanism and molecules to reverse amino acid-mTORC1-autophagy signaling dysfunction in macrophages of patients with advanced atherosclerosis.METHODS: We observed that Gpr137b-ps was upregulated in advanced atherosclerotic plaques. The effect of Gpr137b-ps on the progression of atherosclerosis was studied by generating advanced plaques in ApoE-/- mice with cardiac-specific knockout of Gpr137b-ps. Bone marrow-derived macrophages and mouse mononuclear macrophage cell line RAW264.7 cells were subjected to starvation or amino acid stimulation to study amino acid-mTORC1-autophagy signaling. Using both gain- and loss-of-function approaches, we explored the mechanism of Gpr137b-ps-regulated autophagy.
    RESULTS: Our results demonstrated that Gpr137b-ps deficiency led to enhanced autophagy in macrophages and reduced atherosclerotic lesions, characterized by fewer necrotic cores and less lipid accumulation. Knockdown of Gpr137b-ps increased autophagy and prevented amino acid-induced mTORC1 signaling activation. As the downstream binding protein of Gpr137b-ps, HSC70 (heat shock cognate 70) rescued the impaired autophagy induced by Gpr137b-ps. Furthermore, Gpr137b-ps interfered with the HSC70 binding to G3BP (GTPase-activating protein-binding protein), which tethers the TSC complex to lysosomes and suppresses mTORC1 signaling. In addition to verifying that the NTF2 (nuclear transport factor 2) domain of G3BP binds to HSC70 by in vitro protein synthesis, we further demonstrated that HSC70 binds to the NTF2 domain of G3BP through its W90-F92 motif by using computational modeling.
    CONCLUSIONS: These findings reveal that Gpr137b-ps plays an essential role in the regulation of macrophage autophagy, which is crucial for the progression of advanced atherosclerosis. Gpr137b-ps impairs the interaction of HSC70 with G3BP to regulate amino acid-mTORC1-autophagy signaling, and these results provide a new potential therapeutic direction for the treatment of advanced atherosclerosis.
    Keywords:  atherosclerosis; autophagy; lysosomes; macrophages; pseudogenes
    DOI:  https://doi.org/10.1161/ATVBAHA.123.319037
  21. Nat Commun. 2023 Sep 28. 14(1): 6069
    NLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85α to drive tumorigenesis.
    Feng Zhi, Bowen Li, Chuanxia Zhang, Fan Xia, Rong Wang, Weihong Xie, Sihui Cai, Dawei Zhang, Ren Kong, Yiqiao Hu, Yilin Yang, Ya Peng, Jun Cui.
      The PI3K/AKT pathway plays an essential role in tumour development. NOD-like receptors (NLRs) regulate innate immunity and are implicated in cancer, but whether they are involved in PI3K/AKT pathway regulation is poorly understood. Here, we report that NLRP6 potentiates the PI3K/AKT pathway by binding and destabilizing p85α, the regulatory subunit of PI3K. Mechanistically, NLRP6 recruits the E3 ligase RBX1 to p85α and ubiquitinates lysine 256 on p85α, which is recognized by the autophagy cargo receptor OPTN, causing selective autophagic degradation of p85α and subsequent activation of the PI3K/AKT pathway by reducing PTEN stability. We further show that loss of NLRP6 suppresses cell proliferation, colony formation, cell migration, and tumour growth in glioblastoma cells in vitro and in vivo. Disruption of the NLRP6/p85α interaction using the Pep9 peptide inhibits the PI3K/AKT pathway and generates potent antitumour effects. Collectively, our results suggest that NLRP6 promotes p85α degradation via selective autophagy to drive tumorigenesis, and the interaction between NLRP6 and p85α can be a promising therapeutic target for tumour treatment.
    DOI:  https://doi.org/10.1038/s41467-023-41739-z
  22. Hum Mol Genet. 2023 Sep 26. pii: ddad164. [Epub ahead of print]
    Identification of a muscle-specific isoform of VMA21 as a potent actor in X-linked myopathy with excessive autophagy pathogenesis.
    Ilaria Cocchiararo, Olivia Cattaneo, Jayasimman Rajendran, Florent Chabry, Mélanie Cornut, Hadrien Soldati, Anne Bigot, Kamel Mamchaoui, Sara Gibertini, Axelle Bouche, Daniel J Ham, Thomas Laumonier, Alexandre Prola, Perrine Castets.
      Defective lysosomal acidification is responsible for a large range of multi-systemic disorders associated with impaired autophagy. Diseases caused by mutations in the VMA21 gene stand as exceptions, specifically affecting skeletal muscle (X-linked Myopathy with Excessive Autophagy, XMEA) or liver (Congenital Disorder of Glycosylation). VMA21 chaperones vacuolar (v-) ATPase assembly, which is ubiquitously required for proper lysosomal acidification. The reason VMA21 deficiencies affect specific, but divergent tissues remains unknown. Here, we show that VMA21 encodes a yet-unreported long protein isoform, in addition to the previously described short isoform, which we name VMA21-120 and VMA21-101, respectively. In contrast to the ubiquitous pattern of VMA21-101, VMA21-120 was predominantly expressed in skeletal muscle, and rapidly up-regulated upon differentiation of mouse and human muscle precursors. Accordingly, VMA21-120 accumulated during development, regeneration and denervation of mouse skeletal muscle. In contrast, neither induction nor blockade of autophagy, in vitro and in vivo, strongly affected VMA21 isoform expression. Interestingly, VMA21-101 and VMA21-120 both localized to the sarcoplasmic reticulum of muscle cells, and interacted with the v-ATPase. While VMA21 deficiency impairs autophagy, VMA21-101 or VMA21-120 overexpression had limited impact on autophagic flux in muscle cells. Importantly, XMEA-associated mutations lead to both VMA21-101 deficiency and loss of VMA21-120 expression. These results provide important insights into the clinical diversity of VMA21-related diseases and uncover a muscle-specific VMA21 isoform that potently contributes to XMEA pathogenesis.
    Keywords:  VMA21; XMEA; autophagy; myogenesis; v-ATPase
    DOI:  https://doi.org/10.1093/hmg/ddad164
  23. Plant Physiol. 2023 Sep 29. pii: kiad520. [Epub ahead of print]
    Redox-mediated activation of ATG3 promotes ATG8 lipidation and autophagy progression in Chlamydomonas reinhardtii.
    Manuel J Mallén-Ponce, María Esther Pérez-Pérez.
      Autophagy is one of the main degradative pathways used by eukaryotic organisms to eliminate useless or damaged intracellular material to maintain cellular homeostasis under stress conditions. Mounting evidence indicates a strong interplay between the generation of ROS and the activation of autophagy. Although a tight redox regulation of autophagy has been shown in several organisms, including microalgae, the molecular mechanisms underlying this control remain poorly understood. In this study, we have performed an in-depth in vitro and in vivo redox characterization of ATG3, an E2-activating enzyme involved in ATG8 lipidation and autophagosome formation, from two evolutionary distant unicellular model organisms: the green microalga Chlamydomonas (Chlamydomonas reinhardtii) and the budding yeast Saccharomyces cerevisiae. Our results indicated that ATG3 activity from both organisms is subjected to redox regulation since these proteins require reducing equivalents to transfer ATG8 to the phospholipid phosphatidylethanolamine. We established the catalytic Cys of ATG3 as a redox target in algal and yeast proteins and showed that the oxidoreductase thioredoxin efficiently reduces ATG3. Moreover, in vivo studies revealed that the redox state of ATG3 from Chlamydomonas undergoes profound changes under autophagy-activating stress conditions, such as the absence of photoprotective carotenoids, the inhibition of fatty acid synthesis, or high light irradiance. Thus, our results indicate that the redox-mediated activation of ATG3 regulates ATG8 lipidation under oxidative stress conditions in this model microalga.
    Keywords:  ATG3 E2-activating enzyme; ATG8 lipidation; Autophagy; Chlamydomonas; ROS; Saccharomyces; chloroplast damage; redox regulation; stress
    DOI:  https://doi.org/10.1093/plphys/kiad520
  24. Plants (Basel). 2023 Sep 21. pii: 3339. [Epub ahead of print]12(18):
    Regulation of Tomato Fruit Autophagic Flux and Promotion of Fruit Ripening by the Autophagy-Related Gene SlATG8f.
    Cen Wen, Taimin Luo, Zhuo He, Yunzhou Li, Jianmin Yan, Wen Xu.
      Autophagy is a highly conserved self-degradation process that involves the degradation and recycling of cellular components and organelles. Although the involvement of autophagy in metabolic changes during fruit ripening has been preliminarily demonstrated, the variations in autophagic flux and specific functional roles in tomato fruit ripening remain to be elucidated. In this study, we analyzed the variations in autophagic flux during tomato fruit ripening. The results revealed differential expression of the SlATG8 family members during tomato fruit ripening. Transmission electron microscopy observations and dansylcadaverine (MDC) staining confirmed the presence of autophagy at the cellular level in tomato fruits. Furthermore, the overexpression of SlATG8f induced the formation of autophagosomes, increased autophagic flux within tomato fruits, and effectively enhanced the expression of ATG8 proteins during the color-transition phase of fruit ripening, thus promoting tomato fruit maturation. SlATG8f overexpression also led to the accumulation of vitamin C (VC) and soluble solids while reducing acidity in the fruit. Collectively, our findings highlight the pivotal role of SlATG8f in enhancing tomato fruit ripening, providing insights into the mechanistic involvement of autophagy in this process. This research contributes to a better understanding of the key factors that regulate tomato fruit quality and offers a theoretical basis for tomato variety improvement.
    Keywords:  SlATG8f; autophagic flux; autophagosome; fruit ripening; tomato
    DOI:  https://doi.org/10.3390/plants12183339
  25. Trends Plant Sci. 2023 Sep 22. pii: S1360-1385(23)00297-2. [Epub ahead of print]
    FCS-like zinc finger proteins maintain energy homeostasis during stresses.
    Anthony Artins, Alisdair R Fernie.
      Sucrose non-fermenting kinase 1 (SnRK1) has emerged as a pivotal activator of the autophagy pathway; however, the reciprocal influence of autophagy on SnRK1 remains unknown. Yang et al. have recently revealed the existence of a feedback loop connecting autophagy and SnRK1 in terrestrial plants, involving the novel FCS-like zinc finger (FLZ) class of proteins.
    Keywords:  ATG8; FLZ; SnRK1; autophagy; carbon limitation
    DOI:  https://doi.org/10.1016/j.tplants.2023.09.004
  26. Cancers (Basel). 2023 Sep 12. pii: 4529. [Epub ahead of print]15(18):
    Inhibition of Dipeptidyl Peptidase-4 Activates Autophagy to Promote Survival of Breast Cancer Cells via the mTOR/HIF-1α Pathway.
    Emi Kawakita, Fan Yang, Sen Shi, Yuta Takagaki, Daisuke Koya, Keizo Kanasaki.
      Autophagy plays a complex role in breast cancer cell survival, metastasis, and chemotherapeutic resistance. Dipeptidyl peptidase (DPP)-4, a therapeutic target for type 2 diabetes mellitus, is also involved in autophagic flux. The potential influence of DPP-4 suppression on cancer biology remains unknown. Here, we report that DPP-4 deficiency promotes breast cancer cell survival via the induction of autophagy by the C-X-C motif chemokine 12 (CXCL12)/C-X-C receptor 4 (CXCR4)/mammalian target of rapamycin (mTOR)/hypoxia inducible factor (HIF)-1α axis. DPP-4 knockdown and DPP-4 inhibitor KR62436 (KR) treatment both increased the levels of LC3II and HIF-1α in cultured human breast and mouse mammary cancer cells. The KR-induced autophagic phenotype in cancer cells was inhibited by treatment with the CXCR4 inhibitor AMD3100 and rapamycin. HIF-1α knockdown also suppressed breast cancer autophagy induced by KR. The autophagy inhibitor 3-methyladenine significantly blocked the KR-mediated suppression of cleaved caspase-3 levels and apoptosis in breast cancer cell lines. Finally, we found that the metformin-induced apoptosis of DPP-4-deficient 4T1 mammary cancer cells was associated with the suppression of autophagy. Our findings identify a novel role for DPP-4 inhibition in the promotion of breast cancer survival by inducing CXCL12/CXCR4/mTOR/HIF-1α axis-dependent autophagy. Metformin is a potential drug that counteracts the breast cancer cell survival system.
    Keywords:  DPP-4; HIF-1α; apoptosis; autophagy; breast cancer; metformin
    DOI:  https://doi.org/10.3390/cancers15184529
  27. Antioxidants (Basel). 2023 Aug 22. pii: 1655. [Epub ahead of print]12(9):
    Nitric Oxide Induces Autophagy in Triticum aestivum Roots.
    Farida Minibayeva, Anastasia Mazina, Natalia Gazizova, Svetlana Dmitrieva, Anastasia Ponomareva, Daniya Rakhmatullina.
      Autophagy is a highly conserved process that degrades damaged macromolecules and organelles. Unlike animals, only scant information is available regarding nitric oxide (NO)-induced autophagy in plants. Such lack of information prompted us to study the roles of the NO donors' nitrate, nitrite, and sodium nitroprusside in this catabolic process in wheat roots. Furthermore, spermine, a polyamine that is found in all eukaryotic cells, was also tested as a physiological NO donor. Here, we show that in wheat roots, NO donors and spermine can trigger autophagy, with NO and reactive oxygen species (ROS) playing signaling roles based on the visualization of autophagosomes, analyses of the levels of NO, ROS, mitochondrial activity, and the expression of autophagic (ATG) genes. Treatment with nitrite and nitroprusside causes an energy deficit, a typical prerequisite of autophagy, which is indicated by a fall in mitochondrial potential, and the activity of mitochondrial complexes. On the contrary, spermine sustains energy metabolism by upregulating the activity of appropriate genes, including those that encode glyceraldehyde 3-phosphate dehydrogenase GAPDH and SNF1-related protein kinase 1 SnRK1. Taken together, our data suggest that one of the key roles for NO in plants may be to trigger autophagy via diverse mechanisms, thus facilitating the removal of oxidized and damaged cellular constituencies.
    Keywords:  autophagy; energy metabolism; nitric oxide; plant; spermine
    DOI:  https://doi.org/10.3390/antiox12091655
  28. Eur J Pharmacol. 2023 Sep 24. pii: S0014-2999(23)00569-1. [Epub ahead of print] 176057
    Review of PINK1-Parkin-mediated mitochondrial autophagy in Alzheimer's disease.
    Ting-Yuan Zhou, Rui-Xia Ma, Jia Li, Bin Zou, Hui Yang, Rui-Yin Ma, Zi-Qi Wu, Juan Li, Yao Yao.
      Mitochondrial autophagy plays an important role in maintaining the complexity of mitochondrial functions and removing damaged mitochondria, of which the PINK1-Parkin signal pathway is one of the most classical pathways. Thus, a comprehensive and in-depth interpretation of the PINK1-Parkin signal pathway might deepen our understanding on the impacts of mitochondrial autophagy. Alzheimer's disease (AD) is a classical example of neurodegenerative disease. Research on the pathogenesis and treatments of AD has been a focus of scientific research because of its complexity and the limitations of current drug therapies. It was reported that the pathogenesis of AD might be related to mitochondrial autophagy due to excessive deposition of Aβ protein and aggravation of the phosphorylation of Tau protein. Two key proteins in the PINK1-Parkin signaling pathway, PINK1 and Parkin, have important roles in the folding and accumulation of Aβ protein and the phosphorylation of Tau protein. In addition, the intermediate signal molecules in the PINK1-Parkin signal pathway also have certain effects on AD. In this paper, we first described the role of PINK1-Parkin signal pathway on mitochondrial autophagy, then discussed and analyzed the effect of the PINK1-Parkin signal pathway in AD and other metabolic diseases. Our aim was to provide a theoretical direction to further elucidate the pathogenesis of AD and highlight the key molecules related to AD that could be important targets used for AD drug development.
    Keywords:  AD; Drugs; Mitochondrial autophagy; Neurodegenerative disease; PINK1-Parkin signal pathway; Signal molecules
    DOI:  https://doi.org/10.1016/j.ejphar.2023.176057
  29. Biology (Basel). 2023 Sep 04. pii: 1205. [Epub ahead of print]12(9):
    Interaction between Autophagy and Senescence in Pancreatic Beta Cells.
    Francesko Hela, Cristina Aguayo-Mazzucato.
      Aging leads to an increase in cellular stress due to the fragility of the organism and the inability to cope with it. In this setting, there is a higher chance of developing different cardiometabolic diseases like diabetes. Cellular senescence and autophagy, both hallmarks of aging and stress-coping mechanisms, have gained increased attention for their role in the pathophysiology of diabetes. Studies show that impairing senescence dampens and even prevents diabetes while the role of autophagy is more contradictory, implying a context- and disease-stage-dependent effect. Reports show conflicting data about the effect of autophagy on senescence while the knowledge about this interaction in beta cells remains scarce. Elucidating this interaction between autophagy and senescence in pancreatic beta cells will lead to an identification of their respective roles and the extent of the effect each mechanism has on beta cells and open new horizons for developing novel therapeutic agents. To help illuminate this relationship we will review the latest findings of cellular senescence and autophagy with a special emphasis on pancreatic beta cells and diabetes.
    Keywords:  SASP; beta cells; cellular senescence; diabetes; macroautophagy; senolytics
    DOI:  https://doi.org/10.3390/biology12091205
  30. Nature. 2023 Sep 27.
    Proteome census upon nutrient stress reveals Golgiphagy membrane receptors.
    Kelsey L Hickey, Sharan Swarup, Ian R Smith, Julia C Paoli, Enya Miguel Whelan, Joao A Paulo, J Wade Harper.
      During nutrient stress, macroautophagy degrades cellular macromolecules, thereby providing biosynthetic building blocks while simultaneously remodeling the proteome1,2. While machinery responsible for initiation of macroautophagy is well characterized3,4, our understanding of the extent to which individual proteins, protein complexes and organelles are selected for autophagic degradation, and the underlying targeting mechanisms is limited. Here, we use orthogonal proteomic strategies to provide a spatial proteome census of autophagic cargo during nutrient stress in mammalian cells. We find that macroautophagy has selectivity for recycling membrane-bound organelles (principally Golgi and ER). Through autophagic cargo prioritization, we identify a complex of membrane-embedded proteins, YIPF3 and YIPF4, as receptors for Golgiphagy. During nutrient stress, YIPF3 and YIPF4 interact with ATG8s via LIR motifs and are mobilized into autophagosomes that traffic to lysosomes in a process that requires the canonical autophagic machinery. Cells lacking YIPF3 or YIPF4 are selectively defective in elimination of a specific cohort of Golgi membrane proteins during nutrient stress. Moreover, YIPF3/4 play an analogous role in Golgi remodeling during programmed conversion of stem cells to the neuronal lineage in vitro. Collectively, this study reveals prioritization of membrane protein cargo during nutrient stress-dependent proteome remodeling and identifies an unanticipated Golgi remodeling pathway requiring membrane-embedded receptors.
    DOI:  https://doi.org/10.1038/s41586-023-06657-6
  31. Cells. 2023 09 19. pii: 2310. [Epub ahead of print]12(18):
    Syringin Prevents 6-Hydroxydopamine Neurotoxicity by Mediating the MiR-34a/SIRT1/Beclin-1 Pathway and Activating Autophagy in SH-SY5Y Cells and the Caenorhabditis elegans Model.
    Ru-Huei Fu, Syuan-Yu Hong, Hui-Jye Chen.
      Defective autophagy is one of the cellular hallmarks of Parkinson's disease (PD). Therefore, a therapeutic strategy could be a modest enhancement of autophagic activity in dopamine (DA) neurons to deal with the clearance of damaged mitochondria and abnormal protein aggregates. Syringin (SRG) is a phenolic glycoside derived from the root of Acanthopanax senticosus. It has antioxidant, anti-apoptotic, and anti-inflammatory properties. However, whether it has a preventive effect on PD remains unclear. The present study found that SRG reversed the increase in intracellular ROS-caused apoptosis in SH-SY5Y cells induced by neurotoxin 6-OHDA exposure. Likewise, in C. elegans, degeneration of DA neurons, DA-related food-sensitive behaviors, longevity, and accumulation of α-synuclein were also improved. Studies of neuroprotective mechanisms have shown that SRG can reverse the suppressed expression of SIRT1, Beclin-1, and other autophagy markers in 6-OHDA-exposed cells. Thus, these enhanced the formation of autophagic vacuoles and autophagy activity. This protective effect can be blocked by pretreatment with wortmannin (an autophagosome formation blocker) and bafilomycin A1 (an autophagosome-lysosome fusion blocker). In addition, 6-OHDA increases the acetylation of Beclin-1, leading to its inactivation. SRG can induce the expression of SIRT1 and promote the deacetylation of Beclin-1. Finally, we found that SRG reduced the 6-OHDA-induced expression of miR-34a targeting SIRT1. The overexpression of miR-34a mimic abolishes the neuroprotective ability of SRG. In conclusion, SRG induces autophagy via partially regulating the miR-34a/SIRT1/Beclin-1 axis to prevent 6-OHDA-induced apoptosis and α-synuclein accumulation. SRG has the opportunity to be established as a candidate agent for the prevention and cure of PD.
    Keywords:  6-hydroxydopamine (6-OHDA); Beclin-1; C. elegans; Parkinson’s disease; SH-SY5Y cells; SIRT1; autophagy; miR-34a; syringin; α-synuclein
    DOI:  https://doi.org/10.3390/cells12182310
  32. Pharmaceutics. 2023 Sep 05. pii: 2284. [Epub ahead of print]15(9):
    Autophagy and Biomaterials: A Brief Overview of the Impact of Autophagy in Biomaterial Applications.
    Leila Pirmoradi, Shahla Shojaei, Saeid Ghavami, Atefeh Zarepour, Ali Zarrabi.
      Macroautophagy (hereafter autophagy), a tightly regulated physiological process that obliterates dysfunctional and damaged organelles and proteins, has a crucial role when biomaterials are applied for various purposes, including diagnosis, treatment, tissue engineering, and targeted drug delivery. The unparalleled physiochemical properties of nanomaterials make them a key component of medical strategies in different areas, such as osteogenesis, angiogenesis, neurodegenerative disease treatment, and cancer therapy. The application of implants and their modulatory effects on autophagy have been known in recent years. However, more studies are necessary to clarify the interactions and all the involved mechanisms. The advantages and disadvantages of nanomaterial-mediated autophagy need serious attention in both the biological and bioengineering fields. In this mini-review, the role of autophagy after biomaterial exploitation and the possible related mechanisms are explored.
    Keywords:  angiogenesis; autophagy; biomaterials; neurodegenerative diseases; osteogenesis; tumor cells
    DOI:  https://doi.org/10.3390/pharmaceutics15092284
  33. Biomolecules. 2023 Aug 24. pii: 1297. [Epub ahead of print]13(9):
    Regulation of Phosphoinositide Signaling by Scaffolds at Cytoplasmic Membranes.
    Tianmu Wen, Narendra Thapa, Vincent L Cryns, Richard A Anderson.
      Cytoplasmic phosphoinositides (PI) are critical regulators of the membrane-cytosol interface that control a myriad of cellular functions despite their low abundance among phospholipids. The metabolic cycle that generates different PI species is crucial to their regulatory role, controlling membrane dynamics, vesicular trafficking, signal transduction, and other key cellular events. The synthesis of phosphatidylinositol (3,4,5)-triphosphate (PI3,4,5P3) in the cytoplamic PI3K/Akt pathway is central to the life and death of a cell. This review will focus on the emerging evidence that scaffold proteins regulate the PI3K/Akt pathway in distinct membrane structures in response to diverse stimuli, challenging the belief that the plasma membrane is the predominant site for PI3k/Akt signaling. In addition, we will discuss how PIs regulate the recruitment of specific scaffolding complexes to membrane structures to coordinate vesicle formation, fusion, and reformation during autophagy as well as a novel lysosome repair pathway.
    Keywords:  PI3K-Akt pathway; autophagy; lysosome; phosphoinositide; scaffolding protein
    DOI:  https://doi.org/10.3390/biom13091297
  34. J Biol Chem. 2023 Sep 21. pii: S0021-9258(23)02299-8. [Epub ahead of print] 105271
    Protein interaction network analysis of mTOR signaling reveals modular organization.
    Devin T Wehle, Carter S Bass, Josef Sulc, Ghayda Mirzaa, Stephen E P Smith.
      The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that acts as a central mediator of translation, and plays important roles in cell growth, synaptic plasticity, cancer, and a wide range of developmental disorders. The signaling cascade linking lipid kinases (PI3Ks), protein kinases (AKT) and translation initiation complexes (EIFs) to mTOR has been extensively modeled, but does not fully describe mTOR system behavior. Here, we use quantitative multiplex co-immunoprecipitation to monitor a protein interaction network (PIN) composed of 300+ binary interactions among mTOR-related proteins. Using a simple model system of serum-deprived or fresh-media-fed mouse 3T3 fibroblasts, we observed extensive PIN remodeling involving 27+ individual protein interactions after one hour, despite phosphorylation changes observed after only five minutes. Using small molecule inhibitors of PI3K, AKT, mTOR, MEK and ERK, we define subsets of the PIN, termed 'modules', that respond differently to each inhibitor. Using primary fibroblasts from individuals with overgrowth disorders caused by pathogenic PIK3CA or MTOR variants, we find that hyperactivation of mTOR pathway components is reflected in a hyperactive PIN. Our data define a "modular" organization of the mTOR PIN in which coordinated groups of interactions respond to activation or inhibition of distinct nodes, and demonstrate that kinase inhibitors affect the modular network architecture in a complex manner, inconsistent with simple linear models of signal transduction.
    Keywords:  Protein-protein interaction; mTOR; signal transduction
    DOI:  https://doi.org/10.1016/j.jbc.2023.105271
  35. Mol Immunol. 2023 Sep 27. pii: S0161-5890(23)00192-X. [Epub ahead of print]163 127-135
    Lipopolysaccharide promotes NLRP3 inflammasome activation by inhibiting TFEB-mediated autophagy in NRK-52E cells.
    Dan Song, Wenjing Tao, Feng Liu, Xian Wu, Haiyang Bi, Jianhong Shu, Dong Wang, Xiangchen Li.
      The NLRP3 inflammasome is involved in many inflammatory diseases. Its activity must be strictly controlled to alleviate the inflammatory process. Autophagy plays a protective role in the negative regulation of NLRP3 inflammasome activation. However, the regulatory mechanism of autophagy controlling NLRP3 inflammasome activation remains to be further investigated. Here, we showed that in NRK-52E cells, lipopolysaccharide (LPS) and ATP stimulation significantly decreased mitochondrial membrane potential, increased ROS production and mtDNA copy number in cytosol. Moreover, autophagic flux was blocked when challenged with LPS and ATP as evidenced by increased LC3 II and p62 expression, reduced TFEB and CTSD expression, and impaired lysosomal acid environment. Furthermore, TFEB deficiency increased cytosolic mtDNA and enhanced LPS and ATP induced NLRP3 inflammasome activation and proinflammatory cytokine expression. Taken together, these findings reveal that LPS and ATP stimulation promoted NLRP3 inflammasome activation through inhibiting TFEB-mediated autophagy in NRK-52E cells, and TFEB could be a potential therapeutic target for the treatment of NLRP3 inflammasome-related kidney diseases.
    Keywords:  Autophagy; Inflammation; Lipopolysaccharide; NLRP3; TFEB
    DOI:  https://doi.org/10.1016/j.molimm.2023.09.008
  36. Front Immunol. 2023 ;14 1245443
    p38MAPK/MK2 signaling stimulates host cells autophagy pathways to restrict Salmonella infection.
    Abdulhadi Suwandi, Manoj B Menon, Alexey Kotlyarov, Guntram A Grassl, Matthias Gaestel.
      Autophagy plays an important role in recognizing and protecting cells from invading intracellular pathogens such as Salmonella. In this work, we investigated the role of p38MAPK/MK2 in modulating the host cell susceptibility to Salmonella infection. Inhibition of p38MAPK or MK2 led to a significant increase of bacterial counts in Salmonella infected mouse embryonic fibroblasts (MEFs), as well as in MK2-deficient (Mk2-/-) cells. Furthermore, western blot analysis showed that Mk2-/- cells have lower level of LC3 lipidation, which is the indicator of general autophagy compared to Mk2-rescued cells. In Mk2-/- cells, we also observed lower activated TANK-binding kinase-1 phosphorylation on Ser172 and p62/SQTM1-Ser403 phosphorylation, which are important to promote the translocation of p62 to ubiquitinated microbes and required for efficient autophagy of bacteria. Furthermore, immunofluorescence analysis revealed reduced colocalization of Salmonella with LC3 and p62 in MEFs. Inhibition of autophagy with bafilomycin A1 showed increased bacterial counts in treated cells compared to control cell. Overall, these results indicate that p38MAPK/MK2-mediated protein phosphorylation modulates the host cell susceptibility to Salmonella infection by affecting the autophagy pathways.
    Keywords:  MEFs; MK2; Salmonella; autophagy; cell signaling; infection; p38MAPK; xenophagy
    DOI:  https://doi.org/10.3389/fimmu.2023.1245443
  37. mBio. 2023 Sep 27. e0097723
    PP2C phosphatases Ptc1 and Ptc2 dephosphorylate PGK1 to regulate autophagy and aflatoxin synthesis in the pathogenic fungus Aspergillus flavus.
    Zhuo Zhu, Mingkun Yang, Guang Yang, Bei Zhang, Xiaohong Cao, Jun Yuan, Feng Ge, Shihua Wang.
      Reversible phosphorylation by protein kinases and phosphatases plays a central role in regulating cellular processes. However, knowledge of the functions of protein phosphatase 2C (PP2C) S/T phosphatases in Aspergillus flavus has been unreported until now. Here, we have identified seven members of the PP2C family of protein phosphatases in A. flavus. Evolutionary and functional analyses indicated that two redundant PP2C phosphatases, Ptc1 and Ptc2, are highly conserved and regulate conidia development, aflatoxin synthesis, seed infection, and autophagic vesicle formation. The cytoplasmic proteins Ptc1 and Ptc2 exhibit nuclear infiltration after DNA damage-induced autophagy. Their degradation is closely linked to autophagy induction. The Asp residue coordinated with Mg2+ is critical for phosphatase Ptc1 and Ptc2 activity, thermal stability, and biofunction in A. flavus. An immunoprecipitation-mass spectrometry proteomic investigation indicated that 133 proteins co-interact with Ptc1 and Ptc2. Among these proteins, phosphoglycerate kinase 1 (PGK1) interacts with Ptc1 and Ptc2 and shows high levels of phosphorylation in Δptc1, Δptc2, and Δptc1/ptc2 mutants. Furthermore, PGK1 S203 phosphorylation levels are associated with aflatoxin synthesis and autophagic vesicle formation. Overall, these findings contribute to our understanding of the roles and mechanisms of PP2C family phosphatases in A. flavus and highlight their importance in various cellular processes. Furthermore, it reveals a new regulation model in A. flavus, where Ptc1 and Ptc2 activate autophagy and aflatoxin synthesis by regulating PGK1. IMPORTANCE Aspergillus flavus is a model filamentous fungus that can produce aflatoxins when it infects agricultural crops. This study evaluated the protein phosphatase 2C (PP2C) family as a potential drug target with important physiological functions and pathological significance in A. flavus. We found that two redundant PP2C phosphatases, Ptc1 and Ptc2, regulate conidia development, aflatoxin synthesis, autophagic vesicle formation, and seed infection. The target protein phosphoglycerate kinase 1 (PGK1) that interacts with Ptc1 and Ptc2 is essential to regulate metabolism and the autophagy process. Furthermore, Ptc1 and Ptc2 regulate the phosphorylation level of PGK1 S203, which is important for influencing aflatoxin synthesis. Our results provide a potential target for interdicting the toxicity of A. flavus.
    Keywords:  Aspergillus flavus; IP-MS; PP2C phosphatase; aflatoxin; phosphoglycerate kinase 1
    DOI:  https://doi.org/10.1128/mbio.00977-23
  38. Cells. 2023 Sep 11. pii: 2247. [Epub ahead of print]12(18):
    Obatoclax Rescues FUS-ALS Phenotypes in iPSC-Derived Neurons by Inducing Autophagy.
    Cristina Marisol Castillo Bautista, Kristin Eismann, Marc Gentzel, Silvia Pelucchi, Jerome Mertens, Hannah E Walters, Maximina H Yun, Jared Sterneckert.
      Aging is associated with the disruption of protein homeostasis and causally contributes to multiple diseases, including amyotrophic lateral sclerosis (ALS). One strategy for restoring protein homeostasis and protecting neurons against age-dependent diseases such as ALS is to de-repress autophagy. BECN1 is a master regulator of autophagy; however, is repressed by BCL2 via a BH3 domain-mediated interaction. We used an induced pluripotent stem cell model of ALS caused by mutant FUS to identify a small molecule BH3 mimetic that disrupts the BECN1-BCL2 interaction. We identified obatoclax as a brain-penetrant drug candidate that rescued neurons at nanomolar concentrations by reducing cytoplasmic FUS levels, restoring protein homeostasis, and reducing degeneration. Proteomics data suggest that obatoclax protects neurons via multiple mechanisms. Thus, obatoclax is a candidate for repurposing as a possible ALS therapeutic and, potentially, for other age-associated disorders linked to defects in protein homeostasis.
    Keywords:  FUS; amyotrophic lateral sclerosis; autophagy; phenotypic screening
    DOI:  https://doi.org/10.3390/cells12182247
  39. Leukemia. 2023 Sep 29.
    mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia.
    Natasha Malik, Jodie Hay, Hassan N B Almuhanna, Karen M Dunn, Jamie Lees, Jennifer Cassels, Jiatian Li, Rinako Nakagawa, Owen J Sansom, Alison M Michie.
      Targeted deletion of Raptor, a component of mechanistic target of rapamycin complex 1 (mTORC1), reveals an essential role for mTORC1 in initiation/maintenance of leukemia in a CLL model, resulting from a failure for haemopoietic stem/progenitor cells (HSPCs) to commit to the B cell lineage. Induction of Raptor-deficiency in NSG mice transplanted with Mx1-Raptor CLL progenitor cells (PKCα-KR-transduced HSPCs) after disease establishment revealed a reduction in CLL-like disease load and a significant increase in survival in the mice. Interestingly in an aggressive CLL-like disease model, rapamycin treatment reduced disease burden more effectively than AZD2014 (dual mTORC1/2 inhibitor), indicating a skew towards mTORC1 sensitivity with more aggressive disease. Rapamycin, but not ibrutinib, efficiently targeted the eEF2/eEF2K translation elongation regulatory axis, downstream of mTORC1, resulting in eEF2 inactivation through induction of eEF2T56 phosphorylation. mTOR inhibitor treatment of primary patient CLL cells halted proliferation, at least in part through modulation of eEF2K/eEF2 phosphorylation and expression, reduced protein synthesis and inhibited expression of MCL1, Cyclin A and Cyclin D2. Our studies highlight the importance of translation elongation as a driver of disease progression and identify inactivation of eEF2 activity as a novel therapeutic target for blocking CLL progression.
    DOI:  https://doi.org/10.1038/s41375-023-02043-3
  40. Int J Mol Sci. 2023 Sep 08. pii: 13835. [Epub ahead of print]24(18):
    Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly.
    Anna Picca, Flora Guerra, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi, Cecilia Bucci, Emanuele Marzetti.
      Mitophagy is crucial for maintaining mitochondrial quality. However, its assessment in vivo is challenging. The endosomal-lysosomal system is a more accessible pathway through which subtypes of extracellular vesicles (EVs), which also contain mitochondrial constituents, are released for disposal. The inclusion of mitochondrial components into EVs occurs in the setting of mild mitochondrial damage and during impairment of lysosomal function. By releasing mitochondrial-derived vesicles (MDVs), cells limit the unload of mitochondrial damage-associated molecular patterns with proinflammatory activity. Both positive and negative effects of EVs on recipient cells have been described. Whether this is due to the production of EVs other than those containing mitochondria, such as MDVs, holding specific biological functions is currently unknown. Evidence on the existence of different MDV subtypes has been produced. However, their characterization is not always pursued, which would be relevant to exploring the dynamics of mitochondrial quality control in health and disease. Furthermore, MDV classification may be instrumental in understanding their biological roles and promoting their implementation as biomarkers in clinical studies.
    Keywords:  damage-associated molecular patterns (DAMPs); endosomal–lysosomal system; exosomes; extracellular vesicles; inflammation; mitochondrial DNA; mitochondrial quality control; mitophagy; mitovesicles; oxidative stress
    DOI:  https://doi.org/10.3390/ijms241813835
  41. Mol Cell. 2023 Sep 20. pii: S1097-2765(23)00695-0. [Epub ahead of print]
    Lysosomal cyst(e)ine storage potentiates tolerance to oxidative stress in cancer cells.
    Lixin He, Jinxin Chen, Pinwei Deng, Shumei Huang, Pian Liu, Chanjuan Wang, Xinjian Huang, Yue Li, Boyu Chen, Dongni Shi, Yunyun Xiao, Xiangfu Chen, Ying Ouyang, Libing Song, Chuyong Lin.
      Cyst(e)ine is a key precursor for the synthesis of glutathione (GSH), which protects cancer cells from oxidative stress. Cyst(e)ine is stored in lysosomes, but its role in redox regulation is unclear. Here, we show that breast cancer cells upregulate major facilitator superfamily domain containing 12 (MFSD12) to increase lysosomal cyst(e)ine storage, which is released by cystinosin (CTNS) to maintain GSH levels and buffer oxidative stress. We find that mTORC1 regulates MFSD12 by directly phosphorylating residue T254, while mTORC1 inhibition enhances lysosome acidification that activates CTNS. This switch modulates lysosomal cyst(e)ine levels in response to oxidative stress, fine-tuning redox homeostasis to enhance cell fitness. MFSD12-T254A mutant inhibits MFSD12 function and suppresses tumor progression. Moreover, MFSD12 overexpression correlates with poor neoadjuvant chemotherapy response and prognosis in breast cancer patients. Our findings reveal the critical role of lysosomal cyst(e)ine storage in adaptive redox homeostasis and suggest that MFSD12 is a potential therapeutic target.
    Keywords:  CTNS; GSH; MFSD12; breast cancer; chemotherapy; cyst(e)ine; lysosome; mTORC1; oxidative stress; redox homeostasis
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.032
  42. bioRxiv. 2023 Sep 13. pii: 2023.09.12.556394. [Epub ahead of print]
    DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.
    Ran-Der Hwang, Yu-Ning Lu, Qing Tang, Goran Periz, Giho Park, Xiangning Li, Yang Liu, Tao Zhang, Jiou Wang.
      Proteotoxic stress impairs cellular homeostasis and underlies the pathogeneses of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The proteasomal and autophagic degradation of proteins are two major pathways for protein quality control in the cell. Here, we report a genome-wide CRISPR screen uncovering a major regulator of cytotoxicity resulting from the inhibition of the proteasome. Dihydrolipoamide branched chain transacylase E2 (DBT) was found to be a robust suppressor, loss of which protects against proteasome inhibition-associated cell death through promoting clearance of ubiquitinated proteins. Loss of DBT altered the metabolic and energetic status of the cell and resulted in activation of autophagy in an AMP-activated protein kinase (AMPK)-dependent mechanism in the presence of the proteasomal inhibition. Loss of DBT protected against proteotoxicity induced by ALS-linked mutant TDP-43 in Drosophila and mammalian neurons. DBT is upregulated in tissues from ALS patients. These results demonstrate that DBT is a master switch in the metabolic control of protein quality control with implications in neurodegenerative diseases.
    DOI:  https://doi.org/10.1101/2023.09.12.556394
  43. bioRxiv. 2023 Sep 13. pii: 2023.09.13.556416. [Epub ahead of print]
    Cardiac glycosides restore autophagy flux in an iPSC-derived neuronal model of WDR45 deficiency.
    Apostolos Papandreou, Nivedita Singh, Lorita Gianfrancesco, Dimitri Budinger, Katy Barwick, Alexander Agrotis, Christin Luft, Ying Shao, An-Sofie Lenaerts, Allison Gregory, Suh Young Jeong, Penelope Hogarth, Susan Hayflick, Serena Barral, Janos Kriston-Vizi, Paul Gissen, Manju A Kurian, Robin Ketteler.
      Beta-Propeller Protein-Associated Neurodegeneration (BPAN) is one of the commonest forms of Neurodegeneration with Brain Iron Accumulation, caused by mutations in the gene encoding the autophagy-related protein, WDR45. The mechanisms linking autophagy, iron overload and neurodegeneration in BPAN are poorly understood and, as a result, there are currently no disease-modifying treatments for this progressive disorder. We have developed a patient-derived, induced pluripotent stem cell (iPSC)-based midbrain dopaminergic neuronal cell model of BPAN (3 patient, 2 age-matched controls and 2 isogenic control lines) which shows defective autophagy and aberrant gene expression in key neurodegenerative, neurodevelopmental and collagen pathways. A high content imaging-based medium-throughput blinded drug screen using the FDA-approved Prestwick library identified 5 cardiac glycosides that both corrected disease-related defective autophagosome formation and restored BPAN-specific gene expression profiles. Our findings have clear translational potential and emphasise the utility of iPSC-based modelling in elucidating disease pathophysiology and identifying targeted therapeutics for early-onset monogenic disorders.
    DOI:  https://doi.org/10.1101/2023.09.13.556416
  44. Viruses. 2023 Aug 24. pii: 1805. [Epub ahead of print]15(9):
    Nucleocapsid Protein (N) of Peste des petits ruminants Virus (PPRV) Interacts with Cellular Phosphatidylinositol-3-Kinase (PI3K) Complex-I and Induces Autophagy.
    Yash Chaudhary, Juhi Jain, Sharad Kumar Gaur, Prabhakar Tembhurne, Shanmugam Chandrasekar, Muthuchelvan Dhanavelu, Sharvan Sehrawat, Rajeev Kaul.
      Autophagy is an essential and highly conserved catabolic process in cells, which is important in the battle against intracellular pathogens. Viruses have evolved several ways to alter the host defense mechanisms. PPRV infection is known to modulate the components of a host cell's defense system, resulting in enhanced autophagy. In this study, we demonstrate that the N protein of PPRV interacts with the core components of the class III phosphatidylinositol-3-kinase (PI3K) complex-I and results in the induction of autophagy in the host cell over, thereby expressing this viral protein. Our data shows the interaction between PPRV-N protein and different core components of the autophagy pathway, i.e., VPS34, VPS15, BECN1 and ATG14L. The PPRV-N protein can specifically interact with VPS34 of the PI3K complex-I and colocalize with the proteins of PI3K complex-I in the same sub-cellular compartment, that is, in the cytoplasm. These interactions do not affect the intracellular localization of the different host proteins. The autophagy-related genes were transcriptionally modulated in PPRV-N-expressing cells. The expression of LC3B and SQSTM1/p62 was also modulated in PPRV-N-expressing cells, indicating the induction of autophagic activity. The formation of typical autophagosomes with double membranes was visualized by transmission electron microscopy in PPRV-N-expressing cells. Taken together, our findings provide evidence for the critical role of the N protein of the PPR virus in the induction of autophagy, which is likely to be mediated by PI3K complex-I of the host.
    Keywords:  Autophagy; BECN1; PI3K complex-I; PPRV-N; Peste des petits ruminants virus (PPRV)
    DOI:  https://doi.org/10.3390/v15091805
  45. Metabolism. 2023 Sep 22. pii: S0026-0495(23)00297-4. [Epub ahead of print]148 155693
    ATG14 plays a critical role in hepatic lipid droplet homeostasis.
    Menghao Huang, Yang Zhang, Jimin Park, Kushan Chowdhury, Jiazhi Xu, Alex Lu, Lu Wang, Wenjun Zhang, Burcin Ekser, Liqing Yu, X Charlie Dong.
      BACKGROUND & AIMS: Autophagy-related 14 (ATG14) is a key regulator of autophagy. ATG14 is also localized to lipid droplet; however, the function of ATG14 on lipid droplet remains unclear. In this study, we aimed to elucidate the role of ATG14 in lipid droplet homeostasis.METHODS: ATG14 loss-of-function and gain-of-function in lipid droplet metabolism were analyzed by fluorescence imaging in ATG14 knockdown or overexpression hepatocytes. Specific domains involved in the ATG14 targeting to lipid droplets were analyzed by deletion or site-specific mutagenesis. ATG14-interacting proteins were analyzed by co-immunoprecipitation. The effect of ATG14 on lipolysis was analyzed in human hepatocytes and mouse livers that were deficient in ATG14, comparative gene identification-58 (CGI-58), or both.
    RESULTS: Our data show that ATG14 is enriched on lipid droplets in hepatocytes. Mutagenesis analysis reveals that the Barkor/ATG14 autophagosome targeting sequence (BATS) domain of ATG14 is responsible for the ATG14 localization to lipid droplets. Co-immunoprecipitation analysis illustrates that ATG14 interacts with adipose triglyceride lipase (ATGL) and CGI-58. Moreover, ATG14 also enhances the interaction between ATGL and CGI-58. In vitro lipolysis analysis demonstrates that ATG14 deficiency remarkably decreases triglyceride hydrolysis.
    CONCLUSIONS: Our data suggest that ATG14 can directly enhance lipid droplet breakdown through interactions with ATGL and CGI-58.
    Keywords:  ABHD5; ATGL; Autophagy; CGI-58; Lipolysis
    DOI:  https://doi.org/10.1016/j.metabol.2023.155693
  46. Autophagy Rep. 2023 ;pii: 2252307. [Epub ahead of print]2(1):
    Transcriptional pausing factor M1BP regulates cellular homeostasis by suppressing autophagy and apoptosis in Drosophila eye.
    Anuradha Venkatakrishnan Chimata, Hannah Darnell, Akanksha Raj, Madhuri Kango-Singh, Amit Singh.
      During organogenesis cellular homeostasis plays a crucial role in patterning and growth. The role of promoter proximal pausing of RNA polymerase II, which regulates transcription of several developmental genes by GAGA factor or Motif 1 Binding Protein (M1BP), has not been fully understood in cellular homeostasis. Earlier, we reported that M1BP, a functional homolog of ZKSCAN3, regulates wingless and caspase-dependent cell death (apoptosis) in the Drosophila eye. Further, blocking apoptosis does not fully rescue the M1BPRNAi phenotype of reduced eye. Therefore, we looked for other possible mechanism(s). In a forward genetic screen, members of the Jun-amino-terminal-(NH2)-Kinase (JNK) pathway were identified. Downregulation of M1BP ectopically induces JNK, a pro-death pathway known to activate both apoptosis and caspase-independent (autophagy) cell death. Activation of JNK pathway components can enhance M1BPRNAi phenotype and vice-versa. Downregulation of M1BP ectopically induced JNK signaling, which leads to apoptosis and autophagy. Apoptosis and autophagy are regulated independently by their genetic circuitry. Here, we found that blocking either apoptosis or autophagy alone rescues the reduced eye phenotype of M1BP downregulation; whereas, blocking both apoptosis and autophagy together significantly rescues the M1BP reduced eye phenotype to near wild-type in nearly 85% progeny. This data suggests that the cellular homeostasis response demonstrated by two independent cell death mechanisms, apoptosis and autophagy, can be regulated by a common transcriptional pausing mechanism orchestrated by M1BP. Since these fundamental processes are conserved in higher organisms, this novel functional link between M1BP and regulation of both apoptosis and autophagy can be extrapolated to humans.
    Keywords:  Atg8a; JNK; Promotor proximal pausing; Wg; caspase-independent; cell death
    DOI:  https://doi.org/10.1080/27694127.2023.2252307
  47. Cell Mol Life Sci. 2023 Sep 26. 80(10): 304
    Selective removal of misfolded SOD1 delays disease onset in a mouse model of amyotrophic lateral sclerosis.
    Teng Guan, Ting Zhou, Xiaosha Zhang, Ying Guo, Chaoxian Yang, Justin Lin, Jiasi Vicky Zhang, Yongquan Cheng, Hassan Marzban, Yu Tian Wang, Jiming Kong.
      BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. There is no cure currently. The discovery that mutations in the gene SOD1 are a cause of ALS marks a breakthrough in the search for effective treatments for ALS. SOD1 is an antioxidant that is highly expressed in motor neurons. Human SOD1 is prone to aberrant modifications. Familial ALS-linked SOD1 variants are particularly susceptible to aberrant modifications. Once modified, SOD1 undergoes conformational changes and becomes misfolded. This study aims to determine the effect of selective removal of misfolded SOD1 on the pathogenesis of ALS.METHODS: Based on the chaperone-mediated protein degradation pathway, we designed a fusion peptide named CT4 and tested its efficiency in knocking down intracellularly misfolded SOD1 and its efficacy in modifying the pathogenesis of ALS.
    RESULTS: Expression of the plasmid carrying the CT4 sequence in human HEK cells resulted in robust removal of misfolded SOD1 induced by serum deprivation. Co-transfection of the CT4 and the G93A-hSOD1 plasmids at various ratios demonstrated a dose-dependent knockdown efficiency on G93A-hSOD1, which could be further increased when misfolding of SOD1 was enhanced by serum deprivation. Application of the full-length CT4 peptide to primary cultures of neurons expressing the G93A variant of human SOD1 revealed a time course of the degradation of misfolded SOD1; misfolded SOD1 started to decrease by 2 h after the application of CT4 and disappeared by 7 h. Intravenous administration of the CT4 peptide at 10 mg/kg to the G93A-hSOD1 reduced human SOD1 in spinal cord tissue by 68% in 24 h and 54% in 48 h in presymptomatic ALS mice. Intraperitoneal administration of the CT4 peptide starting from 60 days of age significantly delayed the onset of ALS and prolonged the lifespan of the G93A-hSOD1 mice.
    CONCLUSIONS: The CT4 peptide directs the degradation of misfolded SOD1 in high efficiency and specificity. Selective removal of misfolded SOD1 significantly delays the onset of ALS, demonstrating that misfolded SOD1 is the toxic form of SOD1 that causes motor neuron death. The study proves that selective removal of misfolded SOD1 is a promising treatment for ALS.
    Keywords:  Amyotrophic lateral sclerosis; Chaperone-mediated autophagy; Lysosome; Misfolded SOD1; Protein degradation
    DOI:  https://doi.org/10.1007/s00018-023-04956-9
  48. iScience. 2023 Oct 20. 26(10): 107717
    Role of Fyn and the interleukin-6-STAT-3-autophagy axis in sarcopenia.
    Tsuyoshi Sasaki, Eijiro Yamada, Ryota Uehara, Shuichi Okada, Hirotaka Chikuda, Masanobu Yamada.
      Sarcopenia is the progressive loss of muscle mass wherein Fyn regulates STAT3 to decrease autophagy. To elucidate the role of inflammation in Fyn-STAT3-dependent autophagy and sarcopenia, here we aimed to investigate the underlying mechanisms using two mouse models of primary and secondary sarcopenia: (1) tail suspension and (2) sciatic denervation. In wild-type mice, the expression of Fyn and IL-6 increased significantly. The expression and phosphorylation levels of STAT3 were also significantly augmented, while autophagic activity was abolished. To investigate Fyn-dependency, we used tail suspension with Fyn-null mice. In tail-suspended wild-type mice, IL-6 expression was increased; however, it was abolished in Fyn-null mice, which maintained autophagy and the expression and ablation of STAT3 phosphorylation. In conclusion, Fyn was found to be associated with the IL-6-STAT3-autophagy axis in sarcopenia. This finding permits a better understanding of sarcopenia-associated metabolic diseases and the possible development of therapeutic interventions.
    Keywords:  Biological sciences; Disease
    DOI:  https://doi.org/10.1016/j.isci.2023.107717
  49. J Am Heart Assoc. 2023 Sep 26. e030478
    An mTORC1-Dependent Mouse Model for Cardiac Sarcoidosis.
    Carlos Bueno-Beti, Clarice X Lim, Alexandros Protonotarios, Petra Lujza Szabo, Joseph Westaby, Mario Mazic, Mary N Sheppard, Elijah Behr, Ouafa Hamza, Attila Kiss, Bruno K Podesser, Markus Hengstschläger, Thomas Weichhart, Angeliki Asimaki.
      Background Sarcoidosis is an inflammatory, granulomatous disease of unknown cause affecting multiple organs, including the heart. Untreated, unresolved granulomatous inflammation can lead to cardiac fibrosis, arrhythmias, and eventually heart failure. Here we characterize the cardiac phenotype of mice with chronic activation of mammalian target of rapamycin (mTOR) complex 1 signaling in myeloid cells known to cause spontaneous pulmonary sarcoid-like granulomas. Methods and Results The cardiac phenotype of mice with conditional deletion of the tuberous sclerosis 2 (TSC2) gene in CD11c+ cells (TSC2fl/flCD11c-Cre; termed TSC2KO) and controls (TSC2fl/fl) was determined by histological and immunological stains. Transthoracic echocardiography and invasive hemodynamic measurements were performed to assess myocardial function. TSC2KO animals were treated with either everolimus, an mTOR inhibitor, or Bay11-7082, a nuclear factor-kB inhibitor. Activation of mTOR signaling was evaluated on myocardial samples from sudden cardiac death victims with a postmortem diagnosis of cardiac sarcoidosis. Chronic activation of mTORC1 signaling in CD11c+ cells was sufficient to initiate progressive accumulation of granulomatous infiltrates in the heart, which was associated with increased fibrosis, impaired cardiac function, decreased plakoglobin expression, and abnormal connexin 43 distribution, a substrate for life-threatening arrhythmias. Mice treated with the mTOR inhibitor everolimus resolved granulomatous infiltrates, prevented fibrosis, and improved cardiac dysfunction. In line, activation of mTOR signaling in CD68+ macrophages was detected in the hearts of sudden cardiac death victims who suffered from cardiac sarcoidosis. Conclusions To our best knowledge this is the first animal model of cardiac sarcoidosis that recapitulates major pathological hallmarks of human disease. mTOR inhibition may be a therapeutic option for patients with cardiac sarcoidosis.
    Keywords:  cardiac sarcoidosis; fibrosis; heart; mTORC1; mouse model; sarcoidosis
    DOI:  https://doi.org/10.1161/JAHA.123.030478
  50. Cell Cycle. 2023 Sep 28. 1-14
    Glutamine regulates the cellular proliferation and cell cycle progression by modulating the mTOR mediated protein levels of β-TrCP.
    Pushkar Malakar, Didhiti Singha, Debopriyo Choudhury, Sudhanshu Shukla.
      The amino acid glutamine plays an important role in cell growth and proliferation. Reliance on glutamine has long been considered a hallmark of highly proliferating cancer cells. Development of strategies for cancer therapy that primarily target glutamine metabolism has been an active area of research. Glutamine depletion is associated with growth arrest and apoptosis-induced cell death; however, the molecular mechanisms involved in this process are not clearly understood. Here, we show that glutamine depletion activates the energetic stress AMPK pathway and inhibits mTORC1 activity. Furthermore, inhibition of mTORC1 reduces the protein levels of β-TrCP, resulting in aberrant cell cycle progression and reduced proliferation. In agreement with the role of β-TrCP in glutamine metabolism, knockdown of β-TrCP resulted in proliferation and cell cycle defects similar to those observed for glutamine depletion. In summary, our results provide mechanistic insights into the role of glutamine metabolism in regulation of cell growth and proliferation via β-TrCP, uncovering a previously undescribed molecular process involved in glutamine metabolism.
    Keywords:  Glutamine; cell cycle; mTORC1; proliferation; β-TrCP
    DOI:  https://doi.org/10.1080/15384101.2023.2260166
  51. J Mol Biol. 2023 Sep 27. pii: S0022-2836(23)00404-7. [Epub ahead of print] 168293
    Mechanistic insights into the interactions of Arl8b with the RUN domains of PLEKHM1 and SKIP.
    Xiaohui Qiu, Ying Li, Yingli Wang, Xinyu Gong, Yaru Wang, Lifeng Pan.
      Arl8b, a specific Arf-like family GTPase present on lysosome, and plays critical roles in many lysosome-related cellular processes such as autophagy. The active Arl8b can be specifically recognized by the RUN domains of two Arl8b-effectors PLEKHM1 and SKIP, thereby regulating the autophagosome/lysosome membrane fusion and the intracellular lysosome positioning, respectively. However, the mechanistic bases underlying the interactions of Arl8b with the RUN domains of PLEKHM1 and SKIP remain elusive. Here, we report the two high-resolution crystal structures of the active Arl8b in complex with the RUN domains of PLEKHM1 and SKIP. In addition to elucidating the detailed molecular mechanism governing the specific interactions of the active Arl8b with the RUN domains of PLEKHM1 and SKIP, the determined complex structures also reveal a general binding mode shared by the PLEKHM1 and SKIP RUN domains for interacting with the active Arl8b. Furthermore, we uncovered a competitive relationship between the RUN domains of PLEKHM1 and SKIP in binding to the active Arl8b as well as a unique small GTPase-binding mode adopted by the PLEKHM1 and SKIP RUN domains, thereby enriching the repertoire of the RUN domain/small GTPase interaction modes. In all, our findings provide new mechanistic insights into the interactions of the active Arl8b with PLEKHM1 and SKIP, and are valuable for further understanding the working modes of these proteins in relevant cellular processes.
    Keywords:  Arl8b; Lysosome; PLEKHM1; RUN domain; SKIP
    DOI:  https://doi.org/10.1016/j.jmb.2023.168293
  52. Autophagy. 2023 Sep 28. 1-20
    The lipid basis of cell death and autophagy.
    Zhi Lin, Fei Long, Rui Kang, Daniel J Klionsky, Minghua Yang, Daolin Tang.
      ABBREVIATIONS: ACSL: acyl-CoA synthetase long chain family; DISC: death-inducing signaling complex; DAMPs: danger/damage-associated molecular patterns; Dtgn: dispersed trans-Golgi network; FAR1: fatty acyl-CoA reductase 1; GPX4: glutathione peroxidase 4; LPCAT3: lysophosphatidylcholine acyltransferase 3; LPS: lipopolysaccharide; MUFAs: monounsaturated fatty acids; MOMP: mitochondrial outer membrane permeabilization; MLKL, mixed lineage kinase domain like pseudokinase; oxPAPC: oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine; OxPCs: oxidized phosphatidylcholines; PUFAs: polyunsaturated fatty acids; POR: cytochrome p450 oxidoreductase; PUFAs: polyunsaturated fatty acids; RCD: regulated cell death; RIPK1: receptor interacting serine/threonine kinase 1; SPHK1: sphingosine kinase 1; SOAT1: sterol O-acyltransferase 1; SCP2: sterol carrier protein 2; SFAs: saturated fatty acids; SLC47A1: solute carrier family 47 member 1; SCD: stearoyl-CoA desaturase; VLCFA: very long chain fatty acids.
    Keywords:  Apoptosis; autophagy; cell death; lipid metabolism; pathway
    DOI:  https://doi.org/10.1080/15548627.2023.2259732
  53. Free Radic Biol Med. 2023 Sep 22. pii: S0891-5849(23)00651-2. [Epub ahead of print]208 684-699
    Cathepsin D mediates prenatal caffeine exposure-caused NAFLD susceptibility in male rat offspring by regulating autophagy.
    Cong Zhang, Dingmei Zhang, Hegui Huang, Xiaoqian Lu, Huasong Shi, Kexin Liu, Xiaoling Guo, Rui Zhang, Hui Wang.
      Epidemiological evidence has revealed that non-alcoholic fatty liver disease (NAFLD) harbors an intrauterine origin. Autophagy is known to be involved in the protective mechanism in the development of adult NAFLD, but whether it engages in the occurrence of fetal-originated NAFLD remains unclear. In this study, a rat model of fetal-originated NAFLD was established by giving a high-fat diet or chronic stress after birth on prenatal caffeine exposure (PCE) male offspring. The alterations of liver morphologic analysis, lipid metabolism, and autophagy before and after birth were determined to confirm autophagy mechanism, NAFLD susceptibility, and intrauterine origin in PCE male adult offspring. Our results revealed that PCE-induced intrauterine high concentration of corticosterone exposure blocked autophagic flux by inhibiting cathepsin D expression in hepatocytes, leading to β-oxidation inhibition and lipid accumulation in the liver. Moreover, high concentration of corticosterone upregulated miR-665 by activating the glucocorticoid receptor to suppress cathepsin D, thus causing lysosomal degradation dysfunction and autophagy flux blockade. Notably, hepatic overexpression of cathepsin D could reverse PCE-induced postnatal NAFLD susceptibility in male rat offspring. This study elucidates the epigenetic programming mechanism of intrauterine autophagy-related fetal-originated NAFLD susceptibility, and identifies cathepsin D as its early intervention target, providing an experimental basis for exploring early prevention and treatment strategies for fetal-originated NAFLD.
    Keywords:  Autophagy; Cathepsin D; Intrauterine origin; NAFLD; Prenatal caffeine exposure
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.026
  54. FASEB J. 2023 Oct;37(10): e23175
    Irisin ameliorates diabetic kidney disease by restoring autophagy in podocytes.
    Weiyan Lai, Dan Luo, Yin Li, Yuanqing Li, Qianqian Wang, Zhaoyong Hu, Zengchun Ye, Hui Peng.
      Many studies have highlighted the importance of moderate exercise. While it can attenuate diabetic kidney disease, its mechanism has remained unclear. The level of myokine irisin in plasma increases during exercise. We found that irisin was decreased in diabetic patients and was closely related to renal function, proteinuria, and podocyte autophagy injury. Muscle-specific overexpression of PGC-1α (mPGC-1α) in a mouse model is known to increase plasma irisin levels. The mPGC-1α mice were crossed with db/m mice to obtain db/db mPGC-1α+ mice in the present study. Compared to db/db mice without mPGC-1α, plasma irisin was increased, and albuminuria and glomerular pathological damage were both alleviated in db/db mPGC-1α+ mice. Impaired autophagy in podocytes was restored as well. Irisin inhibited the activation of the PI3K/AKT/mTOR signaling pathway in cultured human podocytes and improved damaged autophagy induced by high glucose levels. Then, db/db mice were treated with recombinant irisin, which had similar beneficial effects on the kidney as those in db/db mPGC-1α+ mice, with alleviated glomerular injury and albuminuria. Moreover, the autophagy in podocytes was also significantly restored. These results suggest that irisin secreted by skeletal muscles protects the kidney from diabetes mellitus damage. It also restores autophagy in podocytes by inhibiting the abnormal activation of the PI3K/AKT/mTOR signaling pathway. Thus, irisin may become a new drug for the prevention and treatment of diabetic nephropathy.
    Keywords:  autophagy; diabetic kidney disease; irisin; muscles; podocytes
    DOI:  https://doi.org/10.1096/fj.202300420R
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