bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2022‒06‒26
fifty-nine papers selected by
Viktor Korolchuk, Newcastle University
  1. Proteasomal inhibition preferentially stimulates lysosome activity relative to autophagic flux in primary astrocytes.
  2. Inhibition of mitoNEET induces Pink1-Parkin-mediated mitophagy.
  3. Balancing nutrient and energy demand and supply via autophagy.
  4. Targeted protein degradation via the autophagy-lysosome system: AUTOTAC (AUTOphagy-TArgeting Chimera).
  5. The evolutionary and functional divergence of the Atg8 autophagy protein superfamily.
  6. Autophagy: Identification of MTMR5 as a neuron-enriched suppressor.
  7. Characterization of Protein-Membrane Interactions in Yeast Autophagy.
  8. Chaperone-Mediated Autophagy and Its Implications for Neurodegeneration and Cancer.
  9. The Translational Regulation in mTOR Pathway.
  10. Targeting autophagy as a therapeutic strategy against pancreatic cancer.
  11. Tollip negatively regulates mitophagy by promoting the mitochondrial processing and cytoplasmic release of PINK1.
  12. The central role of mTORC1 in amino acid sensing.
  13. Diving into the Evolutionary History of HSC70-Linked Selective Autophagy Pathways: Endosomal Microautophagy and Chaperone-Mediated Autophagy.
  14. Parkin, as a Regulator, Participates in Arsenic Trioxide-Triggered Mitophagy in HeLa Cells.
  15. CHK2 Promotes Metabolic Stress-Induced Autophagy through ULK1 Phosphorylation.
  16. The legacy of János Kovács: a lifelong devotion to advancing autophagy research.
  17. A plant nonenveloped double-stranded RNA virus activates and co-opts BNIP3-mediated mitophagy to promote persistent infection in its insect vector.
  18. Glycan degradation promotes macroautophagy.
  19. Role of MST1 in the regulation of autophagy and mitophagy: implications for aging-related diseases.
  20. Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease.
  21. Potentials of autophagy enhancing natural products in the treatment of Parkinson disease.
  22. TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway.
  23. Borcs6 is required for endo-lysosomal degradation during early development.
  24. P. edulis Extract Protects Against Amyloid-β Toxicity in Alzheimer's Disease Models Through Maintenance of Mitochondrial Homeostasis via the FOXO3/DAF-16 Pathway.
  25. Autophagy and autophagy-related molecules in neurodegenerative diseases.
  26. Mechanoautophagy: Synergies Between Autophagy and Cell Mechanotransduction at Adhesive Complexes.
  27. Exocyst functions in plants - secretion and autophagy.
  28. Tracking autophagy process with a through bond energy transfer-based ratiometric two-photon viscosity probe.
  29. PINK1/Parkin-Mediated Mitophagy Plays a Protective Role in Albumin Overload-Induced Renal Tubular Cell Injury.
  30. Insulin and Its Key Role for Mitochondrial Function/Dysfunction and Quality Control: A Shared Link between Dysmetabolism and Neurodegeneration.
  31. LRRK2 and Proteostasis in Parkinson's Disease.
  32. Mitochondrial Quality Control in the Heart: The Balance between Physiological and Pathological Stress.
  33. TRIM72-mediated degradation of the short form of p62/SQSTM1 rheostatically controls selective autophagy in human cells.
  34. Recent advances in autophagy research.
  35. Massive Accumulation of Sphingomyelin Affects the Lysosomal and Mitochondria Compartments and Promotes Apoptosis in Niemann-Pick Disease Type A.
  36. Visual monitoring of the mitochondrial pH changes during mitophagy with a NIR fluorescent probe and its application in tumor imaging.
  37. Extracellular Adenosine Triphosphate Binding to P2Y1 Receptors Prevents Glutamate-Induced Excitotoxicity: Involvement of Erk1/2 Signaling Pathway to Suppress Autophagy.
  38. Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis.
  39. A Dual-Acting Nitric Oxide Donor and Phosphodiesterase 5 Inhibitor Activates Autophagy in Primary Skin Fibroblasts.
  40. Role of mTOR Signaling Cascade in Epidermal Morphogenesis and Skin Barrier Formation.
  41. Protective Effect of Mitophagy Regulated by mTOR Signaling Pathway in Liver Fibrosis Associated with Selenium.
  42. Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62.
  43. Metformin inactivates the cGAS-STING pathway through autophagy and suppresses senescence in nucleus pulposus cells.
  44. Mitochondrial-derived vesicles: Gatekeepers of mitochondrial response to oxidative stress.
  45. Prostaglandin 2α Promotes Autophagy and Mitochondrial Energy Production in Fish Hepatocytes.
  46. Impaired Mitophagy in Sanfilippo A mice Causes Hypertriglyceridemia and Brown Adipose Tissue Activation.
  47. Novel Therapeutic Strategies for Ischemic Stroke: Recent Insights into Autophagy.
  48. ULK1 mediated mitophagy prevents pathological cardiac remodelling and heart failure.
  49. Metformin attenuates cadmium-induced degeneration of spiral ganglion neuron via restoring autophagic flux in primary culture.
  50. Tumor-derived CTF1 (cardiotrophin 1) is a critical mediator of stroma-assisted and autophagy-dependent breast cancer cell migration, invasion and metastasis.
  51. Triptolide promotes autophagy to inhibit mesangial cell proliferation in IgA nephropathy via the CARD9/p38 MAPK pathway.
  52. Supramolecular assembly of GSK3α as a cellular response to amino acid starvation.
  53. Dync1li1 is required for the survival of mammalian cochlear hair cells by regulating the transportation of autophagosomes.
  54. Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes.
  55. Therapeutic Aspects and Molecular Targets of Autophagy to Control Pancreatic Cancer Management.
  56. CRISPR/Cas9-Mediated Constitutive Loss of VCP (Valosin-Containing Protein) Impairs Proteostasis and Leads to Defective Striated Muscle Structure and Function In Vivo.
  57. Phillygenin ameliorates nonalcoholic fatty liver disease via TFEB-mediated lysosome biogenesis and lipophagy.
  58. Interaction between tumor microenvironment, autophagy, and epithelial-mesenchymal transition in tumor progression.
  59. FUS aggregation following ischemic stroke favors brain astrocyte activation through inducing excessive autophagy.
  1. Autophagy. 2022 Jun 19. 1-27
    Proteasomal inhibition preferentially stimulates lysosome activity relative to autophagic flux in primary astrocytes.
    Ruiyi Yuan, Younghee Hahn, Max H Stempel, David K Sidibe, Olivia Laxton, Jessica Chen, Aditi Kulkarni, Sandra Maday.
      Neurons and astrocytes face unique demands on their proteome to enable proper function and survival of the nervous system. Consequently, both cell types are critically dependent on robust quality control pathways such as macroautophagy (hereafter referred to as autophagy) and the ubiquitin-proteasome system (UPS). We previously reported that autophagy is differentially regulated in astrocytes and neurons in the context of metabolic stress, but less is understood in the context of proteotoxic stress induced by inhibition of the UPS. Dysfunction of the proteasome or autophagy has been linked to the progression of various neurodegenerative diseases. Therefore, in this study, we explored the connection between autophagy and the proteasome in primary astrocytes and neurons. Prior studies largely in non-neural models report a compensatory relationship whereby inhibition of the UPS stimulates autophagy. To our surprise, inhibition of the proteasome did not robustly upregulate autophagy in astrocytes or neurons. In fact, the effects on autophagy are modest particularly in comparison to paradigms of metabolic stress. Rather, we find that UPS inhibition in astrocytes induces formation of Ub-positive aggregates that harbor the selective autophagy receptor, SQSTM1/p62, but these structures were not productive substrates for autophagy. By contrast, we observed a significant increase in lysosomal degradation in astrocytes in response to UPS inhibition, but this stimulation was not sufficient to reduce total SQSTM1 levels. Last, UPS inhibition was more toxic in neurons compared to astrocytes, suggesting a cell type-specific vulnerability to proteotoxic stress.Abbreviations: Baf A1: bafilomycin A1; CQ: chloroquine; Epox: epoxomicin; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; p-ULK1: phospho-ULK1; SQSTM1/p62: sequestosome 1; Ub: ubiquitin; ULK1: unc-51 like kinase 1; UPS: ubiquitin-proteasome system.
    Keywords:  Astrocytes; LC3; SQSTM1; autophagy; lysosomes; neurons; proteasome; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2022.2084884
  2. BMB Rep. 2022 Jun 21. pii: 5590. [Epub ahead of print]
    Inhibition of mitoNEET induces Pink1-Parkin-mediated mitophagy.
    Seunghee Lee, Sangguk Lee, Seon-Jin Lee, Su Wol Chung.
      MitoNEET, a mitochondrial outer membrane protein containing the Asn-Glu-Glu-Thr (NEET) sequence, controls the formation of intermitochondrial junctions and confers autophagy resistance. Moreover, mitoNEET as a mitochondrial substrate undergoes ubiquitination by activated Parkin during the initiation of mitophagy. Therefore, mitoNEET is linked to the regulation of autophagy and mitophagy. Mitophagy is the selective removal of the damaged or unnecessary mitochondria, which is crucial to sustaining mitochondrial quality control. In numerous human diseases, the accumulation of damaged mitochondria by impaired mitophagy has been observed. However, the therapeutic strategy targeting of mitoNEET as a mitophagy-enhancing mediator requires further research. Herein, we confirmed that mitophagy is indeed activated by mitoNEET inhibition. CCCP (carbonyl cyanide m-chlorophenyl hydrazone), which leads to mitochondrial depolarization, induces mitochondrial dysfunction and superoxide production. This, in turn, contributes to the induction of mitophagy; mitoNEET protein levels were initially increased before an increase in LC3-Ⅱ protein following CCCP treatment. Pharmacological inhibition of mitoNEET using mitoNEET Ligand-1 (NL-1) promoted accumulation of Pink1 and Parkin, which are mitophagy-associated proteins, and activation of mitochondria-lysosome crosstalk, in comparison to CCCP alone. Inhibition of mitoNEET using NL-1, or mitoNEET shRNA transfected into RAW264.7 cells, abrogated CCCP-induced ROS and mitochondrial cell death; additionally, it activated the expression of PGC-1α and SOD2, regulators of oxidative metabolism. In particular, the increase in PGC-1α, which is a major regulator of mitochondrial biogenesis, promotes mitochondrial quality control. These results indicated that mitoNEET is a potential therapeutic target in numerous human diseases to enhance mitophagy and protect cells by maintaining a network of healthy mitochondria.
  3. Curr Biol. 2022 Jun 20. pii: S0960-9822(22)00707-2. [Epub ahead of print]32(12): R684-R696
    Balancing nutrient and energy demand and supply via autophagy.
    Congcong He.
      Maintaining nutrient and energy homeostasis is crucial for the survival and function of cells and organisms in response to environmental stress. Cells have evolved a stress-induced catabolic pathway, termed autophagy, to adapt to stress conditions such as starvation. During autophagy, damaged or non-essential cellular structures are broken down in lysosomes, and the resulting metabolites are reused for core biosynthetic processes or energy production. Recent studies have revealed that autophagy can target and degrade different types of nutrient stores and produce a variety of metabolites and fuels, including amino acids, nucleotides, lipids and carbohydrates. Here, we will focus on how autophagy functions to balance cellular nutrient and energy demand and supply - specifically, how energy deprivation switches on autophagic catabolism, how autophagy halts anabolism by degrading the protein synthesis machinery, and how bulk and selective autophagy-derived metabolites recycle and feed into a variety of bioenergetic and anabolic pathways during stress conditions. Recent new insights and progress in these areas provide a better understanding of how resource mobilization and reallocation sustain essential metabolic and anabolic activities under unfavorable conditions.
    DOI:  https://doi.org/10.1016/j.cub.2022.04.071
  4. Autophagy. 2022 Jun 19.
    Targeted protein degradation via the autophagy-lysosome system: AUTOTAC (AUTOphagy-TArgeting Chimera).
    Chang Hoon Ji, Min Ju Lee, Hee Yeon Kim, Ah Jung Heo, Daniel Youngjae Park, Yun Kyung Kim, Bo Yeon Kim, Yong Tae Kwon.
      Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several types of degraders that harness the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux remains unavailable. In this study, we developed a general chemical tool by which given intracellular proteins are targeted to macroautophagy for lysosomal degradation. This platform technology, termed AUTOTAC (AUTOphagy-TArgeting Chimera), employs bifunctional molecules composed of target-binding ligands (TBLs) linked to autophagy-targeting ligands (ATLs). Upon binding to targets via the TBL, the ATL binds the ZZ domain of the otherwise dormant autophagy receptor SQSTM1/p62 (sequestosome 1), which activates SQSTM1 associated with targets and sequesters them into oligomeric species for autophagic targeting and lysosomal degradation. AUTOTACs were used to degrade various oncoproteins or aggregation-prone proteins in neurodegeneration both in vitro and/or in vivo. We suggest that AUTOTAC provides a platform for selective proteolysis as a research tool and in drug development.
    Keywords:  N-degron pathway; N-terminal arginylation; SQSTM1/p62; chemical tools; neurodegeneration; protein quality control; proteinopathy; proteolysis; selective autophagy; targeted protein degradation (TPD)
    DOI:  https://doi.org/10.1080/15548627.2022.2091338
  5. Biol Futur. 2022 Jun 22.
    The evolutionary and functional divergence of the Atg8 autophagy protein superfamily.
    Virginia B Varga, Fanni Keresztes, Tímea Sigmond, Tibor Vellai, Tibor Kovács.
      Autophagy is a highly conserved self-degradation process of eukaryotic cells which is required for the effective elimination of damaged and unnecessary cytosolic constituents. Defects in the process can cause the intracellular accumulation of such damages, thereby leading to the senescence and subsequent loss of the affected cell. Defective autophagy hence is implicated in the development of various degenerative processes, including cancer, neurodegenerative diseases, diabetes, tissue atrophy and fibrosis, and immune deficiency, as well as in accelerated aging. The autophagic process is mediated by numerous autophagy-related (ATG) proteins, among which the ATG8/LC3/GABARAP (Microtubule-associated protein 1A/1B-light chain 3/Gammaaminobutyric acid receptor-associated protein) superfamily has a pivotal role in the formation and maturation of autophagosome, a key (macro) autophagic structure (the autophagosome sequesters parts of the cytoplasm which are destined for breakdown). While in the unicellular yeast there is only a single ATG8 protein, metazoan systems usually contain more ATG8 paralogs. ATG8 paralogs generally display tissue-specific expression patterns and their functions are not strictly restricted to autophagy. For example, GABARAP proteins also play a role in intracellular vesicle transport, and, in addition to autophagosome formation, ATG8 also functions in selective autophagy. In this review, we summarize the functional diversity of ATG8/LC3/GABARAP proteins, using tractable genetic models applied in autophagy research.
    Keywords:  ATG8; Autophagy; GABARAP; GATE-16; LC3
    DOI:  https://doi.org/10.1007/s42977-022-00123-6
  6. Curr Biol. 2022 Jun 20. pii: S0960-9822(22)00711-4. [Epub ahead of print]32(12): R574-R577
    Autophagy: Identification of MTMR5 as a neuron-enriched suppressor.
    Maria Chalokh Vogel, Sandra Maday.
      A puzzle of autophagy in neurons is that, unlike in other cells, it is not robustly induced by inhibition of mammalian target of rapamycin (mTOR). A new study now solves this conundrum and establishes that myotubularin-related phosphatase 5 limits the induction of neuronal autophagy by mTOR inhibitors.
    DOI:  https://doi.org/10.1016/j.cub.2022.04.075
  7. Cells. 2022 Jun 09. pii: 1876. [Epub ahead of print]11(12):
    Characterization of Protein-Membrane Interactions in Yeast Autophagy.
    Kelsie A Leary, Michael J Ragusa.
      Cells rely on autophagy to degrade cytosolic material and maintain homeostasis. During autophagy, content to be degraded is encapsulated in double membrane vesicles, termed autophagosomes, which fuse with the yeast vacuole for degradation. This conserved cellular process requires the dynamic rearrangement of membranes. As such, the process of autophagy requires many soluble proteins that bind to membranes to restructure, tether, or facilitate lipid transfer between membranes. Here, we review the methods that have been used to investigate membrane binding by the core autophagy machinery and additional accessory proteins involved in autophagy in yeast. We also review the key experiments demonstrating how each autophagy protein was shown to interact with membranes.
    Keywords:  autophagy; membrane binding proteins; yeast
    DOI:  https://doi.org/10.3390/cells11121876
  8. Int J Gen Med. 2022 ;15 5635-5649
    Chaperone-Mediated Autophagy and Its Implications for Neurodegeneration and Cancer.
    Masresha Ahmed Assaye, Solomon T Gizaw.
      Proteostasis, also known as protein homeostasis, is critical for cell survival. Autophagy is a cellular process that degrades and recycles damaged or long-lived proteins, misfolded proteins, and damaged or abnormal organelles in order to preserve homeostasis. Among the three forms of autophagy, chaperone-mediated autophagy (CMA) is distinct from macroautophagy and microautophagy; it does not require the formation of vacuoles and only degrades selected individual proteins. CMA helps to maintain cellular homeostasis by regulating protein quality, bioenergetics, and substrate-associated cellular processes at the right moment. This pathway's dysfunction has been linked to several diseases and disorders. Neurodegenerative diseases and cancer have received the most attention. In various neurodegenerative disorders, especially in their later stages, CMA activity declines. CMA has been shown to act as a tumor suppressor in cancer by destroying specific tumor promoters. Once a tumor has grown, it also helps tumor survival and the metastatic cascade. The presence of changes in CMA in these diseases disorders raises the idea of targeting CMA to restore cellular homeostasis as a potential therapeutic method. Manipulation of CMA activity may be effective therapeutic strategies for treating these diseases. Therefore, in this paper; we introduce the basic processes, regulatory mechanisms, and physiological functions of CMA; evidences supporting the role of impaired CMA function in neurodegeneration and cancer; and the potential of how targeting CMA could be a promising therapeutic method for the two diseases.
    Keywords:  autophagy; cancer; chaperone; chaperone-mediated autophagy; lysosome; neurodegeneration; therapy
    DOI:  https://doi.org/10.2147/IJGM.S368364
  9. Biomolecules. 2022 Jun 08. pii: 802. [Epub ahead of print]12(6):
    The Translational Regulation in mTOR Pathway.
    Miaomiao Yang, Yanming Lu, Weilan Piao, Hua Jin.
      The mechanistic/mammalian target of rapamycin (mTOR) plays a master role in cell proliferation and growth in response to insulin, amino acids, energy levels, and oxygen. mTOR can coordinate upstream signals with downstream effectors, including transcriptional and translational apparatuses to regulate fundamental cellular processes such as energy utilization, protein synthesis, autophagy, cell growth, and proliferation. Of the above, protein synthesis is highly energy-consuming; thus, mRNA translation is under the tight and immediate control of mTOR signaling. The translational regulation driven by mTOR signaling mainly relies on eukaryotic translation initiation factor 4E (eIF4E)-binding protein (4E-BP), ribosomal protein S6 kinase (S6K), and its downstream players, which are significant in rapid cellular response to environmental change. mTOR signaling not only controls the general mRNA translation, but preferential mRNA translation as well. This means that mTOR signaling shows the stronger selectivity to particular target mRNAs. Some evidence has supported the contribution of 4E-BP and La-related proteins 1 (LARP1) to such translational regulation. In this review, we summarize the mTOR pathway and mainly focus on mTOR-mediated mRNA translational regulation. We introduce the major components of mTOR signaling and their functions in translational control in a general or particular manner, and describe how the specificity of regulation is coordinated. Furthermore, we summarize recent research progress and propose additional ideas for reference. Because the mTOR pathway is on the center of cell growth and metabolism, comprehensively understanding this pathway will contribute to the therapy of related diseases, including cancers, type 2 diabetes, obesity, and neurodegeneration.
    Keywords:  4E-BP; LARP1; S6K; mTOR; translational regulation
    DOI:  https://doi.org/10.3390/biom12060802
  10. J Gastroenterol. 2022 Jun 21.
    Targeting autophagy as a therapeutic strategy against pancreatic cancer.
    Keisuke Yamamoto, Dosuke Iwadate, Hiroyuki Kato, Yousuke Nakai, Keisuke Tateishi, Mitsuhiro Fujishiro.
      Macroautophagy (hereafter autophagy) is a catabolic process through which cytosolic components are captured in the autophagosome and degraded in the lysosome. Autophagy plays two major roles: nutrient recycling under starvation or stress conditions and maintenance of cellular homeostasis by removing the damaged organelles or protein aggregates. In established cancer cells, autophagy-mediated nutrient recycling promotes tumor progression, whereas in normal/premalignant cells, autophagy suppresses tumor initiation by eliminating the oncogenic/harmful molecules. Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is refractory to most currently available treatment modalities, including immune checkpoint blockade and molecular-targeted therapy. One prominent feature of PDAC is its constitutively active and elevated autophagy-lysosome function, which enables PDAC to thrive in its nutrient-scarce tumor microenvironment. In addition to metabolic support, autophagy promotes PDAC progression in a metabolism-independent manner by conferring resistance to therapeutic treatment or facilitating immune evasion. Besides to cell-autonomous autophagy in cancer cells, host autophagy (autophagy in non-cancer cells) supports PDAC progression, further highlighting autophagy as a promising therapeutic target in PDAC. Based on a growing list of compelling preclinical evidence, there are numerous ongoing clinical trials targeting the autophagy-lysosome pathway in PDAC. Given the multifaceted and context-dependent roles of autophagy in both cancer cells and normal host cells, a deeper understanding of the mechanisms underlying the tumor-promoting roles of autophagy as well as of the consequences of autophagy inhibition is necessary for the development of autophagy inhibition-based therapies against PDAC.
    Keywords:  Anti-tumor immunity; Autophagy; Host autophagy; Lysosome; PDAC
    DOI:  https://doi.org/10.1007/s00535-022-01889-1
  11. BMB Rep. 2022 Jun 21. pii: 5642. [Epub ahead of print]
    Tollip negatively regulates mitophagy by promoting the mitochondrial processing and cytoplasmic release of PINK1.
    Woo Hyun Shin, Kwang Chul Chung.
      PTEN-induced putative kinase 1 (PINK1) is a serine/threonine kinase that phosphorylates several substrates and exerts neuroprotective effects against stress-induced apoptotic cell death. Mutations in PINK1 have been linked to autosomal recessive forms of Parkinson's disease (PD). Mitophagy is a type of autophagy that selectively promotes mitochondrial turnover and prevents the accumulation of dysfunctional mitochondria to maintain cellular homeostasis. Toll-interacting protein (Tollip) was initially identified as a negative regulator of IL-1β receptor signaling, suppressing inflammatory TLR signaling cascades. Recently, Tollip has been reported to play a role in autophagy and is implicated in neurodegeneration. In this study, we determined whether Tollip was functionally linked to PINK1-mediated mitophagy. Our results demonstrated that Tollip promoted the mitochondrial processing of PINK1 and altered the localization of PINK1, predominantly to the cytosol. This action was attributed to increased binding of PINK1 to mitochondrial processing peptidase β (MPPβ) and the subsequent increase in MPPβ-mediated mitochondrial PINK1 cleavage. Furthermore, Tollip suppressed mitophagy following carbonyl cyanide m-chlorophenylhydrazone-induced mitochondrial dysfunction. These findings suggest that Tollip inhibits mitophagy via the PINK1/parkin pathway upon mitochondrial damage, leading to the blockade of PINK1-mediated neuroprotection.
  12. Cancer Res. 2022 Jun 24. pii: canres.4403.2021. [Epub ahead of print]
    The central role of mTORC1 in amino acid sensing.
    Shusheng Yue, Guanya Li, Shanping He, Tingting Li.
      The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth that controls cell homeostasis in response to nutrients, growth factors, and other environmental cues. Recent studies have emphasized the importance of lysosomes as a hub for nutrient sensing, especially amino acid sensing by mTORC1. This review highlights recent advances in understanding the amino acid-mTORC1 signaling axis and the role of mTORC1 in cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-4403
  13. Cells. 2022 Jun 16. pii: 1945. [Epub ahead of print]11(12):
    Diving into the Evolutionary History of HSC70-Linked Selective Autophagy Pathways: Endosomal Microautophagy and Chaperone-Mediated Autophagy.
    Simon Schnebert, Maxime Goguet, Emilio J Vélez, Alexandra Depincé, Florian Beaumatin, Amaury Herpin, Iban Seiliez.
      Autophagy is a pleiotropic and evolutionarily conserved process in eukaryotes that encompasses different types of mechanisms by which cells deliver cytoplasmic constituents to the lysosome for degradation. Interestingly, in mammals, two different and specialized autophagic pathways, (i) the chaperone-mediated autophagy (CMA) and (ii) the endosomal microautophagy (eMI), both rely on the use of the same cytosolic chaperone HSPA8 (also known as HSC70) for targeting specific substrates to the lysosome. However, this is not true for all organisms, and differences exist between species with respect to the coexistence of these two autophagic routes. In this paper, we present an in-depth analysis of the evolutionary history of the main components of CMA and eMI and discuss how the observed discrepancies between species may contribute to improving our knowledge of these two functions and their interplays.
    Keywords:  CMA; HSC70; KFERQ; LAMP2A; chaperone-mediated autophagy; eMI; endosomal microautophagy; evolution
    DOI:  https://doi.org/10.3390/cells11121945
  14. Curr Issues Mol Biol. 2022 Jun 20. 44(6): 2759-2771
    Parkin, as a Regulator, Participates in Arsenic Trioxide-Triggered Mitophagy in HeLa Cells.
    Zhewen Zhang, Juan Yi, Bei Xie, Jing Chen, Xueyan Zhang, Li Wang, Jingyu Wang, Jinxia Hou, Hulai Wei.
      Parkin is a well-established synergistic mediator of mitophagy in dysfunctional mitochondria. Mitochondria are the main target of arsenic trioxide (ATO) cytotoxicity, and the effect of mitophagy on ATO action remains unclear. In this study, we used stable Parkin-expressing (YFP-Parkin) and Parkin loss-of-function mutant (Parkin C431S) HeLa cell models to ascertain whether Parkin-mediated mitophagy participates in ATO-induced apoptosis/cell death. Our data showed that the overexpression of Parkin significantly sensitized HeLa cells to ATO-initiated proliferation inhibition and apoptosis; however, the mutation of Parkin C431S significantly weakened this Parkin-mediated responsiveness. Our further investigation found that ATO significantly downregulated two fusion proteins (Mfn1/2) and upregulated fission-related protein (Drp1). Autophagy was also activated as evidenced by the formation of autophagic vacuoles and mitophagosomes, increased expression of PINK1, and recruitment of Parkin to impaired mitochondria followed by their degradation, accompanied by the increased transformation of LC3-I to LC3-II, increased expression of Beclin1 and decreased expression of P62 in YFP-Parkin HeLa cells. Enhanced mitochondrial fragmentation and autophagy indicated that mitophagy was activated. Furthermore, during the process of mitophagy, the overproduction of ROS implied that ROS might represent a key factor that initiates mitophagy following Parkin recruitment to mitochondria. In conclusion, our findings indicate that Parkin is critically involved in ATO-triggered mitophagy and functions as a potential antiproliferative target in cancer cells.
    Keywords:  HeLa; Parkin; apoptosis; arsenic trioxide; autophagy
    DOI:  https://doi.org/10.3390/cimb44060189
  15. Antioxidants (Basel). 2022 Jun 14. pii: 1166. [Epub ahead of print]11(6):
    CHK2 Promotes Metabolic Stress-Induced Autophagy through ULK1 Phosphorylation.
    Ran Guo, Shan-Shan Wang, Xiao-You Jiang, Ye Zhang, Yang Guo, Hong-Yan Cui, Qi-Qiang Guo, Liu Cao, Xiao-Chen Xie.
      Reactive oxygen species (ROS) act as a signaling intermediate to promote cellular adaptation to maintain homeostasis by regulating autophagy during pathophysiological stress. However, the mechanism by which ROS promotes autophagy is still largely unknown. Here, we show that the ATM/CHK2/ULK1 axis initiates autophagy to maintain cellular homeostasis by sensing ROS signaling under metabolic stress. We report that ULK1 is a physiological substrate of CHK2, and that the binding of CHK2 to ULK1 depends on the ROS signal and the phosphorylation of threonine 68 of CHK2 under metabolic stress. Further, CHK2 phosphorylates ULK1 on serine 556, and this phosphorylation is dependent on the ATM/CHK2 signaling pathway. CHK2-mediated phosphorylation of ULK1 promotes autophagic flux and inhibits apoptosis induced by metabolic stress. Taken together, these results demonstrate that the ATM/CHK2/ULK1 axis initiates an autophagic adaptive response by sensing ROS, and it protects cells from metabolic stress-induced cellular damage.
    Keywords:  CHK2; ROS; ULK1; autophagy; oxidative stress
    DOI:  https://doi.org/10.3390/antiox11061166
  16. Autophagy. 2022 Jun 23. 1-3
    The legacy of János Kovács: a lifelong devotion to advancing autophagy research.
    Attila L Kovács, Péter Lőw, Gábor Juhász.
      
    DOI:  https://doi.org/10.1080/15548627.2022.2091263
  17. Autophagy. 2022 Jun 19.
    A plant nonenveloped double-stranded RNA virus activates and co-opts BNIP3-mediated mitophagy to promote persistent infection in its insect vector.
    Qifu Liang, Jiajia Wan, Huan Liu, Dongsheng Jia, Qian Chen, Aiming Wang, Taiyun Wei.
      Mitophagy that selectively eliminates damaged mitochondria is an essential mitochondrial quality control mechanism. Recently, mitophagy has been shown to be induced in host cells infected by a few animal viruses. Here, we report that southern rice black-streaked dwarf virus (SRBSDV), a plant nonenveloped double-stranded RNA virus, can also trigger mitophagy in its planthopper vector to prevent mitochondria-dependent apoptosis and promote persistent viral propagation. We find that the fibrillar structures constructed by the nonstructural protein P7-1 of SRBSDV directly target mitochondria via interaction with the mitophagy receptor BNIP3 (BCL2 interacting protein 3), and these mitochondria are then sequestered within autophagosomes to form mitophagosomes. Moreover, SRBSDV infection or P7-1 expression alone can promote BNIP3 dimerization on the mitochondria, and induce autophagy via the P7-1-ATG8 interaction. Furthermore, SRBSDV infection stimulates the phosphorylation of AMP-activated protein kinase (AMPK), resulting in BNIP3 phosphorylation via the AMPKα-BNIP3 interaction. Together, P7-1 induces BNIP3-mediated mitophagy by promoting the formation of phosphorylated BNIP3 dimers on the mitochondria. Silencing of ATG8, BNIP3, or AMPKα significantly reduces virus-induced mitophagy and viral propagation in insect vectors. These data suggest that in planthopper, SRBSDV-induced mitophagosomes are modified to accommodate virions and facilitate persistent viral propagation. In summary, our results demonstrate a previously unappreciated role of a viral protein in the induction of BNIP3-mediated mitophagy by bridging autophagosomes and mitochondria and reveal the functional importance of virus-induced mitophagy in maintaining persistent viral infection in insect vectors.
    Keywords:  AMPK phosphorylation; ATG8; BNIP3-mediated mitophagy; SRBSDV; apoptosis; autophagosomes; dsRNA virus; insect vector; nonstructural protein; persistent infection
    DOI:  https://doi.org/10.1080/15548627.2022.2091904
  18. Proc Natl Acad Sci U S A. 2022 Jun 28. 119(26): e2111506119
    Glycan degradation promotes macroautophagy.
    Alice D Baudot, Victoria M-Y Wang, Josh D Leach, Jim O'Prey, Jaclyn S Long, Viola Paulus-Hock, Sergio Lilla, David M Thomson, John Greenhorn, Farah Ghaffar, Colin Nixon, Miep H Helfrich, Douglas Strathdee, Judith Pratt, Francesco Marchesi, Sara Zanivan, Kevin M Ryan.
      Macroautophagy promotes cellular homeostasis by delivering cytoplasmic constituents to lysosomes for degradation [Mizushima, Nat. Cell Biol. 20, 521-527 (2018)]. However, while most studies have focused on the mechanisms of protein degradation during this process, we report here that macroautophagy also depends on glycan degradation via the glycosidase, α-l-fucosidase 1 (FUCA1), which removes fucose from glycans. We show that cells lacking FUCA1 accumulate lysosomal glycans, which is associated with impaired autophagic flux. Moreover, in a mouse model of fucosidosis-a disease characterized by inactivating mutations in FUCA1 [Stepien et al., Genes (Basel) 11, E1383 (2020)]-glycan and autophagosome/autolysosome accumulation accompanies tissue destruction. Mechanistically, using lectin capture and mass spectrometry, we identified several lysosomal enzymes with altered fucosylation in FUCA1-null cells. Moreover, we show that the activity of some of these enzymes in the absence of FUCA1 can no longer be induced upon autophagy stimulation, causing retardation of autophagic flux, which involves impaired autophagosome-lysosome fusion. These findings therefore show that dysregulated glycan degradation leads to defective autophagy, which is likely a contributing factor in the etiology of fucosidosis.
    Keywords:  fucosidosis; lysosomes; macroautophagy; α-l-fucosidase 1
    DOI:  https://doi.org/10.1073/pnas.2111506119
  19. J Physiol Biochem. 2022 Jun 21.
    Role of MST1 in the regulation of autophagy and mitophagy: implications for aging-related diseases.
    Huayu Shang, Trisha A VanDusseldorp, Ranggui Ma, Yan Zhao, Jason Cholewa, Nelo Eidy Zanchi, Zhi Xia.
      As a key mechanism to maintain cellular homeostasis under stress conditions, autophagy/mitophagy is related to the occurrence of metabolic disorders, neurodegenerative diseases, cancer, and other aging-related diseases, but the relevant signal pathways regulating autophagy have not been clarified. Mammalian sterile 20-like kinase 1 (MST1) is a central regulatory protein of many metabolic pathways involved in the pathophysiological processes of aging and aging-related diseases and has become a critical integrator affecting autophagic signaling. Recent studies show that MST1 not only suppresses autophagy through directly phosphorylating Beclin-1 and/or inhibiting the protein expression of silent information regulator 1 (SIRT1) in the cytoplasm, but also inhibits BCL2/adenovirus E1B protein-interacting protein 3 (BNIP3)-, FUN14 domain containing 1 (FUNDC1)-, and Parkin (Parkinson protein 2)-mediated mitophagy by interacting with factors such as Ras association domain family 1A (RASSF1A). Indeed, a common pharmacological strategy for anti-aging is to induce autophagy/mitophagy through MST1 inhibition. This article reviews the role and mechanism of MST1 in regulating autophagy during aging, to provide evidence for the development of drugs targeting MST1.
    Keywords:  Aging; Aging-related diseases; Autophagy; Mammalian sterile 20-like kinase 1; Mitophagy
    DOI:  https://doi.org/10.1007/s13105-022-00904-6
  20. Cell Death Differ. 2022 Jun 23.
    Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease.
    Anderson Tan, Renuka Prasad, Chaerin Lee, Eek-Hoon Jho.
      Transcription factor EB (TFEB), a member of the MiT/TFE family of basic helix-loop-helix leucine zipper transcription factors, is an established central regulator of the autophagy/lysosomal-to-nucleus signaling pathway. Originally described as an oncogene, TFEB is now widely known as a regulator of various processes, such as energy homeostasis, stress response, metabolism, and autophagy-lysosomal biogenesis because of its extensive involvement in various signaling pathways, such as mTORC1, Wnt, calcium, and AKT signaling pathways. TFEB is also implicated in various human diseases, such as lysosomal storage disorders, neurodegenerative diseases, cancers, and metabolic disorders. In this review, we present an overview of the major advances in TFEB research over the past 30 years, since its description in 1990. This review also discusses the recently discovered regulatory mechanisms of TFEB and their implications for human diseases. We also summarize the moonlighting functions of TFEB and discuss future research directions and unanswered questions in the field. Overall, this review provides insight into our understanding of TFEB as a major molecular player in human health, which will take us one step closer to promoting TFEB from basic research into clinical and regenerative applications.
    DOI:  https://doi.org/10.1038/s41418-022-01028-6
  21. Drug Metab Pers Ther. 2021 Aug 13. 37(2): 99-110
    Potentials of autophagy enhancing natural products in the treatment of Parkinson disease.
    Taiwo G Olubodun-Obadun, Ismail O Ishola, Olufunmilayo O Adeyemi.
      Parkinson disease (PD) is a progressive neurodegenerative movement disorder characterized by motor and non-motor symptoms due to loss of striatal dopaminergic neurons and disruption of degradation signaling leading to the formation of Lewy bodies (aggregation of α-synuclein). Presently, there are no disease modifying therapy for PD despite improvement in the understanding of the disease pathogenesis. However, the drugs currently used in PD management provide symptomatic relieve for motor symptoms without significant improvement in non-motor complications, thus, a public health burden on caregivers and healthcare systems. There is therefore the need to discover disease modifying therapy with strong potential to halt the disease progression. Recent trend has shown that the dysfunction of lysosomal-autophagy pathway is highly implicated in PD pathology, hence, making autophagy a key player owing to its involvement in degradation and clearance of misfolded α-synuclein (a major hallmark in PD pathology). In this review, we described the current drugs/strategy in the management of PD including targeting the autophagy pathway as a novel approach that could serve as potential intervention for PD management. The discovery of small molecules or natural products capable of enhancing autophagy mechanism could be a promising strategy for PD treatment.
    Keywords:  Parkinson disease; lysosomal-autophagy signaling; movement disorder; non-motor features; phytochemicals; α-synuclein
    DOI:  https://doi.org/10.1515/dmpt-2021-0128
  22. Oncogene. 2022 Jun 24.
    TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway.
    Yujia Li, Qi Yang, Hui Chen, Xiaotian Yang, Jingru Han, Xiaojuan Yao, Xiajie Wei, Jiaoyang Si, Huanling Yao, Hongliang Liu, Lixin Wan, Hushan Yang, Yanming Wang, Dengke Bao.
      The dynamics of mitochondrial biogenesis regulation is critical in maintaining cellular homeostasis for immune regulation and tumor prevention. Here, we report that mitochondrial biogenesis disruption through TFAM reduction significantly impairs mitochondrial function, induces autophagy, and promotes esophageal squamous cell carcinoma (ESCC) growth. We found that TFAM protein reduction promotes mitochondrial DNA (mtDNA) release into the cytosol, induces cytosolic mtDNA stress, subsequently activates the cGAS-STING signaling pathway, thereby stimulating autophagy and ESCC growth. STING depletion or mtDNA degradation by DNase I abrogates mtDNA stress response, attenuates autophagy, and decreases the growth of TFAM depleted cells. In addition, autophagy inhibitor also ameliorates mitochondrial dysfunction-induced activation of the cGAS-STING signaling pathway and ESCC growth. In conclusion, our results indicate that mtDNA stress induced by mitochondria biogenesis perturbation activates the cGAS-STING pathway and autophagy to promote ESCC growth, revealing an underappreciated therapeutic strategy for ESCC.
    DOI:  https://doi.org/10.1038/s41388-022-02365-z
  23. Mol Reprod Dev. 2022 Jun 21.
    Borcs6 is required for endo-lysosomal degradation during early development.
    Charlotte J Bell, Neha Gupta, Kimberly D Tremblay, Jesse Mager.
      Early development and differentiation require precise control of cellular functions. Lysosomal degradation is a critical component of normal cellular homeostasis, allowing for degradation of signaling molecules, proteins, and other macromolecules for cellular remodeling and signaling. Little is known about the role of lysosomal function in mammalian embryos before gastrulation. Borcs6 is a protein involved in lysosomal trafficking as well as endo-lysosomal and autophagosome fusion. Here, we show that Borcs6 is necessary for efficient endo-lysosomal degradation in the early embryo. Although embryos lacking Borcs6 are developmentally comparable to control littermates at E5.5, they are characterized by large cells containing increased levels of late endosomes and abnormal nuclei. Furthermore, these embryos display a skewed ratio of extraembryonic and embryonic cell lineages, are delayed by E6.5, and do not undergo normal gastrulation. These results demonstrate the essential functions of lysosomal positioning and fusion with endosomes during early embryonic development and indicate that the early lethality of BORCS6 mutant embryos is primarily due to defects in the HOPS-related function of BORC rather than lysosomal positioning.
    Keywords:  Borcs6; autophagy; development; knockout; lysosome
    DOI:  https://doi.org/10.1002/mrd.23626
  24. Mol Neurobiol. 2022 Jun 23.
    P. edulis Extract Protects Against Amyloid-β Toxicity in Alzheimer's Disease Models Through Maintenance of Mitochondrial Homeostasis via the FOXO3/DAF-16 Pathway.
    Shu-Qin Cao, Yahyah Aman, Evandro F Fang, Tewin Tencomnao.
      Alzheimer's disease (AD) is a common and devastating disease characterized by pathological aggregations of beta-amyloid (Aβ) plaques extracellularly, and Tau tangles intracellularly. While our understandings of the aetiologies of AD have greatly expanded over the decades, there is no drug available to stop disease progression. Here, we demonstrate the potential of Passiflora edulis (P. edulis) pericarp extract in protecting against Aβ-mediated neurotoxicity in mammalian cells and Caenorhabditis elegans (C. elegans) models of AD. We show P. edulis pericarp protects against memory deficit and neuronal loss, and promotes longevity in the Aβ model of AD via stimulation of mitophagy, a selective cellular clearance of damaged and dysfunctional mitochondria. P. edulis pericarp also restores memory and increases neuronal resilience in a C. elegans Tau model of AD. While defective mitophagy-induced accumulation of damaged mitochondria contributes to AD progression, P. edulis pericarp improves mitochondrial quality and homeostasis through BNIP3/DCT1-dependent mitophagy and SOD-3-dependent mitochondrial resilience, both via increased nuclear translocation of the upstream transcriptional regulator FOXO3/DAF-16. Further studies to identify active molecules in P. edulis pericarp that could maintain neuronal mitochondrial homeostasis may enable the development of potential drug candidates for AD.
    Keywords:  Alzheimer’s disease; DAF-16; DCT-1; Glutamatergic neurons; Mitophagy
    DOI:  https://doi.org/10.1007/s12035-022-02904-5
  25. Animal Model Exp Med. 2022 Jun 22.
    Autophagy and autophagy-related molecules in neurodegenerative diseases.
    Changsong Dou, Yu Zhang, Ling Zhang, Chuan Qin.
      Autophagy is one of the degradation pathways to remove proteins or damaged organelles in cells that plays an important role in neuroprotection. Different stages of autophagy are regulated by autophagy-related genes, and many molecules such as transcription factor EB (TFEB) are involved. The complete autophagy process plays an important role in maintaining the dynamic balance of autophagy and is crucial to the homeostasis of intracellular substance and energy metabolism. Autophagy balance is disrupted in neurodegenerative diseases, accounting for a variety of degeneration disorders. These impairments can be alleviated or treated by the regulation of autophagy through molecules such as TFEB.
    Keywords:  TFEB; autophagy; mitophagy; neurodegenerative
    DOI:  https://doi.org/10.1002/ame2.12229
  26. Front Cell Dev Biol. 2022 ;10 917662
    Mechanoautophagy: Synergies Between Autophagy and Cell Mechanotransduction at Adhesive Complexes.
    Andrea Ravasio, Eugenia Morselli, Cristina Bertocchi.
      Cells are exposed and respond to various mechanical forces and physical cues stemming from their environment. This interaction has been seen to differentially regulate various cellular processes for maintenance of homeostasis, of which autophagy represents one of the major players. In addition, autophagy has been suggested to regulate mechanical functions of the cells including their interaction with the environment. In this minireview, we summarize the state of the art of the fascinating interplay between autophagy and the mechanotransduction machinery associated with cell adhesions, that we name ¨Mechanoautophagy¨.
    Keywords:  Autophagy; Extracellular Matrix; cadherin mediated adhesion; focal adhesion; mechanoautophagy
    DOI:  https://doi.org/10.3389/fcell.2022.917662
  27. FEBS Lett. 2022 Jun 21.
    Exocyst functions in plants - secretion and autophagy.
    Viktor Žárský.
      Tethering complexes mediate vesicle-target compartment contact. Octameric complex exocyst initiates vesicle exocytosis at specific cytoplasmic membrane domains. Plant exocyst is possibly stabilized at the membrane by a direct interaction between SEC3 and EXO70A. Land plants evolved three basic membrane-targeting EXO70 subfamilies, the evolution of which resulted in several types of exocyst with distinct functions within the same cell. Surprisingly, some of these EXO70-exocyst versions are implicated in autophagy as is animal exocyst or are involved in host defense, cell-wall fortification and secondary metabolites transport. Interestingly, EXO70Ds act as selective autophagy receptors in the regulation of cytokinin signalling pathway. Secretion of double membrane autophagy-related structures formed with the contribution of EXO70s to the apoplast hints at the possibility of secretory autophagy in plants.
    Keywords:  EXO70; autophagy; cell wall; endomembrane trafficking; exocyst; plant defense; protein membrane interaction; secondary metabolites; secretion; secretory autophagy
    DOI:  https://doi.org/10.1002/1873-3468.14430
  28. Biosens Bioelectron. 2022 Jun 15. pii: S0956-5663(22)00524-3. [Epub ahead of print]213 114484
    Tracking autophagy process with a through bond energy transfer-based ratiometric two-photon viscosity probe.
    Shuyang Zhai, Wei Hu, Weibo Wang, Li Chai, Qian An, Chunya Li, Zhihong Liu.
      Autophagy is a self-degradation process in cells, which is of vital significance to the health and operation of organisms. Due to the increase of lysosomal viscosity during autophagy, viscosity probes that specifically accumulate in lysosome are powerful tools for monitoring autophagy and investigating related diseases. However, there is still a lack of viscosity-sensitive ratiometric autophagy probes, which restricts the tracking of autophagy with high accuracy in complex physiological environment. Herein, a viscosity-responsive, lysosome targeted two-photon fluorescent probe Lyso-Vis was designed based on through bond energy transfer (TBET) mechanism. The TBET-based probe achieved the separation of two emission baselines, which greatly improved the resolution and reliability of sensing and imaging. Under 810 nm two-photon excitation, the emission intensity ratio of the red and green channel increased with a viscosity dependent manner. Lyso-Vis not only for the first time realized ratiometric sensing of lysosomal viscosity during autophagy process, but also visualized the association of autophagy with inflammation and stroke, and it was applied to explore the activation and inhibition of autophagy during stroke in mice.
    Keywords:  Inflammation and stroke; Lysosomal viscosity; Ratiometric autophagy probes; Through bond energy transfer; Two-photon confocal imaging
    DOI:  https://doi.org/10.1016/j.bios.2022.114484
  29. Front Biosci (Landmark Ed). 2022 Jun 07. 27(6): 184
    PINK1/Parkin-Mediated Mitophagy Plays a Protective Role in Albumin Overload-Induced Renal Tubular Cell Injury.
    Pengpeng Duan, Jin Tan, Yuyang Miao, Qiang Zhang.
      BACKGROUND: Proteinuria is an important symptom of chronic kidney disease irrespective of its initial pathogenesis. Mitochondrial dysfunction is an early pathophysiological event in proteinuria-induced tubular damage. Mitophagy, the selective degradation of damaged mitochondria targeted by autophagy, contributes to mitochondrial homeostasis and is primarily regulated by the PTEN-induced kinase 1 (PINK1)/Parkin pathway. In this study, we evaluated the function of mitophagy in proteinuria-induced tubular injury and mechanism.METHODS: HK-2 cells were transfected with Parkin siRNA or Parkin overexpression plasmids for 48 h followed by treatment with albumin (8 mg/mL) for 8 h. JC-1 staining, ATP detection, and reactive oxygen species (ROS) detection were used to determine mitochondrial function. Immunoblot, LC3/mitochondria co-localization analyses, and Mito-Keima were employed to detect mitophagy. Immunoblot analysis and TUNEL were used to detect apoptosis.
    RESULTS: Albumin overload induced mitochondrial dysfunction and mitophagy activation in HK-2 cells. Parkin knockdown inhibited albumin overload induced-mitophagy. Parkin overexpression further upregulated albumin overload induced-mitophagy. Parkin deficiency aggravated albumin overload-induced mitochondrial dysfunction and the overproduction of ROS, resulting in increased cell injury. Contrarily, Parkin overexpression helped maintain mitochondrial function and attenuate ROS generation, contributing to cell protection.
    CONCLUSIONS: Our results suggest that by clearing damaged mitochondria and maintaining mitochondrial function, PINK1/Parkin-mediated mitophagy contributed to tubular cell survival during albumin overload. PINK1/Parkin-mediated mitophagy may be a potential therapeutic target for proteinuria in tubular epithelial cells.
    Keywords:  PINK1; Parkin; mitochondrial dysfunction; mitophagy; proteinuria; renal tubular epithelial cell
    DOI:  https://doi.org/10.31083/j.fbl2706184
  30. Biology (Basel). 2022 Jun 20. pii: 943. [Epub ahead of print]11(6):
    Insulin and Its Key Role for Mitochondrial Function/Dysfunction and Quality Control: A Shared Link between Dysmetabolism and Neurodegeneration.
    Giacoma Galizzi, Marta Di Carlo.
      Insulin was discovered and isolated from the beta cells of pancreatic islets of dogs and is associated with the regulation of peripheral glucose homeostasis. Insulin produced in the brain is related to synaptic plasticity and memory. Defective insulin signaling plays a role in brain dysfunction, such as neurodegenerative disease. Growing evidence suggests a link between metabolic disorders, such as diabetes and obesity, and neurodegenerative diseases, especially Alzheimer's disease (AD). This association is due to a common state of insulin resistance (IR) and mitochondrial dysfunction. This review takes a journey into the past to summarize what was known about the physiological and pathological role of insulin in peripheral tissues and the brain. Then, it will land in the present to analyze the insulin role on mitochondrial health and the effects on insulin resistance and neurodegenerative diseases that are IR-dependent. Specifically, we will focus our attention on the quality control of mitochondria (MQC), such as mitochondrial dynamics, mitochondrial biogenesis, and selective autophagy (mitophagy), in healthy and altered cases. Finally, this review will be projected toward the future by examining the most promising treatments that target the mitochondria to cure neurodegenerative diseases associated with metabolic disorders.
    Keywords:  insulin; insulin resistance; mitochondrial biogenesis; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.3390/biology11060943
  31. Int J Mol Sci. 2022 Jun 18. pii: 6808. [Epub ahead of print]23(12):
    LRRK2 and Proteostasis in Parkinson's Disease.
    María Dolores Pérez-Carrión, Inmaculada Posadas, Javier Solera, Valentín Ceña.
      Parkinson's disease is a neurodegenerative condition initially characterized by the presence of tremor, muscle stiffness and impaired balance, with the deposition of insoluble protein aggregates in Lewy's Bodies the histopathological hallmark of the disease. Although different gene variants are linked to Parkinson disease, mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are one of the most frequent causes of Parkinson's disease related to genetic mutations. LRRK2 toxicity has been mainly explained by an increase in kinase activity, but alternative mechanisms have emerged as underlying causes for Parkinson's disease, such as the imbalance in LRRK2 homeostasis and the involvement of LRRK2 in aggregation and spreading of α-synuclein toxicity. In this review, we recapitulate the main LRRK2 pathological mutations that contribute to Parkinson's disease and the different cellular and therapeutic strategies devised to correct LRRK2 homeostasis. In this review, we describe the main cellular control mechanisms that regulate LRRK2 folding and aggregation, such as the chaperone network and the protein-clearing pathways such as the ubiquitin-proteasome system and the autophagic-lysosomal pathway. We will also address the more relevant strategies to modulate neurodegeneration in Parkinson's disease through the regulation of LRRK2, using small molecules or LRRK2 silencing.
    Keywords:  LRRK2; LRRK2 silencing; Parkinson’s disease; autophagy; chaperones; proteostasis; α-synuclein
    DOI:  https://doi.org/10.3390/ijms23126808
  32. Biomedicines. 2022 Jun 10. pii: 1375. [Epub ahead of print]10(6):
    Mitochondrial Quality Control in the Heart: The Balance between Physiological and Pathological Stress.
    Giovanni Fajardo, Michael Coronado, Melia Matthews, Daniel Bernstein.
      Alterations in mitochondrial function and morphology are critical adaptations to cardiovascular stress, working in concert in an attempt to restore organelle-level and cellular-level homeostasis. Processes that alter mitochondrial morphology include fission, fusion, mitophagy, and biogenesis, and these interact to maintain mitochondrial quality control. Not all cardiovascular stress is pathologic (e.g., ischemia, pressure overload, cardiotoxins), despite a wealth of studies to this effect. Physiological stress, such as that induced by aerobic exercise, can induce morphologic adaptations that share many common pathways with pathological stress, but in this case result in improved mitochondrial health. Developing a better understanding of the mechanisms underlying alterations in mitochondrial quality control under diverse cardiovascular stressors will aid in the development of pharmacologic interventions aimed at restoring cellular homeostasis.
    Keywords:  biogenesis; fission; fusion; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/biomedicines10061375
  33. Mil Med Res. 2022 Jun 22. 9(1): 35
    TRIM72-mediated degradation of the short form of p62/SQSTM1 rheostatically controls selective autophagy in human cells.
    Cheng-Cheng Wang, Hong Peng, Zi Wang, Jiao Yang, Rong-Gui Hu, Chuan-Yin Li, Wu-Jun Geng.
      
    Keywords:  Alternative splicing; Autophagy; TRIM72; Ubiquitination; p62S
    DOI:  https://doi.org/10.1186/s40779-022-00392-1
  34. Biol Futur. 2022 Jun 22.
    Recent advances in autophagy research.
    Peter Low.
      
    DOI:  https://doi.org/10.1007/s42977-022-00125-4
  35. J Mol Neurosci. 2022 Jun 21.
    Massive Accumulation of Sphingomyelin Affects the Lysosomal and Mitochondria Compartments and Promotes Apoptosis in Niemann-Pick Disease Type A.
    Emma Veronica Carsana, Giulia Lunghi, Simona Prioni, Laura Mauri, Nicoletta Loberto, Alessandro Prinetti, Fabio Andrea Zucca, Rosaria Bassi, Sandro Sonnino, Elena Chiricozzi, Stefano Duga, Letizia Straniero, Rosanna Asselta, Giulia Soldà, Maura Samarani, Massimo Aureli.
      Niemann-Pick type A disease (NPA) is a rare lysosomal storage disorder caused by mutations in the gene coding for the lysosomal enzyme acid sphingomyelinase (ASM). ASM deficiency leads to the consequent accumulation of its uncatabolized substrate, the sphingolipid sphingomyelin (SM), causing severe progressive brain disease. To study the effect of the aberrant lysosomal accumulation of SM on cell homeostasis, we loaded skin fibroblasts derived from a NPA patient with exogenous SM to mimic the levels of accumulation characteristic of the pathological neurons. In SM-loaded NPA fibroblasts, we found the blockage of the autophagy flux and the impairment of the mitochondrial compartment paralleled by the altered transcription of several genes, mainly belonging to the electron transport chain machinery and to the cholesterol biosynthesis pathway. In addition, SM loading induces the nuclear translocation of the transcription factor EB that promotes the lysosomal biogenesis and exocytosis. Interestingly, we obtained similar biochemical findings in the brain of the NPA mouse model lacking ASM (ASMKO mouse) at the neurodegenerative stage. Our work provides a new in vitro model to study NPA etiopathology and suggests the existence of a pathogenic lysosome-plasma membrane axis that with an impairment in the mitochondrial activity is responsible for the cell death.
    Keywords:  Lysosomes; Mitochondria; Niemann-Pick; Plasma membrane; SMPD1; Sphingomyelin
    DOI:  https://doi.org/10.1007/s12031-022-02036-4
  36. Spectrochim Acta A Mol Biomol Spectrosc. 2022 Jun 13. pii: S1386-1425(22)00645-X. [Epub ahead of print]280 121496
    Visual monitoring of the mitochondrial pH changes during mitophagy with a NIR fluorescent probe and its application in tumor imaging.
    Tian-Ran Wang, Qian Chen, Meng-Yu Tang, Yu Zhang, Shi-Li Shen, Xiao-Qun Cao.
      Mitophagy, a mitochondria-selective autophagy process, plays critical roles in maintaining intracellular homeostasis by removing the damaged mitochondria and recycling the nutrients in a lysosome-dependent manner. Mitophagy process could result in the changes of mitochondrial pH. So fluorescent probes for detecting mitochondrial pH during mitophagy are highly needed for exploring the functions of mitochondria. Herein, a series of near-infrared pH probes were designed based on the rhodamine framework. The probes showed high sensitivity for pH with the tunable pKa from 4.74 to 6.54. Particularly, for probe 5 (with the pKa of 6.54), a linear relationship between fluorescence intensity and pH in the range of 5.6-7.2 was observed, which was suitable for mitochondrial pH detection. The probe displayed excellent mitochondria-targeting ability. It was applied to monitor pH changes during mitophagy caused by starvation. Besides, in vivo non-invasive visualization of tumor pH variations was achieved via the fluorescence imaging in the near-infrared region. We anticipate that the probe may be a useful tool for revealing essential information about mitophagy-related research and clinical tumor diagnosis.
    Keywords:  Fluorescent probe; In vivo imaging; Mitochondria; Mitophagy; pH
    DOI:  https://doi.org/10.1016/j.saa.2022.121496
  37. Front Neurosci. 2022 ;16 901688
    Extracellular Adenosine Triphosphate Binding to P2Y1 Receptors Prevents Glutamate-Induced Excitotoxicity: Involvement of Erk1/2 Signaling Pathway to Suppress Autophagy.
    Yiping Xiong, Duanyang Zhou, Kai Zheng, Wenchuan Bi, Yun Dong.
      Glutamate-induced neuroexcitotoxicity could be related to the pathophysiology of some neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. Extracellular ATP exerts a wide variety of functions, such as attenuating Aβ-mediated toxicity, inhibiting N-Methyl-D-Aspartate (NMDA) receptor subunit combinations, and aggravating ischemic brain injury. However, the effect of extracellular ATP on glutamate-induced neuroexcitotoxicity remains largely unknown. Herein, we showed that extracellular ATP prevented the glutamate-induced excitotoxicity via binding to its P2Y1 receptors. We found that excessive glutamate triggered cellular reactive oxygen species (ROS) overproduction and mitochondrial membrane potential damage, which were significantly attenuated by extracellular ATP. Besides, glutamate activated autophagy, as illustrated by the increased protein level of autophagic marker LC3II and decreased level of p62, and glutamate-induced neuroexcitotoxicity could be completely abolished by autophagy inhibitor chloroquine. In addition, we revealed that extracellular ATP activated Erk1/2 signaling to suppress autophagy and to exert its neuroprotective effects, which was further reduced by autophagy agonist rapamycin and the selective Erk1/2 inhibitor PD0325901. Taken together, our findings suggest that extracellular ATP binding to P2Y1 receptors protected against glutamate-induced excitotoxicity via Erk1/2-mediated autophagy inhibition, implying the potential of ATP for the treatment of neurodegenerative disorders.
    Keywords:  Erk1/2 signaling pathway; autophagy; extracellular ATP; neuroexcitotoxicity; neuroprotection
    DOI:  https://doi.org/10.3389/fnins.2022.901688
  38. Biomedicines. 2022 May 27. pii: 1257. [Epub ahead of print]10(6):
    Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis.
    John M Barbaro, Simone Sidoli, Ana Maria Cuervo, Joan W Berman.
      HIV-neurocognitive impairment (HIV-NCI) can be a debilitating condition for people with HIV (PWH), despite the success of antiretroviral therapy (ART). Substance use disorder is often a comorbidity with HIV infection. The use of methamphetamine (meth) increases systemic inflammation and CNS damage in PWH. Meth may also increase neuropathogenesis through the functional dysregulation of cells that harbor HIV. Perivascular macrophages are long-lived reservoirs for HIV in the CNS. The impaired clearance of extracellular debris and increased release of reactive oxygen species (ROS) by HIV-infected macrophages cause neurotoxicity. Macroautophagy is a vital intracellular pathway that can regulate, in part, these deleterious processes. We found in HIV-infected primary human macrophages that meth inhibits phagocytosis of aggregated amyloid-β, increases total ROS, and dysregulates autophagic processes. Treatment with widely prescribed ART drugs had minimal effects, although there may be an improvement in phagocytosis when co-administered with meth. Pharmacologically inhibited lysosomal degradation, but not induction of autophagy, further increased ROS in response to meth. Using mass spectrometry, we identified the differentially expressed proteins in meth-treated, HIV-infected macrophages that participate in phagocytosis, mitochondrial function, redox metabolism, and autophagy. Significantly altered proteins may be novel targets for interventional strategies that restore functional homeostasis in HIV-infected macrophages to improve neurocognition in people with HIV-NCI using meth.
    Keywords:  HIV-NCI; ROS; autophagy; macrophage; methamphetamine; phagocytosis; proteomics
    DOI:  https://doi.org/10.3390/biomedicines10061257
  39. Int J Mol Sci. 2022 Jun 20. pii: 6860. [Epub ahead of print]23(12):
    A Dual-Acting Nitric Oxide Donor and Phosphodiesterase 5 Inhibitor Activates Autophagy in Primary Skin Fibroblasts.
    Esther Martínez-Martínez, Paola Atzei, Christine Vionnet, Carole Roubaty, Stephanie Kaeser-Pebernard, Reto Naef, Jörn Dengjel.
      Wound healing pathologies are an increasing problem in ageing societies. Chronic, non-healing wounds, which cause high morbidity and severely reduce the quality of life of affected individuals, are frequently observed in aged individuals and people suffering from diseases affected by the Western lifestyle, such as diabetes. Causal treatments that support proper wound healing are still scarce. Here, we performed expression proteomics to study the effects of the small molecule TOP-N53 on primary human skin fibroblasts and keratinocytes. TOP-N53 is a dual-acting nitric oxide donor and phosphodiesterase-5 inhibitor increasing cGMP levels to support proper wound healing. In contrast to keratinocytes, which did not exhibit global proteome alterations, TOP-N53 had profound effects on the proteome of skin fibroblasts. In fibroblasts, TOP-N53 activated the cytoprotective, lysosomal degradation pathway autophagy and induced the expression of the selective autophagy receptor p62/SQSTM1. Thus, activation of autophagy might in part be responsible for beneficial effects of TOP-N53.
    Keywords:  NO; autophagy; cGMP; fibroblasts; mass spectrometry; nitric oxide; proteomics; sildenafil; skin; wound healing
    DOI:  https://doi.org/10.3390/ijms23126860
  40. Biology (Basel). 2022 Jun 19. pii: 931. [Epub ahead of print]11(6):
    Role of mTOR Signaling Cascade in Epidermal Morphogenesis and Skin Barrier Formation.
    Juan Wang, Sabine A Eming, Xiaolei Ding.
      The skin epidermis, with its capacity for lifelong self-renewal and rapid repairing response upon injury, must maintain an active status in metabolism. Mechanistic target of rapamycin (mTOR) signaling is a central controller of cellular growth and metabolism that coordinates diverse physiological and pathological processes in a variety of tissues and organs. Recent evidence with genetic mouse models highlights an essential role of the mTOR signaling network in epidermal morphogenesis and barrier formation. In this review, we focus on the recent advances in understanding how mTOR signaling networks, including upstream inputs, kinases and downstream effectors, regulate epidermal morphogenesis and skin barrier formation. Understanding the details of the metabolic signaling will be critical for the development of novel pharmacological approaches to promote skin barrier regeneration and to treat epidermal barrier defect-associated diseases.
    Keywords:  epidermal morphogenesis; epidermis; mTOR; mouse models; skin barrier
    DOI:  https://doi.org/10.3390/biology11060931
  41. Nutrients. 2022 Jun 10. pii: 2410. [Epub ahead of print]14(12):
    Protective Effect of Mitophagy Regulated by mTOR Signaling Pathway in Liver Fibrosis Associated with Selenium.
    Lichun Qiao, Ziwei Guo, Haobiao Liu, Jiaxin Liu, Xue Lin, Huan Deng, Xuan Liu, Yan Zhao, Xiang Xiao, Jian Lei, Jing Han.
      BACKGROUND: As a central organ of energy metabolism, the liver is closely related to selenium for its normal function and disease development. However, the underlying roles of mitochondrial energy metabolism and mitophagy in liver fibrosis associated with selenium remain unclear.METHODS: 28 rats were randomly divided into normal, low-selenium, nano-selenium supplement-1, and supplement-2 groups for a 12-week intervention. We observed pathological and ultrastructural changes in the liver and analyzed the effects of selenium deficiency and nano-selenium supplementation on liver metabolic activities and crucial proteins expression of mammalian target of the rapamycin (mTOR) signaling pathway.
    RESULTS: Selenium deficiency caused liver pathological damage and fibrosis with the occurrence of mitophagy by disrupting normal metabolic activities; meanwhile, the mTOR signaling pathway was up-regulated to enhance mitophagy to clear damaged mitochondria. Furthermore, nano-selenium supplements could reduce the severity of pathological damage and fibrosis in livers and maintain normal energy metabolic activity. With the increased concentrations of nano-selenium supplement, swelling mitochondria and mitophagy gradually decreased, accompanied by the higher expression of mTOR and phosphorylation-modified mTOR proteins and lower expression of unc-51 like autophagy activating kinase 1 (ULK1) and phosphorylation-modified ULK1 proteins.
    CONCLUSIONS: Mitophagy regulated by the mTOR signaling pathway plays a dual protective role on low-selenium inducing liver fibrosis and nano-selenium supplements preventing liver fibrosis. Mitochondrial energy metabolism plays an important role in these processes as well.
    Keywords:  energy metabolism; liver fibrosis; mTOR signaling pathway; mitophagy; selenium
    DOI:  https://doi.org/10.3390/nu14122410
  42. Sci Rep. 2022 Jun 20. 12(1): 10333
    Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62.
    Stephanie U Greer, Jiamin Chen, Margret H Ogmundsdottir, Carlos Ayala, Billy T Lau, Richard Glenn C Delacruz, Imelda T Sandoval, Sigrun Kristjansdottir, David A Jones, Derrick S Haslem, Robin Romero, Gail Fulde, John M Bell, Jon G Jonasson, Eirikur Steingrimsson, Hanlee P Ji, Lincoln D Nadauld.
      Autophagy is a housekeeping mechanism tasked with eliminating misfolded proteins and damaged organelles to maintain cellular homeostasis. Autophagy deficiency results in increased oxidative stress, DNA damage and chronic cellular injury. Among the core genes in the autophagy machinery, ATG7 is required for autophagy initiation and autophagosome formation. Based on the analysis of an extended pedigree of familial cholangiocarcinoma, we determined that all affected family members had a novel germline mutation (c.2000C>T p.Arg659* (p.R659*)) in ATG7. Somatic deletions of ATG7 were identified in the tumors of affected individuals. We applied linked-read sequencing to one tumor sample and demonstrated that the ATG7 somatic deletion and germline mutation were located on distinct alleles, resulting in two hits to ATG7. From a parallel population genetic study, we identified a germline polymorphism of ATG7 (c.1591C>G p.Asp522Glu (p.D522E)) associated with increased risk of cholangiocarcinoma. To characterize the impact of these germline ATG7 variants on autophagy activity, we developed an ATG7-null cell line derived from the human bile duct. The mutant p.R659* ATG7 protein lacked the ability to lipidate its LC3 substrate, leading to complete loss of autophagy and increased p62 levels. Our findings indicate that germline ATG7 variants have the potential to impact autophagy function with implications for cholangiocarcinoma development.
    DOI:  https://doi.org/10.1038/s41598-022-13569-4
  43. J Cell Sci. 2022 Jun 20. pii: jcs.259738. [Epub ahead of print]
    Metformin inactivates the cGAS-STING pathway through autophagy and suppresses senescence in nucleus pulposus cells.
    Chenghao Ren, Jie Jin, Chenchao Li, Jianwei Xiang, Yaosen Wu, Yifei Zhou, Liaojun Sun, Xiaolei Zhang, Naifeng Tian.
      Intervertebral disc degeneration (IVDD) is a complex process involving many factors, among which excessive senescence of nucleus pulposus cells (NPCs) is considered to be the main factor. Our previous study found that metformin may inhibit senescence in nucleus pulposus cells; however, its working mechanism is still largely unknown. In the current study, we found that metformin may inactivate cGAS-STING pathway during oxidative stress. Knock-down of STING may further suppress senescence, indicating metformin may exert its effect through cGAS-STING pathway. Damaged DNA is a major inducer of the activation of cGAS-STING pathway. Mechanistically, our study showed that DNA damage was reduced during metformin treatment; however, suppression of autophagy by 3-methyladenine (3MA) may compromise the effect of metformin on DNA damage. The in vivo study also showed that 3MA may recede the therapeutic effect of metformin on IVDD. Taken together, our results reveal that metformin may suppress senescence via inactivating the cGAS-STING pathway through autophagy, implying the new application of metformin in cGAS-STING pathway related diseases.
    Keywords:  Autophagy; CGAS-STING signaling pathway; Intervertebral disc degeneration; Metformin; Senescence
    DOI:  https://doi.org/10.1242/jcs.259738
  44. Free Radic Biol Med. 2022 Jun 21. pii: S0891-5849(22)00460-9. [Epub ahead of print]
    Mitochondrial-derived vesicles: Gatekeepers of mitochondrial response to oxidative stress.
    Tingting Peng, Yinyin Xie, Hanqing Sheng, Cui Wang, Yajun Lian, Nanchang Xie.
      Mitochondrial quality control (MQC) mechanisms are a series of adaptive responses that ensure the relative stability of mitochondrial morphology, quantity, and quality to preserve cellular survival and function. While MQC mechanisms range from mitochondrial biogenesis and fusion/fission to mitophagy, mitochondrial-derived vesicles (MDVs) may represent an essential component of MQC. MDVs precede mitochondrial autophagy and serve as the first line of defense against oxidative stress by selectively transferring damaged mitochondrial substances to the lysosome for degradation. In fact, the function of MDVs is dependent on the cargo, the shuttle route, and the ultimate destination. Abnormal MDVs disrupt metabolite clearance and the immune response, predisposing to pathological conditions, including neurodegeneration, cardiovascular diseases, and cancers. Therefore, MDV regulation may be a potential therapeutic for the therapy of these diseases. In this review, we highlight recent advances in the study of MDVs and their misregulation in various diseases from the perspectives of formation, cargo selection, regulation, and transportation.
    Keywords:  Aging; Diseases; Mitochondria; Mitochondrial quality control; Mitochondrial-derived vesicle; Therapeutics
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.06.233
  45. Cells. 2022 Jun 09. pii: 1870. [Epub ahead of print]11(12):
    Prostaglandin 2α Promotes Autophagy and Mitochondrial Energy Production in Fish Hepatocytes.
    Jingjing Tian, Yihui Du, Ermeng Yu, Caixia Lei, Yun Xia, Peng Jiang, Hongyan Li, Kai Zhang, Zhifei Li, Wangbao Gong, Jun Xie, Guangjun Wang.
      Fatty liver, characterized by excessive lipid droplet (LD) accumulation in hepatocytes, is a common physiological condition in humans and aquaculture species. Lipid mobilization is an important strategy for modulating the number and size of cellular LDs. Cyclooxygenase (COX)-mediated arachidonic acid derivatives are known to improve lipid catabolism in fish; however, the specific derivatives remain unknown. In the present study, we showed that serum starvation induced LD degradation via autophagy, lipolysis, and mitochondrial energy production in zebrafish hepatocytes, accompanied by activation of the COX pathway. The cellular concentration of PGF2α, but not other prostaglandins, was significantly increased. Administration of a COX inhibitor or interference with PGF2α synthase abolished serum deprivation-induced LD suppression, LD-lysosome colocalization, and expression of autophagic genes. Additionally, exogenous PGF2α suppressed the accumulation of LDs, promoted the accumulation of lysosomes with LD and the autophagy marker protein LC3A/B, and augmented the expression of autophagic genes. Moreover, PGF2α enhanced mitochondrial accumulation and ATP production, and increased the transcript levels of β-oxidation- and mitochondrial respiratory chain-related genes. Collectively, these findings demonstrate that the COX pathway is implicated in lipid degradation induced by energy deprivation, and that PGF2α is a key molecule triggering autophagy, lipolysis, and mitochondrial development in zebrafish hepatocytes.
    Keywords:  ATP; PGF2α; arachidonic acid; cyclooxygenase; eicosanoids; lipid droplets; lipolysis; lipophagy; mitochondria
    DOI:  https://doi.org/10.3390/cells11121870
  46. J Biol Chem. 2022 Jun 21. pii: S0021-9258(22)00601-9. [Epub ahead of print] 102159
    Impaired Mitophagy in Sanfilippo A mice Causes Hypertriglyceridemia and Brown Adipose Tissue Activation.
    Miguel Tillo, William C Lamanna, Chrissa A Dwyer, Daniel R Sandoval, Ariane R Pessentheiner, Norah Al-Azzam, Stéphane Sarrazin, Jon C Gonzales, Shih-Hsin Kan, Alexander Y Andreyev, Nicholas Schultheis, Bryan E Thacker, Charles A Glass, Patricia I Dickson, Raymond Y Wang, Scott B Selleck, Jeffrey D Esko, Philip L S M Gordts.
      Lysosomal storage diseases result in various developmental and physiological complications, including cachexia. To study the causes for the negative energy balance associated with cachexia, we assessed the impact of sulfamidase deficiency and heparan sulfate storage on energy homeostasis and metabolism in a mouse model of Type IIIa mucopolysaccharidosis (MPS IIIa, Sanfilippo A syndrome). At 12 weeks of age, MPS IIIa mice exhibited fasting and postprandial hypertriglyceridemia compared to wild-type mice, with a reduction of white and brown adipose tissue depots. Partitioning of dietary [3H]triolein showed a marked increase in intestinal uptake and secretion, whereas hepatic production and clearance of triglyceride-rich lipoproteins did not differ from wild-type controls. Uptake of dietary triolein was also elevated in brown adipose tissue (BAT), and notable increases in beige adipose tissue occurred, resulting in hyperthermia, hyperphagia, hyperdipsia, and increased energy expenditure. Furthermore, fasted MPS IIIa mice remained hyperthermic when subjected to low temperature, but became cachexic and profoundly hypothermic when treated with a lipolytic inhibitor. We demonstrated the reliance on increased lipid fueling of BAT was driven by a reduced ability to generate energy from stored lipids within the depot. These alterations arose from impaired autophagosome-lysosome fusion, resulting in increased mitochondria content in beige and BAT. Finally, we show the increased mitochondria content in BAT and postprandial dyslipidemia was partially reversed upon a 5-week treatment with recombinant sulfamidase. We hypothesize that increased BAT activity and persistent increases in energy demand in MPS IIIa mice contribute to the negative energy balance observed in MPS IIIa patients.
    Keywords:  Mucopolysaccharidoses; autophagy; dyslipidemia; hyperthermia; mitochondria; sulfamidase
    DOI:  https://doi.org/10.1016/j.jbc.2022.102159
  47. Oxid Med Cell Longev. 2022 ;2022 3450207
    Novel Therapeutic Strategies for Ischemic Stroke: Recent Insights into Autophagy.
    Xiaocheng Lu, Jian Zhang, Yu Ding, Jiang Wu, Gang Chen.
      Stroke is one of the leading causes of death and disability worldwide. Autophagy is a conserved cellular catabolic pathway that maintains cellular homeostasis by removal of damaged proteins and organelles, which is critical for the maintenance of energy and function homeostasis of cells. Accumulating evidence demonstrates that autophagy plays important roles in pathophysiological mechanisms under ischemic stroke. Previous investigations show that autophagy serves as a "double-edged sword" in ischemic stroke as it can either promote the survival of neuronal cells or induce cell death in special conditions. Following ischemic stroke, autophagy is activated or inhibited in several cell types in brain, including neurons, astrocytes, and microglia, as well as microvascular endothelial cells, which involves in inflammatory activation, modulation of microglial phenotypes, and blood-brain barrier permeability. However, the exact mechanisms of underlying the role of autophagy in ischemic stroke are not fully understood. This review focuses on the recent advances regarding potential molecular mechanisms of autophagy in different cell types. The focus is also on discussing the "double-edged sword" effect of autophagy in ischemic stroke and its possible underlying mechanisms. In addition, potential therapeutic strategies for ischemic stroke targeting autophagy are also reviewed.
    DOI:  https://doi.org/10.1155/2022/3450207
  48. Cardiovasc Res. 2022 Jun 21. pii: cvac101. [Epub ahead of print]
    ULK1 mediated mitophagy prevents pathological cardiac remodelling and heart failure.
    Rimpy Dhingra, Lorrie A Kirshenbaum.
      The defects in mitochondrial clearance mechanisms can trigger adverse cardiac remodeling and severely impair cardiac performance. A new study identifies Ulk1/Rab9 mediated alternative mitophagy to be important for mitochondrial clearance in heart under pressure overload conditions. Moreover, the defects in ULK1 mediated alternative mitophagy resulted in accumulation of damaged mitochondria, severe hypertrophy, fibrosis, and cardiac dysfunction in response to TAC induced pressure overload. The findings highlight Ulk1/Rab9 mediated alternative mitophagy as a prominent mode of mitophagy and quality control in response to pressure overload hypertrophy.
    Keywords:  Heart failure; Hypertrophy; Mitochondria; Mitophagy; Pressure-overload
    DOI:  https://doi.org/10.1093/cvr/cvac101
  49. J Inorg Biochem. 2022 Jun 12. pii: S0162-0134(22)00190-8. [Epub ahead of print]234 111901
    Metformin attenuates cadmium-induced degeneration of spiral ganglion neuron via restoring autophagic flux in primary culture.
    Qian Li, Liuqian Wang, Di Ji, Wei Yu, Yan Zhang, Yanghong Xiang, Chao Zhou, Liting Wang, Ping Deng, Huifeng Pi, Yonghui Lu, Qinlong Ma, Mindi He, Lei Zhang, Zhengping Yu, Anchun Deng.
      Cadmium (Cd), a common environmental and occupational toxicant, is an important risk factor for hearing loss. After exposure, Cd accumulates in the inner ear and induces spiral ganglion neuron (SGN) degeneration; however, the underlying mechanisms are poorly understood. Dysfunctional autophagy has been implicated in many neurodegenerative diseases, including Cd-induced neurotoxicity. Metformin has been validated to confer not only anti-hyperglycaemic but also neuroprotective effects. However, the relationship between autophagy dysfunction, SGN degeneration, and the effect of metformin on Cd-induced SGN neurotoxicity has not yet been established. In this study, we demonstrate that metformin notably attenuates Cd-evoked SGN degeneration by restoring impaired autophagy flux, as evidenced by the suppression of Cd-induced elevation of autophagy markers microtubule-associated protein 1A/1B-light chain 3-II (LC3-II) and autophagy substrate protein p62 in degenerated SGN. Blockage of autophagy flux by chloroquine abolished metformin-induced neuroprotection against Cd-induced neurotoxicity in SGN. The results of this study reveal that autophagy dysfunction is an important component of Cd-induced SGN degeneration, and metformin may be a potential protective agent for attenuating SGN degeneration following Cd exposure.
    Keywords:  Autophagy; Cadmium; Hearing loss; Metformin; Neurotoxicity; Spiral ganglion neuron
    DOI:  https://doi.org/10.1016/j.jinorgbio.2022.111901
  50. Autophagy. 2022 Jun 19.
    Tumor-derived CTF1 (cardiotrophin 1) is a critical mediator of stroma-assisted and autophagy-dependent breast cancer cell migration, invasion and metastasis.
    Yunus Akkoc, Kubilay Dalci, Hacer Ezgi Karakas, Secil Erbil-Bilir, Orcun Yalav, Gurhan Sakman, Faruk Celik, Soykan Arikan, Umit Zeybek, Melek Ergin, Hikmet Akkiz, Ece Dilege, Joern Dengjel, A Isin Dogan-Ekici, Devrim Gozuacik.
      Macroautophagy/autophagy is an evolutionarily conserved cellular stress response mechanism. Autophagy induction in the tumor microenvironment (stroma) has been shown to support tumor metabolism. However, cancer cell-derived secreted factors that initiate communication with surrounding cells and stimulate autophagy in the tumor microenvironment are not fully documented. We identified CTF1/CT-1 (cardiotrophin 1) as an activator of autophagy in fibroblasts and breast cancer-derived carcinoma-associated fibroblasts (CAFs). We showed that CTF1 stimulated phosphorylation and nuclear translocation of STAT3, initiating transcriptional activation of key autophagy proteins. Additionally, following CTF1 treatment, AMPK and ULK1 activation was observed. We provided evidence that autophagy was important for CTF1-dependent ACTA2/α-SMA accumulation, stress fiber formation and fibroblast activation. Moreover, promotion of breast cancer cell migration and invasion by activated fibroblasts depended on CTF1 and autophagy. Analysis of the expression levels of CTF1 in patient-derived breast cancer samples led us to establish a correlation between CTF1 expression and autophagy in the tumor stroma. In line with our in vitro data on cancer migration and invasion, higher levels of CTF1 expression in breast tumors was significantly associated with lymph node metastasis in patients. Therefore, CTF1 is an important mediator of tumor-stroma interactions, fibroblast activation and cancer metastasis, and autophagy plays a key role in all these cancer-related events.
    Keywords:  Autophagy; breast cancer; carcinoma-associated fibroblast; cardiotrophin 1; tumor stroma
    DOI:  https://doi.org/10.1080/15548627.2022.2090693
  51. Cell Prolif. 2022 Jun 22. e13278
    Triptolide promotes autophagy to inhibit mesangial cell proliferation in IgA nephropathy via the CARD9/p38 MAPK pathway.
    Lu Zhao, Zhixin Lan, Liang Peng, Lili Wan, Di Liu, Xia Tan, Chengyuan Tang, Guochun Chen, Hong Liu.
      BACKGROUND: Mesangial cell proliferation is the most basic pathological feature of immunoglobulin A nephropathy (IgAN); however, the specific underlying mechanism and an appropriate therapeutic strategy are yet to be unearthed. This study aimed to investigate the therapeutic effect of triptolide (TP) on IgAN and the mechanism by which TP regulates autophagy and proliferation of mesangial cells through the CARD9/p38 MAPK pathway.METHODS: We established a TP-treated IgAN mouse model and produced IgA1-induced human mesangial cells (HMC) and divided them into control, TP, IgAN, and IgAN+TP groups. The levels of mesangial cell proliferation (PCNA, cyclin D1, cell viability, and cell cycle) and autophagy (P62, LC3 II, and autophagy flux rate) were measured, with the autophagy inhibitor 3-Methyladenine used to explore the relationship between autophagy and proliferation. We observed CARD9 expression in renal biopsies from patients and analyzed its clinical significance. CARD9 siRNA and overexpression plasmids were constructed to investigate the changes in mesangial cell proliferation and autophagy as well as the expression of CARD9 and p-p38 MAPK/p38 MAPK following TP treatment.
    RESULTS: Administering TP was safe and effectively alleviated mesangial cell proliferation in IgAN mice. Moreover, TP inhibited IgA1-induced HMC proliferation by promoting autophagy. The high expression of CARD9 in IgAN patients was positively correlated with the severity of HMC proliferation. CARD9/p38 MAPK was involved in the regulation of HMC autophagy and proliferation, and TP promoted autophagy to inhibit HMC proliferation by downregulating the CARD9/p38 MAPK pathway in IgAN.
    CONCLUSION: TP promotes autophagy to inhibit mesangial cell proliferation in IgAN via the CARD9/p38 MAPK pathway.
    DOI:  https://doi.org/10.1111/cpr.13278
  52. Mol Cell. 2022 Jun 21. pii: S1097-2765(22)00492-0. [Epub ahead of print]
    Supramolecular assembly of GSK3α as a cellular response to amino acid starvation.
    Laura Hinze, Sabine Schreek, Andre Zeug, Nurul Khalida Ibrahim, Beate Fehlhaber, Lorent Loxha, Buesra Cinar, Evgeni Ponimaskin, James Degar, Connor McGuckin, Gabriela Chiosis, Cornelia Eckert, Gunnar Cario, Beat Bornhauser, Jean-Pierre Bourquin, Martin Stanulla, Alejandro Gutierrez.
      The tolerance of amino acid starvation is fundamental to robust cellular fitness. Asparagine depletion is lethal to some cancer cells, a vulnerability that can be exploited clinically. We report that resistance to asparagine starvation is uniquely dependent on an N-terminal low-complexity domain of GSK3α, which its paralog GSK3β lacks. In response to depletion of specific amino acids, including asparagine, leucine, and valine, this domain mediates supramolecular assembly of GSK3α with ubiquitin-proteasome system components in spatially sequestered cytoplasmic bodies. This effect is independent of mTORC1 or GCN2. In normal cells, GSK3α promotes survival during essential amino acid starvation. In human leukemia, GSK3α body formation predicts asparaginase resistance, and sensitivity to asparaginase combined with a GSK3α inhibitor. We propose that GSK3α body formation provides a cellular mechanism to maximize the catalytic efficiency of proteasomal protein degradation in response to amino acid starvation, an adaptive response co-opted by cancer cells for asparaginase resistance.
    Keywords:  GSK3; Wnt; asparaginase; protein degradation; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.molcel.2022.05.025
  53. PLoS Genet. 2022 Jun 21. 18(6): e1010232
    Dync1li1 is required for the survival of mammalian cochlear hair cells by regulating the transportation of autophagosomes.
    Yuan Zhang, Shasha Zhang, Han Zhou, Xiangyu Ma, Leilei Wu, Mengyao Tian, Siyu Li, Xiaoyun Qian, Xia Gao, Renjie Chai.
      Dync1li1, a subunit of cytoplasmic dynein 1, is reported to play important roles in intracellular retrograde transport in many tissues. However, the roles of Dync1li1 in the mammalian cochlea remain uninvestigated. Here we first studied the expression pattern of Dync1li1 in the mouse cochlea and found that Dync1li1 is highly expressed in hair cells (HCs) in both neonatal and adult mice cochlea. Next, we used Dync1li1 knockout (KO) mice to investigate its effects on hearing and found that deletion of Dync1li1 leads to early onset of progressive HC loss via apoptosis and to subsequent hearing loss. Further studies revealed that loss of Dync1li1 destabilizes dynein and alters the normal function of dynein. In addition, Dync1li1 KO results in a thinner Golgi apparatus and the accumulation of LC3+ autophagic vacuoles, which triggers HC apoptosis. We also knocked down Dync1li1 in the OC1 cells and found that the number of autophagosomes were significantly increased while the number of autolysosomes were decreased, which suggested that Dync1li1 knockdown leads to impaired transportation of autophagosomes to lysosomes and therefore the accumulation of autophagosomes results in HC apoptosis. Our findings demonstrate that Dync1li1 plays important roles in HC survival through the regulation of autophagosome transportation.
    DOI:  https://doi.org/10.1371/journal.pgen.1010232
  54. Cell. 2022 Jun 23. pii: S0092-8674(22)00652-3. [Epub ahead of print]185(13): 2292-2308.e20
    Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes.
    Meiqin Hu, Ping Li, Ce Wang, Xinghua Feng, Qi Geng, Wei Chen, Matangi Marthi, Wenlong Zhang, Chenlang Gao, Whitney Reid, Joel Swanson, Wanlu Du, Richard I Hume, Haoxing Xu.
      Lysosomes require an acidic lumen between pH 4.5 and 5.0 for effective digestion of macromolecules. This pH optimum is maintained by proton influx produced by the V-ATPase and efflux through an unidentified "H+ leak" pathway. Here we show that TMEM175, a genetic risk factor for Parkinson's disease (PD), mediates the lysosomal H+ leak by acting as a proton-activated, proton-selective channel on the lysosomal membrane (LyPAP). Acidification beyond the normal range potently activated LyPAP to terminate further acidification of lysosomes. An endogenous polyunsaturated fatty acid and synthetic agonists also activated TMEM175 to trigger lysosomal proton release. TMEM175 deficiency caused lysosomal over-acidification, impaired proteolytic activity, and facilitated α-synuclein aggregation in vivo. Mutational and pH normalization analyses indicated that the channel's H+ conductance is essential for normal lysosome function. Thus, modulation of LyPAP by cellular cues may dynamically tune the pH optima of endosomes and lysosomes to regulate lysosomal degradation and PD pathology.
    Keywords:  Proton channel; acidification; degradation; lysosome; pH optimum
    DOI:  https://doi.org/10.1016/j.cell.2022.05.021
  55. Biomedicines. 2022 Jun 20. pii: 1459. [Epub ahead of print]10(6):
    Therapeutic Aspects and Molecular Targets of Autophagy to Control Pancreatic Cancer Management.
    Md Ataur Rahman, Kazi Rejvee Ahmed, M D Hasanur Rahman, Md Anowar Khasru Parvez, In-Seon Lee, Bonglee Kim.
      Pancreatic cancer (PC) begins within the organ of the pancreas, which produces digestive enzymes, and is one of the formidable cancers for which appropriate treatment strategies are urgently needed. Autophagy occurs in the many chambers of PC tissue, including cancer cells, cancer-related fibroblasts, and immune cells, and can be fine-tuned by various promotive and suppressive signals. Consequently, the impacts of autophagy on pancreatic carcinogenesis and progression depend greatly on its stage and conditions. Autophagy inhibits the progress of preneoplastic damage during the initial phase. However, autophagy encourages tumor formation during the development phase. Several studies have reported that both a tumor-promoting and a tumor-suppressing function of autophagy in cancer that is likely cell-type dependent. However, autophagy is dispensable for pancreatic ductal adenocarcinoma (PDAC) growth, and clinical trials with autophagy inhibitors, either alone or in combination with other therapies, have had limited success. Autophagy's dual mode of action makes it therapeutically challenging despite autophagy inhibitors providing increased longevity in medical studies, highlighting the need for a more rigorous review of current findings and more precise targeting strategies. Indeed, the role of autophagy in PC is complicated, and numerous factors must be considered when transitioning from bench to bedside. In this review, we summarize the evidence for the tumorigenic and protective role of autophagy in PC tumorigenesis and describe recent advances in the understanding of how autophagy may be regulated and controlled in PDAC.
    Keywords:  PC; PDAC; autophagy; pancreatic cancer; pancreatic ductal adenocarcinoma; tumor-promoting; tumor-suppressive
    DOI:  https://doi.org/10.3390/biomedicines10061459
  56. Int J Mol Sci. 2022 Jun 16. pii: 6722. [Epub ahead of print]23(12):
    CRISPR/Cas9-Mediated Constitutive Loss of VCP (Valosin-Containing Protein) Impairs Proteostasis and Leads to Defective Striated Muscle Structure and Function In Vivo.
    Philipp Voisard, Federica Diofano, Amelia A Glazier, Wolfgang Rottbauer, Steffen Just.
      Valosin-containing protein (VCP) acts as a key regulator of cellular protein homeostasis by coordinating protein turnover and quality control. Mutations in VCP lead to (cardio-)myopathy and neurodegenerative diseases such as inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD) or amyotrophic lateral sclerosis (ALS). To date, due to embryonic lethality, no constitutive VCP knockout animal model exists. Here, we generated a constitutive CRISPR/Cas9-induced vcp knockout zebrafish model. Similar to the phenotype of vcp morphant knockdown zebrafish embryos, we found that vcp-null embryos displayed significantly impaired cardiac and skeletal muscle function. By ultrastructural analysis of skeletal muscle cells and cardiomyocytes, we observed severely disrupted myofibrillar organization and accumulation of inclusion bodies as well as mitochondrial degeneration. vcp knockout was associated with a significant accumulation of ubiquitinated proteins, suggesting impaired proteasomal function. Additionally, markers of unfolded protein response (UPR)/ER-stress and autophagy-related mTOR signaling were elevated in vcp-deficient embryos, demonstrating impaired proteostasis in VCP-null zebrafish. In conclusion, our findings demonstrate the successful generation of a stable constitutive vcp knockout zebrafish line that will enable characterization of the detailed mechanistic underpinnings of vcp loss, particularly the impact of disturbed protein homeostasis on organ development and function in vivo.
    Keywords:  CRISPR/Cas9; VCP; VCPopathies; disease modeling; protein homeostasis; zebrafish
    DOI:  https://doi.org/10.3390/ijms23126722
  57. Phytomedicine. 2022 Aug;pii: S0944-7113(22)00314-2. [Epub ahead of print]103 154235
    Phillygenin ameliorates nonalcoholic fatty liver disease via TFEB-mediated lysosome biogenesis and lipophagy.
    Wenling Zhou, Xu Yan, Yuanyuan Zhai, Hao Liu, Lingling Guan, Yuan Qiao, Jizhi Jiang, Liang Peng.
      BACKGROUND: Lipophagy is an autophagic process, which delivers the intracellular lipid droplets to the lysosomes for degradation. Recent studies revealed that the impairment of lysosomal biogenesis and autophagic flux led to dysregulation of lipophagy in hepatocytes, which exacerbated the development of nonalcoholic fatty liver disease (NAFLD). Therefore, agents restoring autophagic flux and lipophagy in hepatocytes may have therapeutic potential against this increasingly prevalent disease. Phillygenin (PHI), a lignin extracted from Forsythia suspense, exerts hepatoprotective and anti-inflammatory effects. However, the effect of PHI on NAFLD remains unknown.PURPOSE: This study aimed to investigate the protective effect of PHI on NAFLD and elucidate the underlying mechanism.
    METHODS: The effects of PHI were examined in palmitate (PA)-stimulated AML12 cells and primary hepatocytes, as well as in NAFLD mice induced by a high-fat diet (HFD). We also used transcription factor EB (TFEB) knockdown hepatocytes and hepatocyte-specific TFEB knockout (TFEBΔhep) mice for mechanistic studies. In vivo and in vitro studies were performed using western blots, immunofluorescence techniques, and transmission electron microscopy.
    RESULTS: Our results indicated that autophagic flux and lysosome biogenesis in PA-stimulated hepatocytes were impaired. PHI alleviated lipid deposition by increasing lysosomal biogenesis and autophagic flux. It also stimulated the release of endoplasmic reticulum Ca2+ to activate calcineurin, which regulated TFEB dephosphorylation and nuclear translocation, and promoted lysosomal biogenesis. In addition, PHI blocked the NLRP3 inflammasome pathway and improved hepatocyte inflammation in an autophagy-dependent manner. Consistent with the in vitro results, PHI improved hepatic steatosis and inflammation in HFD mice, but these beneficial effects were eliminated in hepatocyte-specific TFEB knockout mice.
    CONCLUSION: Despite PHI has been reported to have anti-hepatic fibrosis effects, whether it has a hepatoprotective effects against NAFLD and the underlying molecular mechanism remain unclear. Herein, we found that PHI restored lipophagy and suppressed lipid accumulation and inflammation by regulating the Ca2+-calcineurin-TFEB axis in hepatocytes. Thus, PHI represents a therapeutic candidate for the treatment of NAFLD.
    Keywords:  Autophagic flux; Lipophagy; NAFLD; Phillygenin; TFEB
    DOI:  https://doi.org/10.1016/j.phymed.2022.154235
  58. Cancer Treat Res Commun. 2022 Jun 13. pii: S2468-2942(22)00082-X. [Epub ahead of print]32 100592
    Interaction between tumor microenvironment, autophagy, and epithelial-mesenchymal transition in tumor progression.
    Wen-Ming Wang, Hua Shen, Zi-Ning Liu, Yuan-Yuan Chen, Li-Jun Hou, Yi Ding.
      Tumor microenvironment (TME) is the ecosystem surrounding a tumor to influence tumor cells' growth, metastasis and immunological battlefield, in which the tumor systems fight against the body system. TME has been considered as the essential link between the tumorigenesis and development of neoplasm. Both nutrients intake and tumor progression to malignancy require the participation of components in TME. Epithelial-mesenchymal transition (EMT) is a key step in the metastasis of tumor cells. Cells that lost polarity and acquired migration ability are prone to metastasize. Autophagy is an important self-protective mechanism in tumor cells and a necessity for the tumor cells to respond to harmful stress. Protective autophagy benefits tumor cells while abnormal autophagy leads to cell injury or death. EMT and autophagy are directly regulated by TME. To date, there are numerous studies on TME, autophagy and EMT separately, but few on their complex interrelationships. This review aims to comprehensively analyze the existing mechanisms and convincing evidence so far to seek novel therapeutic strategies and research directions.
    Keywords:  Autophagy; Epithelial-mesenchymal transition (EMT); Stress; Tumor; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.ctarc.2022.100592
  59. Exp Neurol. 2022 Jun 16. pii: S0014-4886(22)00169-8. [Epub ahead of print]355 114144
    FUS aggregation following ischemic stroke favors brain astrocyte activation through inducing excessive autophagy.
    Shusheng Wu, Yuye Yin, Longfei Du.
      As is the case with neurodegenerative diseases, abnormal accumulation of aggregated proteins in neurons and glial are also known to implicate in the pathogenesis of ischemic stroke. However, the potential role of protein aggregates in brain ischemia remains largely unknown. Fused in Sarcoma (FUS) protein has a vital role in RNA metabolism and regulating cellular homeostasis. FUS pathology has been demonstrated in the formation of toxic aggregates and critically affecting cell viability in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but whether this also applies to neurological injury following cerebral ischemia is unclear. Herein, we demonstrated a critical role of aggregated FUS in astrocyte activation caused by cerebral ischemia and a possible underlying molecular mechanism. Cerebral ischemic injury significantly induced the formation of cytoplasmic FUS aggregates in reactive astrocytes and injured neurons, thereby aggravating neurofunctional damages and worsening stroke outcomes. Further analysis revealed that extranuclear aggregation of FUS in astrocytes was involved in the induction of excessive autophagy, which contributes to autophagic cell injury or death. In conclusion, our results reveal the important contribution of FUS aggregates in promoting astrocyte activation in stroke pathology independent of its transcriptional regulation activity. We thus propose that aggregation of FUS is an important pathological process in ischemic stroke and targeting FUS aggregates might be of unique therapeutic value in the development of future treatment strategies for ischemic stroke.
    Keywords:  Astrocytes; Autophagy; FUS; FUS aggregation; Ischemic stroke; Protein aggregation
    DOI:  https://doi.org/10.1016/j.expneurol.2022.114144
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