bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2021‒08‒08
43 papers selected by
Viktor Korolchuk, Newcastle University
  1. Molecular functions of autophagy adaptors upon ubiquitin-driven mitophagy.
  2. Autophagy ENDing unproductive phase-separated endocytic protein deposits.
  3. Pharmacological rescue of impaired mitophagy in Parkinson's disease-related LRRK2 G2019S knock-in mice.
  4. Role of FAM134 paralogues in endoplasmic reticulum remodeling, ER-phagy, and Collagen quality control.
  5. Lipid Droplets and Their Autophagic Turnover via the Raft-Like Vacuolar Microdomains.
  6. mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership.
  7. Multiple structural rearrangements mediated by high-plasticity regions in Atg3 are key for efficient conjugation of Atg8 to PE during autophagy.
  8. An Overview of the Perspective of Cellular Autophagy: Mechanism, Regulation, and the Role of Autophagy Dysregulation in the Pathogenesis of Diseases.
  9. Longitudinal tracking of neuronal mitochondria delineates PINK1/Parkin-dependent mechanisms of mitochondrial recycling and degradation.
  10. Communication Between Autophagy and Insulin Action: At the Crux of Insulin Action-Insulin Resistance?
  11. Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation.
  12. Selective increment of phosphatidylserine on the autophagic body membrane in the yeast vacuole.
  13. mTOR signaling mediates ILC3-driven immunopathology.
  14. Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function.
  15. Arginine-selective modulation of the lysosomal transporter PQLC2 through a gate-tuning mechanism.
  16. Mammalian Target of Rapamycin Signaling Pathway Regulates Mitochondrial Quality Control of Brown Adipocytes in Mice.
  17. Rethinking Lysosomes and Lysosomal Disease.
  18. Knockdown of PEX16 Induces Autophagic Degradation of Peroxisomes.
  19. Autophagy promotes invadopodia formation in human ovarian cancer cells via the p62-extracellular signal-regulated kinase 1/2 pathway.
  20. A fluorescence imaging based-assay to monitor mitophagy in cultured hepatocytes and mouse liver.
  21. P62 Links the Autophagy Pathway and the Ubiquitin-Proteasome System in Endothelial Cells during Atherosclerosis.
  22. TFEB Signalling-Related MicroRNAs and Autophagy.
  23. Exendin-4 stimulates autophagy in pancreatic β-cells via the RAPGEF/EPAC-Ca2+-PPP3/calcineurin-TFEB axis.
  24. Mycobacterium tuberculosis PE_PGRS20 and PE_PGRS47 Proteins Inhibit Autophagy by Interaction with Rab1A.
  25. Autophagy in Xp11 translocation renal cell carcinoma: from bench to bedside.
  26. Tomatidine provides mitophagy-independent neuroprotection after ischemic injury.
  27. Exocyst protein subnetworks integrate Hippo and mTOR signaling to promote virus detection and cancer.
  28. Self-eating and Heart: The Emerging Roles of Autophagy in Calcific Aortic Valve Disease.
  29. The PI3K/AKT/mTOR signaling pathway inhibitors enhance radiosensitivity in cancer cell lines.
  30. BNIP3-Dependent Mitophagy via PGC1α Promotes Cartilage Degradation.
  31. Rapamycin Plus Doxycycline Combination Affects Growth Arrest and Selective Autophagy-Dependent Cell Death in Breast Cancer Cells.
  32. Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways.
  33. Potential Therapeutic Approaches through Modulating the Autophagy Process for Skin Barrier Dysfunction.
  34. Mitophagy: At the heart of mitochondrial quality control in cardiac aging and frailty.
  35. Melatonin Treatment Improves Renal Fibrosis via miR-4516/SIAH3/PINK1 Axis.
  36. RNA-Dependent Protein Kinase is Required for Interferon-γ-induced Autophagy in MG63 Osteosarcoma Cells.
  37. H2O2-mediated autophagy during ethanol metabolism.
  38. Mitochondrial Modulations, Autophagy Pathways Shifts in Viral Infections: Consequences of COVID-19.
  39. p53 Deacetylation Alleviates Sepsis-Induced Acute Kidney Injury by Promoting Autophagy.
  40. S-Palmitoylation determines TMEM55B-dependent positioning of lysosomes.
  41. Reactive Oxygen Species as a Link between Antioxidant Pathways and Autophagy.
  42. Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging.
  43. Ouabain and chloroquine trigger senolysis of BRAF-V600E-induced senescent cells by targeting autophagy.
  1. Biochim Biophys Acta Gen Subj. 2021 Jul 28. pii: S0304-4165(21)00131-8. [Epub ahead of print]1865(10): 129972
    Molecular functions of autophagy adaptors upon ubiquitin-driven mitophagy.
    Koji Yamano, Waka Kojima.
      BACKGROUND: Perturbations in organellar health can lead to an accumulation of unwanted and/or damaged organelles that are toxic to the cell and which can contribute to the onset of neurodegenerative diseases such as Parkinson's disease. Mitochondrial health is particularly critical given the indispensable role the organelle has not only in adenosine triphosphate production but also other metabolic processes. Byproducts of oxidative respiration, such as reactive oxygen species, however, can negatively impact mitochondrial fitness. Consequently, selective degradation of damaged mitochondria, which occurs via a specific autophagic process termed mitophagy, is essential for normal cell maintenance.SCOPE OF REVIEW: Recent accumulating evidence has shown that autophagy adaptors (also referred to as autophagy receptors) play critical roles in connecting ubiquitinated mitochondria with the autophagic machinery of the autophagy-lysosome pathway that is required for degradation. In this review, we focus on our current understanding of the autophagy adaptor mechanisms underlying PINK1/Parkin-driven mitophagy.
    MAJOR CONCLUSIONS: Although autophagy adaptors are canonically defined as proteins that possess ubiquitin-binding domains and ATG8s-binding motifs, the recent identification of novel binding partners has contributed to the development of a more sophisticated model for how autophagy adaptors contribute to the molecular hub that organizes autophagic cargo-degradation.
    GENERAL SIGNIFICANCE: Although mitophagy is recognized as one of the selective autophagy pathways that removes dysfunctional mitochondria, a more nuanced understanding of the interactions connecting autophagy adaptors and their associated proteins is needed to gain deeper insights into the fundamental biological processes underlying human diseases, including neurodegenerative disorders. This review is part of a Special Issue entitled Mitophagy.
    DOI:  https://doi.org/10.1016/j.bbagen.2021.129972
  2. Autophagy. 2021 Aug 02. 1-2
    Autophagy ENDing unproductive phase-separated endocytic protein deposits.
    Florian Wilfling, Chia-Wei Lee, Philipp S Erdmann, Wolfgang Baumeister.
      Selective disposal of a wide range of cellular entities by macroautophagy/autophagy is achieved through a special class of proteins called autophagy receptors, which link corresponding cargo to the membrane-bound autophagosomal protein Atg8/LC3. In pursuit of novel autophagy receptors and their cargo, we uncovered a previously undescribed autophagy pathway for removal of aberrant clathrin-mediated endocytosis (CME) protein condensates in S. cerevisiae. Of these CME proteins, Ede1 functions as an autophagy receptor, harboring distinct Atg8-binding domains and driving phase separation into condensates. The aberrant CME condensates at the plasma membrane (PM) exhibit a drop-like structure surrounded by a fenestrated ER, which are engulfed in pieces in an Ede1-dependent manner by autophagy. Thus, our work suggests that aberrant CME is a target for autophagic degradation, with the scaffold protein Ede1 serving as a built-in autophagy receptor that monitors the assembly status of the CME machinery.
    Keywords:  Atg11; Cathrin-mediated endocytosis; Ede1; budding yeast; intrinsic receptor; phase separation; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1957567
  3. Elife. 2021 Aug 03. pii: e67604. [Epub ahead of print]10
    Pharmacological rescue of impaired mitophagy in Parkinson's disease-related LRRK2 G2019S knock-in mice.
    Francois Singh, Alan R Prescott, Philippa Rosewell, Graeme Ball, Alastair D Reith, Ian G Ganley.
      Parkinson's disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation - key features of the autophagy of mitochondria, known as mitophagy. Here, we investigated the role of LRRK2, a protein kinase frequently mutated in PD, in this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues. Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice. This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic Parkinson's disease, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.
    Keywords:  LRRK2; Mitophagy; cell biology; kinase inhibitor; mito-QC; mouse; neuroscience; parkinson's disease
    DOI:  https://doi.org/10.7554/eLife.67604
  4. EMBO Rep. 2021 Aug 02. e52289
    Role of FAM134 paralogues in endoplasmic reticulum remodeling, ER-phagy, and Collagen quality control.
    Alessio Reggio, Viviana Buonomo, Rayene Berkane, Ramachandra M Bhaskara, Mariana Tellechea, Ivana Peluso, Elena Polishchuk, Giorgia Di Lorenzo, Carmine Cirillo, Marianna Esposito, Adeela Hussain, Antje K Huebner, Christian A Hübner, Carmine Settembre, Gerhard Hummer, Paolo Grumati, Alexandra Stolz.
      Degradation of the endoplasmic reticulum (ER) via selective autophagy (ER-phagy) is vital for cellular homeostasis. We identify FAM134A/RETREG2 and FAM134C/RETREG3 as ER-phagy receptors, which predominantly exist in an inactive state under basal conditions. Upon autophagy induction and ER stress signal, they can induce significant ER fragmentation and subsequent lysosomal degradation. FAM134A, FAM134B/RETREG1, and FAM134C are essential for maintaining ER morphology in a LC3-interacting region (LIR)-dependent manner. Overexpression of any FAM134 paralogue has the capacity to significantly augment the general ER-phagy flux upon starvation or ER-stress. Global proteomic analysis of FAM134 overexpressing and knockout cell lines reveals several protein clusters that are distinctly regulated by each of the FAM134 paralogues as well as a cluster of commonly regulated ER-resident proteins. Utilizing pro-Collagen I, as a shared ER-phagy substrate, we observe that FAM134A acts in a LIR-independent manner and compensates for the loss of FAM134B and FAM134C, respectively. FAM134C instead is unable to compensate for the loss of its paralogues. Taken together, our data show that FAM134 paralogues contribute to common and unique ER-phagy pathways.
    Keywords:  Collagen; ER stress; ER-phagy; FAM134; autophagy
    DOI:  https://doi.org/10.15252/embr.202052289
  5. Int J Mol Sci. 2021 Jul 29. pii: 8144. [Epub ahead of print]22(15):
    Lipid Droplets and Their Autophagic Turnover via the Raft-Like Vacuolar Microdomains.
    Muhammad Arifur Rahman, Ravinder Kumar, Enrique Sanchez, Taras Y Nazarko.
      Although once perceived as inert structures that merely serve for lipid storage, lipid droplets (LDs) have proven to be the dynamic organelles that hold many cellular functions. The LDs' basic structure of a hydrophobic core consisting of neutral lipids and enclosed in a phospholipid monolayer allows for quick lipid accessibility for intracellular energy and membrane production. Whereas formed at the peripheral and perinuclear endoplasmic reticulum, LDs are degraded either in the cytosol by lipolysis or in the vacuoles/lysosomes by autophagy. Autophagy is a regulated breakdown of dysfunctional, damaged, or surplus cellular components. The selective autophagy of LDs is called lipophagy. Here, we review LDs and their degradation by lipophagy in yeast, which proceeds via the micrometer-scale raft-like lipid domains in the vacuolar membrane. These vacuolar microdomains form during nutrient deprivation and facilitate internalization of LDs via the vacuolar membrane invagination and scission. The resultant intra-vacuolar autophagic bodies with LDs inside are broken down by vacuolar lipases and proteases. This type of lipophagy is called microlipophagy as it resembles microautophagy, the type of autophagy when substrates are sequestered right at the surface of a lytic compartment. Yeast microlipophagy via the raft-like vacuolar microdomains is a great model system to study the role of lipid domains in microautophagic pathways.
    Keywords:  autophagy; lipid droplets; lipid rafts; lipophagy; microautophagy; microlipophagy; organelle homeostasis; vacuolar microdomains; vacuole; yeast
    DOI:  https://doi.org/10.3390/ijms22158144
  6. Int J Mol Sci. 2021 Jul 29. pii: 8149. [Epub ahead of print]22(15):
    mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership.
    Angel Cayo, Raúl Segovia, Whitney Venturini, Rodrigo Moore-Carrasco, Claudio Valenzuela, Nelson Brown.
      Cellular senescence is a form of proliferative arrest triggered in response to a wide variety of stimuli and characterized by unique changes in cell morphology and function. Although unable to divide, senescent cells remain metabolically active and acquire the ability to produce and secrete bioactive molecules, some of which have recognized pro-inflammatory and/or pro-tumorigenic actions. As expected, this "senescence-associated secretory phenotype (SASP)" accounts for most of the non-cell-autonomous effects of senescent cells, which can be beneficial or detrimental for tissue homeostasis, depending on the context. It is now evident that many features linked to cellular senescence, including the SASP, reflect complex changes in the activities of mTOR and other metabolic pathways. Indeed, the available evidence indicates that mTOR-dependent signaling is required for the maintenance or implementation of different aspects of cellular senescence. Thus, depending on the cell type and biological context, inhibiting mTOR in cells undergoing senescence can reverse senescence, induce quiescence or cell death, or exacerbate some features of senescent cells while inhibiting others. Interestingly, autophagy-a highly regulated catabolic process-is also commonly upregulated in senescent cells. As mTOR activation leads to repression of autophagy in non-senescent cells (mTOR as an upstream regulator of autophagy), the upregulation of autophagy observed in senescent cells must take place in an mTOR-independent manner. Notably, there is evidence that autophagy provides free amino acids that feed the mTOR complex 1 (mTORC1), which in turn is required to initiate the synthesis of SASP components. Therefore, mTOR activation can follow the induction of autophagy in senescent cells (mTOR as a downstream effector of autophagy). These functional connections suggest the existence of autophagy regulatory pathways in senescent cells that differ from those activated in non-senescence contexts. We envision that untangling these functional connections will be key for the generation of combinatorial anti-cancer therapies involving pro-senescence drugs, mTOR inhibitors, and/or autophagy inhibitors.
    Keywords:  autophagy; mTOR; senescence
    DOI:  https://doi.org/10.3390/ijms22158149
  7. Autophagy. 2021 Jul 31. 1-4
    Multiple structural rearrangements mediated by high-plasticity regions in Atg3 are key for efficient conjugation of Atg8 to PE during autophagy.
    Hana Popelka, Daniel J Klionsky.
      The Atg3 protein is highly homologous from yeast to human. Atg3 functions as an E2-like enzyme promoting conjugation of Atg8-family proteins to phosphatidylethanolamine (PE), a lipid molecule embedded in the growing phagophore membrane during stress-induced autophagy. Over the last decade, Atg3 became one of the most explored autophagy proteins, resulting in observations that provided specific insights into the structural mechanisms of its function. In this article, we describe a recent study by Ye et al. that reveals, using the human ATG3, how the membrane binding capability of the enzyme is tightly linked to its conjugation activity. We summarize the current knowledge on important mechanisms that involve protein-protein or protein-membrane interactions of Atg3 and that ultimately lead to efficient Atg8-PE conjugation.Abbreviations: AH: amphipathic helix; FR: flexible region; HR: handle region; NMR: nuclear magnetic resonance.
    Keywords:  Circular dichroism; LC3B lipidation; NMR spectroscopy; liposomes; protein intrinsic disorder
    DOI:  https://doi.org/10.1080/15548627.2021.1954457
  8. J Microsc Ultrastruct. 2021 Apr-Jun;9(2):9(2): 47-54
    An Overview of the Perspective of Cellular Autophagy: Mechanism, Regulation, and the Role of Autophagy Dysregulation in the Pathogenesis of Diseases.
    Yasser M Alharbi, Abdulhadi I Bima, Ayman Z Elsamanoudy.
      Autophagy is a cellular process that eliminates unnecessary cytoplasmic materials, such as long-age proteins, destroyed organelles, and foreign microorganisms. Macroautophagy (MaA), chaperone-mediated autophagy, and microautophagy are the three main types of autophagy. It is regulated by the integration of signaling from the AMPK and mTOR-ULK1 pathways. Autophagy plays a physiological role in health, and its dysregulation could be a pathophysiologic mechanism in different disease conditions. In the current study, we reviewed papers of Google Scholar database, PubMed, PubMed Central, Cochrane Database of Systematic Reviews, MEDLINE, and MedlinePlus with no time limitation and a recent World Health Organization report. In the current review, it could be concluded that autophagy plays many physiological functions, including immune system modulation, and regulates different cellular processes such as metabolism, protein synthesis, and cellular transportation. Dysregulation of autophagy is implicated in tumorigenesis, aging, age-related neurodegeneration, and endothelial dysfunctions. Autophagy dysregulation is also implicated in the newly discovered CoV-COVID-19 pathogenesis.
    Keywords:  Autophagy; COVID-19; dysregulation; endothelial dysfunctions
    DOI:  https://doi.org/10.4103/JMAU.JMAU_33_20
  9. Sci Adv. 2021 Aug;pii: eabf6580. [Epub ahead of print]7(32):
    Longitudinal tracking of neuronal mitochondria delineates PINK1/Parkin-dependent mechanisms of mitochondrial recycling and degradation.
    Huihui Li, Zak Doric, Amandine Berthet, Danielle M Jorgens, Mai K Nguyen, Ivy Hsieh, Julia Margulis, Rebecca Fang, Jayanta Debnath, Hiromi Sesaki, Steve Finkbeiner, Eric Huang, Ken Nakamura.
      Altered mitochondrial quality control and dynamics may contribute to neurodegenerative diseases, including Parkinson's disease, but we understand little about these processes in neurons. We combined time-lapse microscopy and correlative light and electron microscopy to track individual mitochondria in neurons lacking the fission-promoting protein dynamin-related protein 1 (Drp1) and delineate the kinetics of PINK1-dependent pathways of mitochondrial quality control. Depolarized mitochondria recruit Parkin to the outer mitochondrial membrane, triggering autophagosome formation, rapid lysosomal fusion, and Parkin redistribution. Unexpectedly, these mitolysosomes are dynamic and persist for hours. Some are engulfed by healthy mitochondria, and others are deacidified before bursting. In other cases, Parkin is directly recruited to the matrix of polarized mitochondria. Loss of PINK1 blocks Parkin recruitment, causes LC3 accumulation within mitochondria, and exacerbates Drp1KO toxicity to dopamine neurons. These results define a distinct neuronal mitochondrial life cycle, revealing potential mechanisms of mitochondrial recycling and signaling relevant to neurodegeneration.
    DOI:  https://doi.org/10.1126/sciadv.abf6580
  10. Front Cell Dev Biol. 2021 ;9 708431
    Communication Between Autophagy and Insulin Action: At the Crux of Insulin Action-Insulin Resistance?
    Scott Frendo-Cumbo, Victoria L Tokarz, Philip J Bilan, John H Brumell, Amira Klip.
      Insulin is a paramount anabolic hormone that promotes energy-storage in adipose tissue, skeletal muscle and liver, and these responses are significantly attenuated in insulin resistance leading to type 2 diabetes. Contrasting with insulin's function, macroautophagy/autophagy is a physiological mechanism geared to the degradation of intracellular components for the purpose of energy production, building-block recycling or tissue remodeling. Given that both insulin action and autophagy are dynamic phenomena susceptible to the influence of nutrient availability, it is perhaps not surprising that there is significant interaction between these two major regulatory mechanisms. This review examines the crosstalk between autophagy and insulin action, with specific focus on dysregulated autophagy as a cause or consequence of insulin resistance.
    Keywords:  adipose tissue; autophagy; insulin action; insulin resistance; liver; obesity; skeletal muscle; type 2 diabetes
    DOI:  https://doi.org/10.3389/fcell.2021.708431
  11. Development. 2021 Aug 06. pii: dev.199686. [Epub ahead of print]
    Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation.
    Grigor Varuzhanyan, Mark S Ladinsky, Shun-Ichi Yamashita, Manabu Abe, Kenji Sakimura, Tomotake Kanki, David C Chan.
      Male germline development involves choreographed changes to mitochondrial number, morphology, and organization. Mitochondrial reorganization during spermatogenesis was recently shown to require mitochondrial fusion and fission. Mitophagy, the autophagic degradation of mitochondria, is another mechanism for controlling mitochondrial number and physiology, but its role during spermatogenesis is largely unknown. During post-meiotic spermatid development, restructuring of the mitochondrial network results in packing of mitochondria into a tight array in the sperm midpiece to fuel motility. Here, we show that disruption of mouse Fis1 in the male germline results in early spermatid arrest that is associated with increased mitochondrial content. Mutant spermatids coalesce into multinucleated giant cells (GCs) that accumulate mitochondria of aberrant ultrastructure and numerous mitophagic and autophagic intermediates, suggesting a defect in mitophagy. We conclude that Fis1 regulates mitochondrial morphology and turnover to promote spermatid maturation.
    Keywords:  Autophagy; Mitochondrial dynamics; Mitophagy; Spermatid; Spermatogenesis
    DOI:  https://doi.org/10.1242/dev.199686
  12. FEBS Lett. 2021 Aug 02.
    Selective increment of phosphatidylserine on the autophagic body membrane in the yeast vacuole.
    Yuki Yamakuchi, Yuna Kurokawa, Rikako Konishi, Kayoko Fukuda, Tatsunori Masatani, Akikazu Fujita.
      In yeast cells, the autophagosome is a double-membrane structure; the inner membrane becomes the autophagic body membrane in the vacuole. Vacuolar enzymes degrade the autophagic body. There is no critical information regarding its selective degradation. Using the electron microscopy method, distributions of four phospholipids were examined in the autophagosomal and autophagic body membranes upon autophagy induction. The labeling of phosphatidylserine (PtdSer) in the autophagic body membrane dramatically increased after it converted from the autophagosome, but remained low in the vacuolar membrane. PtdSer in the autophagic body membrane also increased in atg15∆ yeast. These results suggest that the selective increment of PtdSer in the autophagic body, but not the vacuolar, membrane, can explain the selective degradation of the autophagic membrane.
    Keywords:  autophagy; electron microscopy; freeze fracture; lipids; nanoscale; phosphatidylcholine; phosphatidylserine; phosphoinositide
    DOI:  https://doi.org/10.1002/1873-3468.14167
  13. Mucosal Immunol. 2021 Aug 02.
    mTOR signaling mediates ILC3-driven immunopathology.
    Claudia Teufel, Edit Horvath, Annick Peter, Caner Ercan, Salvatore Piscuoglio, Michael N Hall, Daniela Finke, Frank M Lehmann.
      Innate lymphoid cells (ILCs) have a protective immune function at mucosal tissues but can also contribute to immunopathology. Previous work has shown that the serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1) is involved in generating protective ILC3 cytokine responses during bacterial infection. However, whether mTORC1 also regulates IFN-γ-mediated immunopathology has not been investigated. In addition, the role of mTORC2 in ILC3s is unknown. Using mice specifically defective for either mTORC1 or mTORC2 in ILC3s, we show that both mTOR complexes regulate the maintenance of ILC3s at steady state and pathological immune response during colitis. mTORC1 and to a lesser extend mTORC2 promote the proliferation of ILC3s in the small intestine. Upon activation, intestinal ILC3s produce less IFN-γ in the absence of mTOR signaling. During colitis, loss of both mTOR complexes in colonic ILC3s results in the reduced production of inflammatory mediators, recruitment of neutrophils and immunopathology. Similarly, treatment with rapamycin after colitis induction ameliorates the disease. Collectively, our data show a critical role for both mTOR complexes in controlling ILC3 cell numbers and ILC3-driven inflammation in the intestine.
    DOI:  https://doi.org/10.1038/s41385-021-00432-4
  14. PLoS Genet. 2021 Aug;17(8): e1009688
    Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function.
    Tadashi Yamamuro, Shuhei Nakamura, Yu Yamano, Tsutomu Endo, Kyosuke Yanagawa, Ayaka Tokumura, Takafumi Matsumura, Kiyonori Kobayashi, Hideto Mori, Yusuke Enokidani, Gota Yoshida, Hitomi Imoto, Tsuyoshi Kawabata, Maho Hamasaki, Akiko Kuma, Sohei Kuribayashi, Kentaro Takezawa, Yuki Okada, Manabu Ozawa, Shinichiro Fukuhara, Takashi Shinohara, Masahito Ikawa, Tamotsu Yoshimori.
      Autophagy degrades unnecessary proteins or damaged organelles to maintain cellular function. Therefore, autophagy has a preventive role against various diseases including hepatic disorders, neurodegenerative diseases, and cancer. Although autophagy in germ cells or Sertoli cells is known to be required for spermatogenesis and male fertility, it remains poorly understood how autophagy participates in spermatogenesis. We found that systemic knockout mice of Rubicon, a negative regulator of autophagy, exhibited a substantial reduction in testicular weight, spermatogenesis, and male fertility, associated with upregulation of autophagy. Rubicon-null mice also had lower levels of mRNAs of Sertoli cell-related genes in testis. Importantly, Rubicon knockout in Sertoli cells, but not in germ cells, caused a defect in spermatogenesis and germline stem cell maintenance in mice, indicating a critical role of Rubicon in Sertoli cells. In mechanistic terms, genetic loss of Rubicon promoted autophagic degradation of GATA4, a transcription factor that is essential for Sertoli cell function. Furthermore, androgen antagonists caused a significant decrease in the levels of Rubicon and GATA4 in testis, accompanied by elevated autophagy. Collectively, we propose that Rubicon promotes Sertoli cell function by preventing autophagic degradation of GATA4, and that this mechanism could be regulated by androgens.
    DOI:  https://doi.org/10.1371/journal.pgen.1009688
  15. Proc Natl Acad Sci U S A. 2021 Aug 10. pii: e2025315118. [Epub ahead of print]118(32):
    Arginine-selective modulation of the lysosomal transporter PQLC2 through a gate-tuning mechanism.
    Xavier Leray, Rossella Conti, Yan Li, Cécile Debacker, Florence Castelli, François Fenaille, Anselm A Zdebik, Michael Pusch, Bruno Gasnier.
      Lysosomes degrade excess or damaged cellular components and recycle their building blocks through membrane transporters. They also act as nutrient-sensing signaling hubs to coordinate cell responses. The membrane protein PQ-loop repeat-containing protein 2 (PQLC2; "picklock two") is implicated in both functions, as it exports cationic amino acids from lysosomes and serves as a receptor and amino acid sensor to recruit the C9orf72/SMCR8/WDR41 complex to lysosomes upon nutrient starvation. Its transport activity is essential for drug treatment of the rare disease cystinosis. Here, we quantitatively studied PQLC2 transport activity using electrophysiological and biochemical methods. Charge/substrate ratio, intracellular pH, and reversal potential measurements showed that it operates in a uniporter mode. Thus, PQLC2 is uncoupled from the steep lysosomal proton gradient, unlike many lysosomal transporters, enabling bidirectional cationic amino acid transport across the organelle membrane. Surprisingly, the specific presence of arginine, but not other substrates (lysine, histidine), in the discharge ("trans") compartment impaired PQLC2 transport. Kinetic modeling of the uniport cycle recapitulated the paradoxical substrate-yet-inhibitor behavior of arginine, assuming that bound arginine facilitates closing of the transporter's cytosolic gate. Arginine binding may thus tune PQLC2 gating to control its conformation, suggesting a potential mechanism for nutrient signaling by PQLC2 to its interaction partners.
    Keywords:  PQLC2; arginine-sensing; gating; lysosome; transporter
    DOI:  https://doi.org/10.1073/pnas.2025315118
  16. Front Physiol. 2021 ;12 638352
    Mammalian Target of Rapamycin Signaling Pathway Regulates Mitochondrial Quality Control of Brown Adipocytes in Mice.
    Bahetiyaer Huwatibieke, Wenzhen Yin, Lingchao Liu, Yuxin Jin, Xinxin Xiang, Jingyan Han, Weizhen Zhang, Yin Li.
      The mammalian target of rapamycin (mTOR) is an important protein kinase that senses changes in extracellular and intracellular energy levels and plays a key role in regulating energy metabolism. Brown adipose tissue, which can be converted to white adipose tissue, contains a large number of mitochondria and regulates energy expenditure through thermogenesis. Because obesity is a process of fat accumulation due to chronic excessive energy intake, we attempted to determine whether the mTOR signaling pathway can affect the mitochondrial quality control of brown adipocytes through sensing energy status, thereby regulating brown/white adipocyte transformation. In the present study, through activation or inhibition of mTOR signaling, we detected mitochondrial biogenesis, dynamics, and autophagy-related markers in brown adipocytes. We found that activation of mTOR signaling downregulated the expression of mitochondrial biogenesis, dynamics, and autophagy-relevant markers and inhibited the mitochondrial quality control of brown adipocytes, indicating a phenotypic transformation of brown to white adipocytes. In contrast, inhibition of mTOR signaling upregulated the expression of mitochondrial biogenesis, dynamics, and mitophagy-relevant markers and strengthened mitochondrial quality control, suggesting an inhibition of the phenotypic transformation of brown to white adipocytes. In conclusion, the mTOR signaling pathway plays an important role in modulating the transformation of adipocytes by regulating mitochondrial quality control.
    Keywords:  brown adipose tissue; mammalian target of rapamycin; mitochondria; obesity; white adipose tissue
    DOI:  https://doi.org/10.3389/fphys.2021.638352
  17. Neurosci Lett. 2021 Aug 03. pii: S0304-3940(21)00533-4. [Epub ahead of print] 136155
    Rethinking Lysosomes and Lysosomal Disease.
    Steven U Walkley.
      Lysosomal storage diseases were recognized and defined over a century ago as a class of disorders affecting mostly children and causing systemic disease often accompanied by major neurological consequences. Since their discovery, research focused on understanding their causes has been an important driver of our ever-expanding knowledge of cell biology and the central role that lysosomes play in cell function. Today we recognize over 50 so-called storage diseases, with most understood at the level of gene, protein and pathway involvement, but few fully clarified in terms of how the defective lysosomal function causes brain disease; even fewer have therapies that can effectively rescue brain function. Importantly, we also recognize that storage diseases are not simply a class of lysosomal disorders all by themselves, as increasingly a critical role for the greater lysosomal system with its endosomal, autophagosomal and salvage streams has also emerged in a host of neurodevelopmental and neurodegenerative diseases. Despite persistent challenges across all aspects of these complex disorders, and as reflected in this and other articles focused on lysosomal storage diseases in this special issue of Neuroscience Letters, the progress and promise to both understand and effectively treat these conditions has never been greater.
    Keywords:  Autophagosome; Endosome; Lysosomal storage disorders; Lysosome; Neurodegenerative disorders; Neurodevelopmental disorders; TFEB; mTOR
    DOI:  https://doi.org/10.1016/j.neulet.2021.136155
  18. Int J Mol Sci. 2021 Jul 26. pii: 7989. [Epub ahead of print]22(15):
    Knockdown of PEX16 Induces Autophagic Degradation of Peroxisomes.
    Xiaofan Wei, Yunash Maharjan, Debra Dorotea, Raghbendra-Kumar Dutta, Donghyun Kim, Hyunsoo Kim, Yizhu Mu, Channy Park, Raekil Park.
      Peroxisome abundance is regulated by homeostasis between the peroxisomal biogenesis and degradation processes. Peroxin 16 (PEX16) is a peroxisomal protein involved in trafficking membrane proteins for de novo peroxisome biogenesis. The present study demonstrates that PEX16 also modulates peroxisome abundance through pexophagic degradation. PEX16 knockdown in human retinal pigment epithelial-1 cells decreased peroxisome abundance and function, represented by reductions in the expression of peroxisome membrane protein ABCD3 and the levels of cholesterol and plasmalogens, respectively. The activation of pexophagy under PEX16 knockdown was shown by (i) abrogated peroxisome loss under PEX16 knockdown in autophagy-deficient ATG5 knockout cell lines, and (ii) increased autophagy flux and co-localization of p62-an autophagy adaptor protein-with ABCD3 in the presence of the autophagy inhibitor chloroquine. However, the levels of cholesterol and plasmalogens did not recover despite the restoration of peroxisome abundance following chloroquine treatment. Thus, PEX16 is indispensable for maintaining peroxisome homeostasis by regulating not only the commonly known biogenesis pathway but also the autophagic degradation of peroxisomes.
    Keywords:  PEX16; autophagy; chloroquine; peroxins; peroxisomes; pexophagy
    DOI:  https://doi.org/10.3390/ijms22157989
  19. Exp Ther Med. 2021 Sep;22(3): 952
    Autophagy promotes invadopodia formation in human ovarian cancer cells via the p62-extracellular signal-regulated kinase 1/2 pathway.
    Zizhen Zhou, Jia Zhao, Yanan Liu, Xiaoyu Yan, Hongyu Sun, Meihui Xia, Jing Su.
      Invasiveness and metastatic potential are among the most essential characteristics of malignant tumors. Furthermore, it has been reported that autophagy and invasion are enhanced when tumor cells are grown in adverse conditions, such as nutritional deficiency and starvation. However, the association between autophagy and invasion remains largely unclear. In the present study, Earle's balanced salt solution (EBSS) was used to induce autophagy and an autophagy inhibitor was used to block autophagy. The results of Transwell assays revealed that autophagy inhibition limited the invasiveness of human ovarian cancer cells. Furthermore, the results of invadopodia formation assay indicated that autophagy stimulated invadopodia formation, and the selective autophagy receptor and signaling adaptor, sequestosome-1 (SQSTM1/p62 or simply p62), was closely associated with invadopodia formation in human ovarian cancer SKOV3 cells. The results of western blot analysis indicated that autophagy induced changes in p62 protein levels and p62 then functioned as a negative regulator of extracellular signal-regulated kinase 1/2 (ERK1/2) activity and invadopodia formation. The interaction between autophagy and invasion may thus be a self-protective mechanism for tumor cells in an unfavorable environment of nutritional deficiency, that maintains their survival and leads to increased invasiveness. An exploration of the intrinsic link between autophagy and invasion may provide a novel theoretical basis to reverse the resistance of tumor cells to a nutritional deficient environment.
    Keywords:  ERK1/2; autophagy; invadopodia; p62
    DOI:  https://doi.org/10.3892/etm.2021.10384
  20. Liver Res. 2021 Mar;5(1): 16-20
    A fluorescence imaging based-assay to monitor mitophagy in cultured hepatocytes and mouse liver.
    Xiaowen Ma, Wen-Xing Ding.
      Background and aim: Mitophagy is a lysosomal degradation pathway that selectively removes damaged, aged and dysfunctional mitochondria. Recent advances in understanding mitophagy highlight its importance in various physiological and pathological conditions including liver diseases. However, reliable quantitative assays to monitor mitophagy in cultured cells and in tissues are still scarce.Methods: We describe a detailed protocol for monitoring mitophagy in primary cultured hepatocytes and mouse livers using cytochrome C oxidase subunit 8 (Cox8)-enhanced green fluorescent protein (EGFP)-mCherry, a dual color fluorescence based-imaging method.
    Results: Mitochondria are visualized in yellow fluorescence due to the merged EGFP and mCherry signal. In contrast, autolysosome enclosed mitochondria are shown as red puncta due to quenching of EGFP green fluorescence in acidic compartments. Quantifying the number of red-only puncta in each cell can obtain a quantitative measure for mitophagy.
    Conclusions: Cox8-EGFP-mCherry assay can specifically target to mitochondria and be used to monitor mitophagy in vitro and in vivo.
    Keywords:  Autophagy; Cox8-EGFP-mCherry; Fluorescence microscopy; Lysosome; Mitochondria
    DOI:  https://doi.org/10.1016/j.livres.2020.12.002
  21. Int J Mol Sci. 2021 Jul 21. pii: 7791. [Epub ahead of print]22(15):
    P62 Links the Autophagy Pathway and the Ubiquitin-Proteasome System in Endothelial Cells during Atherosclerosis.
    SeJeong Kim, WoongJin Lee, KyoungJoo Cho.
      Among autophagy-related molecules, p62/SQSTM1 is an adaptor for identifying and delivering intracellular cargo for degradation. Since ubiquitination is reversible, it has a switch role in autophagy. Ubiquitination is also involved in regulating autophagy in a timely manner. This study aimed to elucidate how p62-mediated autophagy is regulated in human endothelial cells and macrophages under atherosclerotic conditions, focusing on the lysosomal and proteasomal pathways. Co-cultured HUVECs and THP-1 cells were exposed to oxLDL (50 μg/mL) and autophagy was assessed. To downregulate p62, siRNA was administered, and the E3 ligases were inhibited by Heclin or MLN4924 treatment under the condition that cellular inflammatory processes were stimulated by oxLDL simultaneously initiated autophagy. Downregulating p62 induced an alternative degradation system, and the E3 ligases were found to be involved in the progression of atherosclerosis. Collectively, the present study demonstrated that the endothelial lipid accumulation under atherosclerotic conditions was caused by lysosomal dysfunction associated with autophagy.
    Keywords:  E3 ligase; atherosclerosis; autophagy; endothelial cell; oxLDL
    DOI:  https://doi.org/10.3390/ijms22157791
  22. Biomolecules. 2021 Jul 04. pii: 985. [Epub ahead of print]11(7):
    TFEB Signalling-Related MicroRNAs and Autophagy.
    Davide Corà, Federico Bussolino, Gabriella Doronzo.
      The oncogenic Transcription Factor EB (TFEB), a member of MITF-TFE family, is known to be the most important regulator of the transcription of genes responsible for the control of lysosomal biogenesis and functions, autophagy, and vesicles flux. TFEB activation occurs in response to stress factors such as nutrient and growth factor deficiency, hypoxia, lysosomal stress, and mitochondrial damage. To reach the final functional status, TFEB is regulated in multimodal ways, including transcriptional rate, post-transcriptional regulation, and post-translational modifications. Post-transcriptional regulation is in part mediated by miRNAs. miRNAs have been linked to many cellular processes involved both in physiology and pathology, such as cell migration, proliferation, differentiation, and apoptosis. miRNAs also play a significant role in autophagy, which exerts a crucial role in cell behaviour during stress or survival responses. In particular, several miRNAs directly recognise TFEB transcript or indirectly regulate its function by targeting accessory molecules or enzymes involved in its post-translational modifications. Moreover, the transcriptional programs triggered by TFEB may be influenced by the miRNA-mediated regulation of TFEB targets. Finally, recent important studies indicate that the transcription of many miRNAs is regulated by TFEB itself. In this review, we describe the interplay between miRNAs with TFEB and focus on how these types of crosstalk affect TFEB activation and cellular functions.
    Keywords:  TFEB; autophagy; miRNA
    DOI:  https://doi.org/10.3390/biom11070985
  23. Autophagy. 2021 Aug 02. 1-17
    Exendin-4 stimulates autophagy in pancreatic β-cells via the RAPGEF/EPAC-Ca2+-PPP3/calcineurin-TFEB axis.
    Francesco P Zummo, Stanislaus I Krishnanda, Merilin Georgiou, Finbarr Pm O'Harte, Vadivel Parthsarathy, Kirsty S Cullen, Minna Honkanen-Scott, James Am Shaw, Penny E Lovat, Catherine Arden.
      Macroautophagy/autophagy is critical for the regulation of pancreatic β-cell mass and its deregulation has been implicated in the pathogenesis of type 2 diabetes (T2D). We have previously shown that treatment of pancreatic β-cells with the GLP1R (glucagon like peptide 1 receptor) agonist exendin-4 stimulates autophagic flux in a setting of chronic nutrient excess. The aim of this study was to identify the underlying pathways contributing to enhanced autophagic flux.Pancreatic β-cells (INS-1E),mouse and human islets were treated with glucolipotoxic stress (0.5 mM palmitate and 25 mM glucose) in the presence of exendin-4. Consistent with our previous work, exendin-4 stimulated autophagic flux. Using chemical inhibitors and siRNA knockdown, we identified RAPGEF4/EPAC2 (Rap guanine nucleotide exchange factor 4) and downstream calcium signaling to be essential for regulation of autophagic flux by exendin-4. This pathway was independent of AMPK and MTOR signaling. Further analysis identified PPP3/calcineurin and its downstream regulator TFEB (transcription factor EB) as key proteins mediating exendin-4 induced autophagy. Importantly, inhibition of this pathway prevented exendin-4-mediated cell survival and overexpression of TFEB mimicked the cell protective effects of exendin-4 in INS-1E and human islets. Moreover, treatment of db/db mice with exendin-4 for 21 days increased the expression of lysosomal markers within the pancreatic islets. Collectively our data identify the RAPGEF4/EPAC2-calcium-PPP3/calcineurin-TFEB axis as a key mediator of autophagic flux, lysosomal function and cell survival in pancreatic β-cells. Pharmacological modulation of this axis may offer a novel therapeutic target for the treatment of T2D.Abbreviations: AKT1/protein kinase B: AKT serine/threonine kinase 1; AMPK: 5' AMP-activated protein kinase; CAMKK: calcium/calmodulin-dependent protein kinase kinase; cAMP: cyclic adenosine monophosphate; CASP3: caspase 3; CREB: cAMP response element-binding protein; CTSD: cathepsin D; Ex4: exendin-4(1-39); GLP-1: glucagon like peptide 1; GLP1R: glucagon like peptide 1 receptor; GLT: glucolipotoxicity; INS: insulin; MTOR: mechanistic target of rapamycin kinase; NFAT: nuclear factor of activated T-cells; PPP3/calcineurin: protein phosphatase 3; PRKA/PKA: protein kinase cAMP activated; RAPGEF3/EPAC1: Rap guanine nucleotide exchange factor 3; RAPGEF4/EPAC2: Rap guanine nucleotide exchange factor 4; SQSTM1/p62: sequestosome 1; T2D: type 2 diabetes; TFEB: transcription factor EB.
    Keywords:  Autophagy; GLP1R agonists; PPP3/calcineurin; RAPGEF4; TFEB; diabetes; pancreatic β-cell
    DOI:  https://doi.org/10.1080/15548627.2021.1956123
  24. mSphere. 2021 Aug 04. e0054921
    Mycobacterium tuberculosis PE_PGRS20 and PE_PGRS47 Proteins Inhibit Autophagy by Interaction with Rab1A.
    Emily J Strong, Tony W Ng, Steven A Porcelli, Sunhee Lee.
      Autophagy is a fundamental cellular process that has important roles in innate and adaptive immunity against a broad range of microbes. Many pathogenic microbes have evolved mechanisms to evade or exploit autophagy. It has been previously demonstrated that induction of autophagy can suppress the intracellular survival of mycobacteria, and several PE_PGRS family proteins of Mycobacterium tuberculosis have been proposed to act as inhibitors of autophagy to promote mycobacterial survival. However, the mechanisms by which these effectors inhibit autophagy have not been defined. Here, we report detailed studies of M. tuberculosis deletion mutants of two genes, pe_pgrs20 and pe_pgrs47, that we previously reported as having a role in preventing autophagy of infected host cells. These mutants resulted in increased autophagy and reduced intracellular survival of M. tuberculosis in macrophages. This phenotype was accompanied by increased cytokine production and antigen presentation by infected cells. We further demonstrated that autophagy inhibition by PE_PGRS20 and PE_PGRS47 resulted from canonical autophagy rather than autophagy flux inhibition. Using macrophages transfected to express PE_PGRS20 or PE_PGRS47, we showed that these proteins inhibited autophagy initiation directly by interacting with Ras-related protein Rab1A. Silencing of Rab1A in mammalian cells rescued the survival defects of the pe_pgrs20 and pe_pgrs47 deletion mutant strains and reduced cytokine secretion. To our knowledge, this is the first study to identify mycobacterial effectors that directly interact with host proteins responsible for autophagy initiation. IMPORTANCE Tuberculosis is a significant global infectious disease caused by infection of the lungs with Mycobacterium tuberculosis, which then resides and replicates mainly within host phagocytic cells. Autophagy is a complex host cellular process that helps control intracellular infections and enhance innate and adaptive immune responses. During coevolution with humans, M. tuberculosis has acquired various mechanisms to inhibit host cellular processes, including autophagy. We identified two related M. tuberculosis proteins, PE_PGRS20 and PE_PGRS47, as the first reported examples of specific mycobacterial effectors interfering with the initiation stage of autophagy. Autophagy regulation by these PE_PGRS proteins leads to increased bacterial survival in phagocytic cells and increased autophagic degradation of mycobacterial antigens to stimulate adaptive immune responses. A better understanding of how M. tuberculosis regulates autophagy in host cells could facilitate the design of new and more effective therapeutics or vaccines against tuberculosis.
    Keywords:  Mycobacterium tuberculosis; PE_PGRS proteins; autophagy; host-pathogen interactions; innate immunity
    DOI:  https://doi.org/10.1128/mSphere.00549-21
  25. Mol Cell Biochem. 2021 Aug 03.
    Autophagy in Xp11 translocation renal cell carcinoma: from bench to bedside.
    Huimin Sun, Xing Wei, Changchun Zeng.
      Xp11 translocation renal cell carcinoma (tRCC) characterized by the rearrangement of the TFE3 is recently identified as a unique subtype of RCC that urgently requires effective prevention and treatment strategies. Therefore, determining suitable therapeutic targets and fully understanding the biological significance of tRCC is essential. The importance of autophagy is increasingly acknowledged because it shows carcinogenic activity or suppressor effect. Autophagy is a physiological cellular process critical to maintaining cell homeostasis, which is involved in the lysosomal degradation of cytoplasmic organelles and macromolecules via the lysosomal pathway, suggesting that targeting autophagy is a potential therapeutic approach for cancer therapies. However, the underlying mechanism of autophagy in tRCC is still ambiguous. In this review, we summarize the autophagy-related signaling pathways associated with tRCC. Moreover, we examine the roles of autophagy and the immune response in tumorigenesis and investigate how these factors interact to facilitate or prevent tumorigenesis. Besides, we review the findings regarding the treatment of tRCC via induction or inhibition of autophagy. Hopefully, this study will shed some light on the functions and implications of autophagy and emphasize its role as a potential molecular target for therapeutic intervention in tRCC.
    Keywords:  Autophagy; Mechanism; TFE3; Therapy; Xp11 translocation renal cell carcinoma
    DOI:  https://doi.org/10.1007/s11010-021-04235-w
  26. FEBS Open Bio. 2021 Aug 04.
    Tomatidine provides mitophagy-independent neuroprotection after ischemic injury.
    Yu-Ting Wang, Li-Na Zhang, Xiao-Cui Lyu, Yue Li, Anil Ahsan, Zikai Feng, Xiangnan Zhang.
      Cerebral ischemia is one of the leading causes of human mortality and disability worldwide. The treatment of cerebral ischemia is refractory due to its short therapeutic window and lack of effective clinical drugs. Mitophagy, the autophagic elimination of damaged mitochondria, attenuates neuronal injury in cerebral ischemia, indicating the potential of mitophagy inducers as therapies for cerebral ischemia. We previously determined that, by enhancing autophagy flux, the steroidal alkaloid tomatidine can function as a neuroprotective agent against ischemic injury. However, its effects on mitophagy remain unknown. For this purpose, neuroblastoma cell lines Neuro-2a (N2a) and SH-SY5Y were subjected to ischemic injury induced by oxygen-glucose deprivation/reperfusion (OGD/R), then treated with tomatidine. OGD/R induced a general decrease of cellular contents, and the present study revealed that tomatidine had no impact on mitophagy. In addition, tomatidine did not affect mitochondrial contents, including translocase of outer mitochondrial membrane 20 (TOM20) and voltage-dependent anion channel 1 (VDAC1), in either OGD/R-treated or intact SH-SY5H cells. Our results indicate that tomatidine exhibits its neuroprotective effects by enhancing autophagy but potentially mitophagy-independent manner, and provide insights for further investigation into its mechanism(s) and potential therapeutic use against cerebral ischemia.
    Keywords:  autophagy; cerebral ischemia; mitophagy; tomatidine
    DOI:  https://doi.org/10.1002/2211-5463.13265
  27. Cell Rep. 2021 Aug 03. pii: S2211-1247(21)00918-9. [Epub ahead of print]36(5): 109491
    Exocyst protein subnetworks integrate Hippo and mTOR signaling to promote virus detection and cancer.
    Aubhishek Zaman, Xiaofeng Wu, Andrew Lemoff, Sivaramakrishna Yadavalli, Jeon Lee, Chensu Wang, Jonathan Cooper, Elizabeth A McMillan, Charles Yeaman, Hamid Mirzaei, Michael A White, Trever G Bivona.
      The exocyst is an evolutionarily conserved protein complex that regulates vesicular trafficking and scaffolds signal transduction. Key upstream components of the exocyst include monomeric RAL GTPases, which help mount cell-autonomous responses to trophic and immunogenic signals. Here, we present a quantitative proteomics-based characterization of dynamic and signal-dependent exocyst protein interactomes. Under viral infection, an Exo84 exocyst subcomplex assembles the immune kinase Protein Kinase R (PKR) together with the Hippo kinase Macrophage Stimulating 1 (MST1). PKR phosphorylates MST1 to activate Hippo signaling and inactivate Yes Associated Protein 1 (YAP1). By contrast, a Sec5 exocyst subcomplex recruits another immune kinase, TANK binding kinase 1 (TBK1), which interacted with and activated mammalian target of rapamycin (mTOR). RALB was necessary and sufficient for induction of Hippo and mTOR signaling through parallel exocyst subcomplex engagement, supporting the cellular response to virus infection and oncogenic signaling. This study highlights RALB-exocyst signaling subcomplexes as mechanisms for the integrated engagement of Hippo and mTOR signaling in cells challenged by viral pathogens or oncogenic signaling.
    Keywords:  Hippo pathway; PKR; RAL; TBK1; autophagy; cancer cell survival; exocyst; innate immune signaling; mTOR; virus
    DOI:  https://doi.org/10.1016/j.celrep.2021.109491
  28. Aging Dis. 2021 Aug;12(5): 1287-1303
    Self-eating and Heart: The Emerging Roles of Autophagy in Calcific Aortic Valve Disease.
    Yunlong Fan, Jiakang Shao, Shixiong Wei, Chao Song, Yanan Li, Shengli Jiang.
      Autophagy is a self-degradative pathway by which subcellular elements are broken down intracellularly to maintain cellular homeostasis. Cardiac autophagy commonly decreases with aging and is accompanied by the accumulation of misfolded proteins and dysfunctional organelles, which are undesirable to the cell. Reduction of autophagy over time leads to aging-related cardiac dysfunction and is inversely related to longevity. However, despite the increasing interest in autophagy in cardiac diseases and aging, the process remains an undervalued and disregarded object in calcific valvular disease. Neither the nature through which autophagy is triggered nor the interplay between autophagic machinery and targeted molecules during aortic valve calcification are fully understood. Recently, the upregulation of autophagy has been shown to result in cardioprotective effects against cell death as well as its origin. Here, we review the evidence that shows how autophagy can be both beneficial and detrimental as it pertains to aortic valve calcification in the heart.
    Keywords:  autophagy; calcific aortic valve disease; calcification; cell death; heart aging
    DOI:  https://doi.org/10.14336/AD.2021.0101
  29. Mol Biol Rep. 2021 Aug 06.
    The PI3K/AKT/mTOR signaling pathway inhibitors enhance radiosensitivity in cancer cell lines.
    Alireza Mardanshahi, Nasrin Abbasi Gharibkandi, Samaneh Vaseghi, Seyed Mohammad Abedi, Sajjad Molavipordanjani.
      INTRODUCTION: Radiotherapy is one of the most common types of cancer treatment modalities. Radiation can affect both cancer and normal tissues, which limits the whole delivered dose. It is well documented that radiation activates phosphatidylinositol 3-kinase (PI3K) and AKT signaling pathway; hence, the inhibition of this pathway enhances the radiosensitivity of tumor cells. The mammalian target of rapamycin (mTOR) is a regulator that is involved in autophagy, cell growth, proliferation, and survival.CONCLUSION: The inhibition of mTOR as a downstream mediator of the PI3K/AKT signaling pathway represents a vital option for more effective cancer treatments. The combination of PI3K/AKT/mTOR inhibitors with radiation can increase the radiosensitivity of malignant cells to radiation by autophagy activation. Therefore, this review aims to discuss the impact of such inhibitors on the cell response to radiation.
    Keywords:  Inhibitor; PI3K/AKT; Radiation; Radiosensitivity; mTOR
    DOI:  https://doi.org/10.1007/s11033-021-06607-3
  30. Cells. 2021 Jul 20. pii: 1839. [Epub ahead of print]10(7):
    BNIP3-Dependent Mitophagy via PGC1α Promotes Cartilage Degradation.
    Deokha Kim, Jinsoo Song, Eun-Jung Jin.
      Since mitochondria are suggested to be important regulators in maintaining cartilage homeostasis, turnover of mitochondria through mitochondrial biogenesis and mitochondrial degradation may play an important role in the pathogenesis of osteoarthritis (OA). Here, we found that mitochondrial dysfunction is closely associated with OA pathogenesis and identified the peroxisome proliferator-activated receptor-gamma co-activator 1-alpha (PGC1α) as a potent regulator. The expression level of PGC1α was significantly decreased under OA conditions, and knockdown of PGC1α dramatically elevated the cartilage degradation by upregulating cartilage degrading enzymes and apoptotic cell death. Interestingly, the knockdown of PGC1α activated the parkin RBR E3 ubiquitin protein ligase (PRKN)-independent selective mitochondria autophagy (mitophagy) pathway through the upregulation of BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (BNIP3). The overexpression of BNIP3 stimulated mitophagy and cartilage degradation by upregulating cartilage-degrading enzymes and chondrocyte death. We identified microRNA (miR)-126-5p as an upstream regulator for PGC1α and confirmed the direct binding between miR-126-5p and 3' untranslated region (UTR) of PGC1α. An in vivo OA mouse model induced by the destabilization of medial meniscus (DMM) surgery, and the delivery of antago-miR-126 via intra-articular injection significantly decreased cartilage degradation. In sum, the loss of PGC1α in chondrocytes due to upregulation of miR-126-5p during OA pathogenesis resulted in the activation of PRKN-independent mitophagy through the upregulation of BNIP3 and stimulated cartilage degradation and apoptotic death of chondrocytes. Therefore, the regulation of PGC1α:BNIP3 mitophagy axis could be of therapeutic benefit to cartilage-degrading diseases.
    Keywords:  BNIP3; PGC1A; autophagy; miR-126-5p; mitophagy; osteoarthritis
    DOI:  https://doi.org/10.3390/cells10071839
  31. Int J Mol Sci. 2021 Jul 27. pii: 8019. [Epub ahead of print]22(15):
    Rapamycin Plus Doxycycline Combination Affects Growth Arrest and Selective Autophagy-Dependent Cell Death in Breast Cancer Cells.
    Titanilla Dankó, Gábor Petővári, Dániel Sztankovics, Dorottya Moldvai, Regina Raffay, Péter Lőrincz, Tamás Visnovitz, Viktória Zsiros, Gábor Barna, Ágnes Márk, Ildikó Krencz, Anna Sebestyén.
      Metabolic alteration is characteristic during tumour growth and therapy; however, targeting metabolic rewiring could overcome therapy resistance. mTOR hyperactivity, autophagy and other metabolic processes, including mitochondrial functions, could be targeted in breast cancer progression. We investigated the growth inhibitory mechanism of rapamycin + doxycycline treatment in human breast cancer model systems. Cell cycle and cell viability, including apoptotic and necrotic cell death, were analysed using flow cytometry, caspase activity measurements and caspase-3 immunostainings. mTOR-, autophagy-, necroptosis-related proteins and treatment-induced morphological alterations were analysed by WesTM, Western blot, immunostainings and transmission electron microscopy. The rapamycin + doxycycline combination decreased tumour proliferation in about 2/3rd of the investigated cell lines. The continuous treatment reduced tumour growth significantly both in vivo and in vitro. The effect after short-term treatment was reversible; however, autophagic vacuoles and degrading mitochondria were detected simultaneously, and the presence of mitophagy was also observed after the long-term rapamycin + doxycycline combination treatment. The rapamycin + doxycycline combination did not cause apoptosis or necrosis/necroptosis, but the alterations in autophagy- and mitochondria-related protein levels (LC3-B-II/I, p62, MitoTracker, TOM20 and certain co-stainings) were correlated to autophagy induction and mitophagy, without mitochondria repopulation. Based on these results, we suggest considering inducing metabolic stress and targeting mTOR hyperactivity and mitochondrial functions in combined anti-cancer treatments.
    Keywords:  autophagy; cell death; doxycycline; mitophagy; rapamycin; tumour growth
    DOI:  https://doi.org/10.3390/ijms22158019
  32. Biomolecules. 2021 Jul 09. pii: 1002. [Epub ahead of print]11(7):
    Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways.
    Kenneth Maiese.
      Neurodegenerative disorders affect fifteen percent of the world's population and pose a significant financial burden to all nations. Cognitive impairment is the seventh leading cause of death throughout the globe. Given the enormous challenges to treat cognitive disorders, such as Alzheimer's disease, and the inability to markedly limit disease progression, circadian clock gene pathways offer an exciting strategy to address cognitive loss. Alterations in circadian clock genes can result in age-related motor deficits, affect treatment regimens with neurodegenerative disorders, and lead to the onset and progression of dementia. Interestingly, circadian pathways hold an intricate relationship with autophagy, the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), and the trophic factor erythropoietin. Autophagy induction is necessary to maintain circadian rhythm homeostasis and limit cortical neurodegenerative disease, but requires a fine balance in biological activity to foster proper circadian clock gene regulation that is intimately dependent upon mTOR, SIRT1, FoxOs, and growth factor expression. Circadian rhythm mechanisms offer innovative prospects for the development of new avenues to comprehend the underlying mechanisms of cognitive loss and forge ahead with new therapeutics for dementia that can offer effective clinical treatments.
    Keywords:  Alzheimer’s disease; FoxO; Parkinson’s disease; autophagy; circadian rhythm; dementia; erythropoietin; forkhead; glymphatic pathway; mechanistic target of rapamycin (mTOR); silent mating type information regulation 2 homolog 1; sleep fragmentation
    DOI:  https://doi.org/10.3390/biom11071002
  33. Int J Mol Sci. 2021 Jul 23. pii: 7869. [Epub ahead of print]22(15):
    Potential Therapeutic Approaches through Modulating the Autophagy Process for Skin Barrier Dysfunction.
    Min Sik Choi, Yoon-Jee Chae, Ji Woong Choi, Ji-Eun Chang.
      Autophagy is an attractive process to researchers who are seeking novel potential treatments for various diseases. Autophagy plays a critical role in degrading damaged cellular organelles, supporting normal cell development, and maintaining cellular homeostasis. Because of the various effects of autophagy, recent human genome research has focused on evaluating the relationship between autophagy and a wide variety of diseases, such as autoimmune diseases, cancers, and inflammatory diseases. The skin is the largest organ in the body and provides the first line of defense against environmental hazards, including UV damage, chemical toxins, injuries, oxidative stress, and microorganisms. Autophagy takes part in endogenous defense mechanisms by controlling skin homeostasis. In this manner, regulating autophagy might contribute to the treatment of skin barrier dysfunctions. Various studies are ongoing to elucidate the association between autophagy and skin-related diseases in order to find potential therapeutic approaches. However, little evidence has been gathered about the relationship between autophagy and the skin. In this review, we highlight the previous findings of autophagy and skin barrier disorders and suggest potential therapeutic strategies. The recent research regarding autophagy in acne and skin aging is also discussed.
    Keywords:  acne; autophagy; infectious skin diseases; psoriasis; skin aging; skin barrier dysfunction; skin cancer; vitiligo
    DOI:  https://doi.org/10.3390/ijms22157869
  34. Exp Gerontol. 2021 Aug 03. pii: S0531-5565(21)00290-4. [Epub ahead of print] 111508
    Mitophagy: At the heart of mitochondrial quality control in cardiac aging and frailty.
    Anna Picca, Riccardo Calvani, Hélio José Coelho-Júnior, Emanuele Marzetti.
      Cardiovascular disease is highly prevalent among older adults and poses a huge burden on morbidity, disability, and mortality. The age-related increased vulnerability of the cardiovascular system towards stressors is as a pathophysiological trait of cardiovascular disease. This has been associated with a progressive deterioration of blood vessels and decline in heart function during aging. Cardiomyocytes rely mostly on oxidative metabolism for deploying their activities and mitochondrial metabolism is crucial to this purpose. Dysmorphic, inefficient, and oxidant-producing mitochondria have been identified in aged cardiomyocytes in the setting of cardiac structural and functional alterations. These aberrant organelles are thought to arise from inefficient mitochondrial quality control, which has therefore been place in the spotlight as a relevant mechanism of cardiac aging. As a result of alterations in mitochondrial quality control and imbalanced oxidant defense, mitochondrial damage accumulates and contributes to cardiac frailty. Herein, we discuss the contribution of defective mitochondrial quality control pathways to cardiac frailty. Emerging findings pointing towards the exploitation of these pathways as therapeutic targets against cardiac aging and cardiovascular disease will also be illustrated.
    Keywords:  Autophagy; Cardioprotection; Extracellular vesicles; Mitochondrial derived vesicles; Mitochondrial quality control; Therapeutics
    DOI:  https://doi.org/10.1016/j.exger.2021.111508
  35. Cells. 2021 Jul 03. pii: 1682. [Epub ahead of print]10(7):
    Melatonin Treatment Improves Renal Fibrosis via miR-4516/SIAH3/PINK1 Axis.
    Yeo Min Yoon, Gyeongyun Go, Sungtae Yoon, Ji Ho Lim, Gaeun Lee, Jun Hee Lee, Sang Hun Lee.
      Dysregulation in mitophagy, in addition to contributing to imbalance in the mitochondrial dynamic, has been implicated in the development of renal fibrosis and progression of chronic kidney disease (CKD). However, the current understanding of the precise mechanisms behind the pathogenic loss of mitophagy remains unclear for developing cures for CKD. We found that miR-4516 is downregulated and its target SIAH3, an E3 ubiquitin protein ligase that reduces PINK1 accumulation to damaged mitochondria, is upregulated in the renal cortex of CKD mice. Here, we demonstrated that melatonin injection induces miR-4516 expression and suppresses SIAH3, and promotes PINK1/Parkin-mediated mitophagy. Furthermore, we demonstrated that melatonin injection attenuates the pathological features of CKD by improving mitochondrial homeostasis. Our data supports that mitochondrial autophagy regulation by activating miR-4516/SIAH3/PINK1 mitophagy signaling axis can be a viable new strategy for treating CKD.
    Keywords:  PINK1; SIAH3; chronic kidney disease; melatonin; miR-4516; mitophagy; renal fibrosis
    DOI:  https://doi.org/10.3390/cells10071682
  36. Gene. 2021 Aug 02. pii: S0378-1119(21)00460-1. [Epub ahead of print] 145865
    RNA-Dependent Protein Kinase is Required for Interferon-γ-induced Autophagy in MG63 Osteosarcoma Cells.
    Jie Xu, Yuqing Ji, Kristen L Shogren, Scott H Okuno, Michael J Yaszemski, Avudaiappan Maran.
      Osteosarcoma is a bone tumor that mainly affects children and adolescents. Interferons (IFNs) have been shown to exert antitumor effects in osteosarcoma cells, although the molecular mechanisms have not been fully realized. We investigated IFN-γ actions on osteosarcoma cells. Our results show that IFN-γ induces the accumulation of autophagosomes in osteosarcoma cells. IFN-γ treatment leads to the conversion of autophagy marker light chain 3 (LC3)-I to LC3-II in osteosarcoma cells, and this conversion is accompanied by puncta formation. Also, IFN-γ-mediated induction of autophagosome formation and autophagic flux require RNA-dependent protein kinase (PKR) activity. In addition, our findings show that IFN-γ-mediated osteosarcoma cell death is not dependent on PKR. Our study suggests that IFN-γ has differential effects that lead to induction of cell death and autophagy in osteosarcoma cells. Further evaluation of the IFN-γ-mediated molecular mechanism could lead to improved understanding of and targeted treatment strategies for osteosarcoma.
    Keywords:  PKR; autophagy; interferon-γ; osteosarcoma
    DOI:  https://doi.org/10.1016/j.gene.2021.145865
  37. Redox Biol. 2021 Jul 24. pii: S2213-2317(21)00240-8. [Epub ahead of print]46 102081
    H2O2-mediated autophagy during ethanol metabolism.
    Cheng Chen, Shijin Wang, Linna Yu, Johannes Mueller, Franco Fortunato, Vanessa Rausch, Sebastian Mueller.
      BACKGROUND: Alcoholic liver disease (ALD) is the most common liver disease worldwide and its underlying molecular mechanisms are still poorly understood. Moreover, conflicting data have been reported on potentially protective autophagy, the exact role of ethanol-metabolizing enzymes and ROS.METHODS: Expression of LC3B, CYP2E1, and NOX4 was studied in a mouse model of acute ethanol exposure by immunoblotting and immunohistochemistry. Autophagy was further studied in primary mouse hepatocytes and huh7 cells in response to ethanol and its major intermediator acetaldehyde. Experiments were carried out in cells overexpressing CYP2E1 and knock down of NOX4 using siRNA. The response to external H2O2 was studied by using the GOX/CAT system. Autophagic flux was monitored using the mRFP-GFP-LC3 plasmid, while rapamycin and chloroquine served as positive and negative controls.
    RESULTS: Acute ethanol exposure of mice over 24 h significantly induced autophagy as measured by LC3B expression but also induced the ROS-generating CYP2E1 and NOX4 enzymes. Notably, ethanol but not its downstream metabolite acetaldehyde induced autophagy in primary mouse hepatocytes. In contrast, autophagy could only be induced in huh7 cells in the presence of overexpressed CYP2E1. In addition, overexpression of NOX4 also significantly increased autophagy, which could be blocked by siRNA mediated knock down. The antioxidant N-acetylcysteine (NAC) also efficiently blocked CYP2E1-and NOX4-mediated induction of autophagy. Finally, specific and non-toxic production of H2O2 by the GOX/CAT system as evidenced by elevated peroxiredoxin (Prx-2) also induced LC3B which was efficiently blocked by NAC. H2O2 strongly increased the autophagic flux as measured by mRFP-GFP-LC3 plasmid.
    CONCLUSION: We here provide evidence that short-term ethanol exposure induces autophagy in hepatocytes both in vivo and in vitro through the generation of ROS. These data suggest that suppression of autophagy by ethanol is most likely due to longer alcohol exposure during chronic alcohol consumption with the accumulation of e.g. misfolded proteins.
    Keywords:  Alcohol liver disease (ALD); Cytochrome P450 2E1(CYP2E1); Ethanol metabolism; Hydrogen peroxide (H(2)O(2)); NADPH oxidase (NOX); Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.redox.2021.102081
  38. Int J Mol Sci. 2021 Jul 30. pii: 8180. [Epub ahead of print]22(15):
    Mitochondrial Modulations, Autophagy Pathways Shifts in Viral Infections: Consequences of COVID-19.
    Shailendra Pratap Singh, Salomon Amar, Pinky Gehlot, Sanjib K Patra, Navjot Kanwar, Abhinav Kanwal.
      Mitochondria are vital intracellular organelles that play an important role in regulating various intracellular events such as metabolism, bioenergetics, cell death (apoptosis), and innate immune signaling. Mitochondrial fission, fusion, and membrane potential play a central role in maintaining mitochondrial dynamics and the overall shape of mitochondria. Viruses change the dynamics of the mitochondria by altering the mitochondrial processes/functions, such as autophagy, mitophagy, and enzymes involved in metabolism. In addition, viruses decrease the supply of energy to the mitochondria in the form of ATP, causing viruses to create cellular stress by generating ROS in mitochondria to instigate viral proliferation, a process which causes both intra- and extra-mitochondrial damage. SARS-COV2 propagates through altering or changing various pathways, such as autophagy, UPR stress, MPTP and NLRP3 inflammasome. Thus, these pathways act as potential targets for viruses to facilitate their proliferation. Autophagy plays an essential role in SARS-COV2-mediated COVID-19 and modulates autophagy by using various drugs that act on potential targets of the virus to inhibit and treat viral infection. Modulated autophagy inhibits coronavirus replication; thus, it becomes a promising target for anti-coronaviral therapy. This review gives immense knowledge about the infections, mitochondrial modulations, and therapeutic targets of viruses.
    Keywords:  COVID-19; SARS-COV2; autophagy; mitochondria; potential targets; viral infections
    DOI:  https://doi.org/10.3390/ijms22158180
  39. Front Immunol. 2021 ;12 685523
    p53 Deacetylation Alleviates Sepsis-Induced Acute Kidney Injury by Promoting Autophagy.
    Maomao Sun, Jiaxin Li, Liangfeng Mao, Jie Wu, Zhiya Deng, Man He, Sheng An, Zhenhua Zeng, Qiaobing Huang, Zhongqing Chen.
      Recent studies have shown that autophagy upregulation can attenuate sepsis-induced acute kidney injury (SAKI). The tumor suppressor p53 has emerged as an autophagy regulator in various forms of acute kidney injury (AKI). Our previous studies showed that p53 acetylation exacerbated hemorrhagic shock-induced AKI and lipopolysaccharide (LPS)-induced endothelial barrier dysfunction. However, the role of p53-regulated autophagy in SAKI has not been examined and requires clarification. In this study, we observed the dynamic changes of autophagy in renal tubular epithelial cells (RTECs) and verified the protective effects of autophagy activation on SAKI. We also examined the changes in the protein expression, intracellular distribution (nuclear and cytoplasmic), and acetylation/deacetylation levels of p53 during SAKI following cecal ligation and puncture (CLP) or LPS treatment in mice and in a LPS-challenged human RTEC cell line (HK-2 cells). After sepsis stimulation, the autophagy levels of RTECs increased temporarily, followed by a sharp decrease. Autophagy inhibition was accompanied by an increased renal tubular injury score. By contrast, autophagy agonists could reduce renal tubular damage following sepsis. Surprisingly, the expression of p53 protein in both the renal cortex and HK-2 cells did not significantly change following sepsis stimulation. However, the translocation of p53 from the nucleus to the cytoplasm increased, and the acetylation of p53 was enhanced. In the mechanistic study, we found that the induction of p53 deacetylation, due to either the resveratrol/quercetin -induced activation of the deacetylase Sirtuin 1 (Sirt1) or the mutation of the acetylated lysine site in p53, promoted RTEC autophagy and alleviated SAKI. In addition, we found that acetylated p53 was easier to bind with Beclin1 and accelerated its ubiquitination-mediated degradation. Our study underscores the importance of deacetylated p53-mediated RTEC autophagy in future SAKI treatments.
    Keywords:  acute kidney injury; autophagy; deacetylation; p53; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2021.685523
  40. J Cell Sci. 2021 Aug 05. pii: jcs.258566. [Epub ahead of print]
    S-Palmitoylation determines TMEM55B-dependent positioning of lysosomes.
    Sönke Rudnik, Saskia Heybrock, Paul Saftig, Markus Damme.
      The spatio-temporal cellular distribution of lysosomes depends on active transport mainly driven by microtubule-motors such as kinesins and dynein. Different protein complexes attach these molecular motors to their vesicular cargo: TMEM55B, as an integral lysosomal membrane protein, is a component of such a complex mediating the retrograde transport of lysosomes by establishing an interaction with the cytosolic scaffold protein JIP4 and dynein/dynactin. Here we show that TMEM55B and its paralog TMEM55A are S-palmitoylated proteins and lipidated at multiple cysteine-residues. Mutation of all cysteines in TMEM55B prevents S-palmitoylation and causes the retention of the mutated protein in the Golgi-apparatus. Consequently, non-palmitoylated TMEM55B is no longer able to modulate lysosomal positioning and the perinuclear clustering of lysosomes. Additional mutagenesis of the dileucine-based lysosomal sorting motif in non-palmitoylated TMEM55B leads to partial missorting to the plasma membrane instead of retention in the Golgi, implicating a direct effect of S-palmitoylation on the adaptor-protein-dependent sorting of TMEM55B. Our data suggest a critical role of S-palmitoylation on the trafficking of TMEM55B and TMEM55B-dependent lysosomal positioning.
    Keywords:  Acyl-RAC; Lysosomal positioning; S-palmitoylation; TMEM55A; TMEM55B
    DOI:  https://doi.org/10.1242/jcs.258566
  41. Oxid Med Cell Longev. 2021 ;2021 5583215
    Reactive Oxygen Species as a Link between Antioxidant Pathways and Autophagy.
    Dan Li, Zongxian Ding, Kaili Du, Xiangshi Ye, Shixue Cheng.
      Reactive oxygen species (ROS) are highly reactive molecules that can oxidize proteins, lipids, and DNA. Under physiological conditions, ROS are mainly generated in the mitochondria during aerobic metabolism. Under pathological conditions, excessive ROS disrupt cellular homeostasis. High levels of ROS result in severe oxidative damage to the cellular machinery. However, a low/mild level of ROS could serve as a signal to trigger cell survival mechanisms. To prevent and cope with oxidative damage to biomolecules, cells have developed various antioxidant and detoxifying mechanisms. Meanwhile, ROS can initiate autophagy, a process of self-clearance, which helps to reduce oxidative damage by engulfing and degrading oxidized substance. This review summarizes the interactions among ROS, autophagy, and antioxidant pathways. The effects of natural phytochemicals on autophagy induction, antioxidation, and dual-function are also discussed.
    DOI:  https://doi.org/10.1155/2021/5583215
  42. Int J Mol Sci. 2021 Jul 30. pii: 8179. [Epub ahead of print]22(15):
    Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging.
    Jean-Philippe Leduc-Gaudet, Sabah N A Hussain, Esther Barreiro, Gilles Gouspillou.
      The maintenance of mitochondrial integrity is critical for muscle health. Mitochondria, indeed, play vital roles in a wide range of cellular processes, including energy supply, Ca2+ homeostasis, retrograde signaling, cell death, and many others. All mitochondria-containing cells, including skeletal muscle cells, dispose of several pathways to maintain mitochondrial health, including mitochondrial biogenesis, mitochondrial-derived vesicles, mitochondrial dynamics (fusion and fission process shaping mitochondrial morphology), and mitophagy-the process in charge of the removal of mitochondria though autophagy. The loss of skeletal muscle mass (atrophy) is a major health problem worldwide, especially in older people. Currently, there is no treatment to counteract the progressive decline in skeletal muscle mass and strength that occurs with aging, a process termed sarcopenia. There is increasing data, including our own, suggesting that accumulation of dysfunctional mitochondria contributes to the development of sarcopenia. Impairments in mitochondrial dynamics and mitophagy were recently proposed to contribute to sarcopenia. This review summarizes the current state of knowledge on the role played by mitochondrial dynamics and mitophagy in skeletal muscle health and in the development of sarcopenia. We also highlight recent studies showing that enhancing mitophagy in skeletal muscle is a promising therapeutic target to prevent or even treat skeletal muscle dysfunction in the elderly.
    Keywords:  aging; autophagy; mitochondrial dynamics; mitophagy; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms22158179
  43. Aging Cell. 2021 Aug 06. e13447
    Ouabain and chloroquine trigger senolysis of BRAF-V600E-induced senescent cells by targeting autophagy.
    Valentin L'Hôte, Régis Courbeyrette, Guillaume Pinna, Jean-Christophe Cintrat, Gwenaëlle Le Pavec, Agnès Delaunay-Moisan, Carl Mann, Jean-Yves Thuret.
      The expression of BRAF-V600E triggers oncogene-induced senescence in normal cells and is implicated in the development of several cancers including melanoma. Here, we report that cardioglycosides such as ouabain are potent senolytics in BRAF senescence. Sensitization by ATP1A1 knockdown and protection by supplemental potassium showed that senolysis by ouabain was mediated by the Na,K-ATPase pump. Both ion transport inhibition and signal transduction result from cardioglycosides binding to Na,K-ATPase. An inhibitor of the pump that does not trigger signaling was not senolytic despite blocking ion transport, demonstrating that signal transduction is required for senolysis. Ouabain triggered the activation of Src, p38, Akt, and Erk in BRAF-senescent cells, and signaling inhibitors prevented cell death. The expression of BRAF-V600E increased ER stress and autophagy in BRAF-senescent cells and sensitized the cell to senolysis by ouabain. Ouabain inhibited autophagy flux, which was restored by signaling inhibitors. Consequently, we identified autophagy inhibitor chloroquine as a novel senolytic in BRAF senescence based on the mode of action of cardioglycosides. Our work underlies the interest of characterizing the mechanisms of senolytics to discover novel compounds and identifies the endoplasmic reticulum stress-autophagy tandem as a new vulnerability in BRAF senescence that can be exploited for the development of further senolytic strategies.
    Keywords:  Na,K-ATPase; Src; cardioglycosides; cellular senescence; endoplasmic reticulum stress; melanoma; senolytic
    DOI:  https://doi.org/10.1111/acel.13447
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