bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2021‒05‒30
47 papers selected by
Viktor Korolchuk, Newcastle University
  1. Autophagy in metabolism and quality control: opposing, complementary or interlinked functions?
  2. SAMM50 acts with p62 in piecemeal basal- and OXPHOS-induced mitophagy of SAM and MICOS components.
  3. Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels.
  4. Small but mighty: Atg8s and Rabs in Membrane Dynamics during Autophagy.
  5. Atg32 dependent mitophagy sustains spermidine and nitric oxide required for heat stress tolerance in S. cerevisiae.
  6. Cdc14 phosphatase downmodulates ESCRT-0 complex formation on vacuolar membranes and microautophagy after TORC1 inactivation.
  7. Monitoring PINK1-Parkin Signaling Using Dopaminergic Neurons from iPS Cells.
  8. Emerging roles of ATG proteins and membrane lipids in autophagosome formation.
  9. A unique COPII population in plant autophagy.
  10. TDP-43 proteinopathy occurs independently of autophagic substrate accumulation and underlies nuclear defects in Niemann-Pick C disease.
  11. Yeast mitophagy: Unanswered questions.
  12. The P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2.
  13. The autophagy protein Becn1 improves insulin sensitivity by promoting adiponectin secretion via exocyst binding.
  14. Cellular functions regulated by deubiquitinating enzymes in neurodegenerative diseases.
  15. Small molecule probes for targeting autophagy.
  16. Casting iron into the cell fate mold.
  17. The Rab7 effector WDR91 promotes autophagy-lysosome degradation in neurons by regulating lysosome fusion.
  18. Enrichment of NPC1-deficient cells with the lipid LBPA stimulates autophagy, improves lysosomal function, and reduces cholesterol storage.
  19. A mTORC1-mediated cyst(e)ine sensing mechanism governing GPX4 synthesis and ferroptosis.
  20. Cell type-specific YAP1-WWTR1/TAZ transcriptional responses after autophagy perturbations are determined by levels of α-catenins (CTNNA1 and CTNNA3).
  21. CERKL, a retinal dystrophy gene, regulates mitochondrial function and dynamics in the mammalian retina.
  22. Regulation of autophagy by VPS34 branched ubiquitination controls proteostasis and liver metabolism.
  23. TORC2 inhibition of α-arrestin Aly3 mediates cell surface persistence of S. pombe Ght5 glucose transporter in low glucose.
  24. The role of OFD1 in selective autophagy.
  25. Compound essential oils relieve oxidative stress caused by PM2 .5 exposure by inhibiting autophagy through the AMPK/mTOR pathway.
  26. Transcription- and phosphorylation-dependent control of a functional interplay between XBP1s and PINK1 governs mitophagy and potentially impacts Parkinson disease pathophysiology.
  27. HMGB1 downregulation in retinal pigment epithelial cells protects against diabetic retinopathy through the autophagy-lysosome pathway.
  28. Advanced oxidation protein products impair autophagic flux in macrophage by inducing lysosomal dysfunction via activation of PI3K-Akt-mTOR pathway in Crohn's disease.
  29. Understanding amphisomes.
  30. Lysosome positioning and mTOR activity in Lowe syndrome.
  31. A conserved klo-1-mpk-1 pathway regulates autophagy and modulates longevity in Caenorhabditis elegans.
  32. The mitochondrial fission factor FIS1 promotes stemness of human lung cancer stem cells via mitophagy.
  33. Targeting one-carbon metabolism requires mTOR inhibition: a new therapeutic approach in osteosarcoma.
  34. Autophagy-related genes serve as heat shock protein 90 co-chaperones in disease resistance against cassava bacterial blight.
  35. The ubiquitin-proteasome system and autophagy: self-digestion for metabolic health.
  36. Chronic cold exposure induces autophagy to promote fatty acid oxidation, mitochondrial turnover, and thermogenesis in brown adipose tissue.
  37. The therapeutic effect of TBK1 in intervertebral disc degeneration via coordinating selective autophagy and autophagic functions.
  38. Dual regulation of fatty acid synthase (FASN) expression by O-GlcNAc transferase (OGT) and mTOR pathway in proliferating liver cancer cells.
  39. In vivo genome-wide CRISPR screen reveals breast cancer vulnerabilities and synergistic mTOR/Hippo targeted combination therapy.
  40. Acetylation-dependent regulation of TPD52 isoform 1 modulates chaperone-mediated autophagy in prostate cancer.
  41. Placental mTOR-Complex1 regulates fetal programming of obesity and insulin resistance in mice.
  42. Endoplasmic Reticulum (ER) and ER-Phagy.
  43. Mitochondrial Fusion Protein Mfn2 and Its Role in Heart Failure.
  44. Regulation of nuclear mTORC1.
  45. AMPK: Potential Therapeutic Target for Vascular Calcification.
  46. Autophagy deficiency downregulates O6methylguanine-DNA methyltransferase and increases chemosensitivity of liver cancer cells.
  47. Compromised autophagy.
  1. Autophagy. 2021 May 26.
    Autophagy in metabolism and quality control: opposing, complementary or interlinked functions?
    Vojo Deretic, Guido Kroemer.
      The sensu stricto autophagy, macroautophagy, is considered to be both a metabolic process as well as a bona fide quality control process. The question as to how these two aspects of autophagy are coordinated and whether and why they overlap has implications for fundamental aspects, pathophysiological effects, and pharmacological manipulation of autophagy. At the top of the regulatory cascade controlling autophagy are master regulators of cellular metabolism, such as MTOR and AMPK, which render the system responsive to amino acid and glucose starvation. At the other end exists a variety of specific autophagy receptors, engaged in the selective removal of a diverse array of intracellular targets, from protein aggregates/condensates to whole organelles such as mitochondria, ER, peroxisomes, lysosomes and lipid droplets. Are the roles of autophagy in metabolism and quality control mutually exclusive, independent or interlocked? How are priorities established? What are the molecular links between both phenomena? This article will provide a starting point to formulate these questions, the responses to which should be taken into consideration in future autophagy-based interventions.
    Keywords:  AMPK; ATG; Aging; Akt; Alzheimer’s disease; ESCRT; FOXO; LC3; MTOR; NAD; NASH; Obesity; Parkinson’s Disease; RagA/B; SIRT1; SIRT3; Selective autophagy; TBK1; TCA; TFEB; Tor; acetyl CoA; autophagy; calcienurin; cancer; cardiovascular; diabetes; endoplasmic reticulum; fatty acids; ferritin; galectin; glycogen; glycolysis; heart; immunity; infection; insulin; lipid droplets; liver; lysosomes; metabolism; mitochondria; mitophagy; neurodegeneration; nutrition; oxidative phosphorylation; p62 SQSTM1; peroxisome; quality control; sirtuin
    DOI:  https://doi.org/10.1080/15548627.2021.1933742
  2. J Cell Biol. 2021 Aug 02. pii: e202009092. [Epub ahead of print]220(8):
    SAMM50 acts with p62 in piecemeal basal- and OXPHOS-induced mitophagy of SAM and MICOS components.
    Yakubu Princely Abudu, Birendra Kumar Shrestha, Wenxin Zhang, Anthimi Palara, Hanne Britt Brenne, Kenneth Bowitz Larsen, Deanna Lynn Wolfson, Gianina Dumitriu, Cristina Ionica Øie, Balpreet Singh Ahluwalia, Gahl Levy, Christian Behrends, Sharon A Tooze, Stephane Mouilleron, Trond Lamark, Terje Johansen.
      Mitophagy is the degradation of surplus or damaged mitochondria by autophagy. In addition to programmed and stress-induced mitophagy, basal mitophagy processes exert organelle quality control. Here, we show that the sorting and assembly machinery (SAM) complex protein SAMM50 interacts directly with ATG8 family proteins and p62/SQSTM1 to act as a receptor for a basal mitophagy of components of the SAM and mitochondrial contact site and cristae organizing system (MICOS) complexes. SAMM50 regulates mitochondrial architecture by controlling formation and assembly of the MICOS complex decisive for normal cristae morphology and exerts quality control of MICOS components. To this end, SAMM50 recruits ATG8 family proteins through a canonical LIR motif and interacts with p62/SQSTM1 to mediate basal mitophagy of SAM and MICOS components. Upon metabolic switch to oxidative phosphorylation, SAMM50 and p62 cooperate to mediate efficient mitophagy.
    DOI:  https://doi.org/10.1083/jcb.202009092
  3. Autophagy. 2021 May 24. 1-22
    Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels.
    Barbara J Bailus, Stephen M Scheeler, Jesse Simons, Maria A Sanchez, Kizito-Tshitoko Tshilenge, Jordi Creus-Muncunill, Swati Naphade, Alejandro Lopez-Ramirez, Ningzhe Zhang, Kuruwitage Lakshika Madushani, Stanislav Moroz, Ashley Loureiro, Katherine H Schreiber, Felix Hausch, Brian K Kennedy, Michelle E Ehrlich, Lisa M Ellerby.
      Current disease-modifying therapies for Huntington disease (HD) focus on lowering mutant HTT (huntingtin; mHTT) levels, and the immunosuppressant drug rapamycin is an intriguing therapeutic for aging and neurological disorders. Rapamycin interacts with FKBP1A/FKBP12 and FKBP5/FKBP51, inhibiting the MTORC1 complex and increasing cellular clearance mechanisms. Whether the levels of FKBP (FK506 binding protein) family members are altered in HD models and if these proteins are potential therapeutic targets for HD have not been investigated. Here, we found levels of FKBP5 are significantly reduced in HD R6/2 and zQ175 mouse models and human HD isogenic neural stem cells and medium spiny neurons derived from induced pluripotent stem cells. Moreover, FKBP5 interacts and colocalizes with HTT in the striatum and cortex of zQ175 mice and controls. Importantly, when we decreased FKBP5 levels or activity by genetic or pharmacological approaches, we observed reduced levels of mHTT in our isogenic human HD stem cell model. Decreasing FKBP5 levels by siRNA or pharmacological inhibition increased LC3-II levels and macroautophagic/autophagic flux, suggesting autophagic cellular clearance mechanisms are responsible for mHTT lowering. Unlike rapamycin, the effect of pharmacological inhibition with SAFit2, an inhibitor of FKBP5, is MTOR independent. Further, in vivo treatment for 2 weeks with SAFit2, results in reduced HTT levels in both HD R6/2 and zQ175 mouse models. Our studies establish FKBP5 as a protein involved in the pathogenesis of HD and identify FKBP5 as a potential therapeutic target for HD.Abbreviations : ACTB/β-actin: actin beta; AD: Alzheimer disease; BafA1: bafilomycin A1; BCA: bicinchoninic acid; BBB: blood brain barrier; BSA: bovine serum albumin; CoIP: co-immunoprecipitation; DMSO: dimethyl sulfoxide; DTT: dithiothreitol; FKBPs: FK506 binding proteins; HD: Huntington disease; HTT: huntingtin; iPSC: induced pluripotent stem cells; MAP1LC3/LC3:microtubule associated protein 1 light chain 3; MAPT/tau: microtubule associated protein tau; MES: 2-ethanesulfonic acid; MOPS: 3-(N-morphorlino)propanesulfonic acid); MSN: medium spiny neurons; mHTT: mutant huntingtin; MTOR: mechanistic target of rapamycin kinase; NSC: neural stem cells; ON: overnight; PD: Parkinson disease; PPIase: peptidyl-prolyl cis/trans-isomerases; polyQ: polyglutamine; PPP1R1B/DARPP-32: protein phosphatase 1 regulatory inhibitor subunit 1B; PTSD: post-traumatic stress disorder; RT: room temperature; SQSTM1/p62: sequestosome 1; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TBST:Tris-buffered saline, 0.1% Tween 20; TUBA: tubulin; ULK1: unc-51 like autophagy activating kinase 1; VCL: vinculin; WT: littermate controls.
    Keywords:  Autophagy; Huntington disease; SAFit2; fkbp12.6/fkbp1b; fkbp12/fkbp1a; fkbp51/fkbp5; fkbp52/fkbp4; induced pluripotent stem cells
    DOI:  https://doi.org/10.1080/15548627.2021.1904489
  4. Biochim Biophys Acta Mol Cell Res. 2021 May 25. pii: S0167-4889(21)00118-X. [Epub ahead of print] 119064
    Small but mighty: Atg8s and Rabs in Membrane Dynamics during Autophagy.
    Saskia Barz, Franziska Kriegenburg, Pablo Sánchez-Martín, Claudine Kraft.
      Autophagy is a degradative pathway during which autophagosomes are formed that enwrap cytosolic material destined for turnover within the lytic compartment. Autophagosome biogenesis requires controlled lipid and membrane rearrangements to allow the formation of an autophagosomal seed and its subsequent elongation into a fully closed and fusion-competent double membrane vesicle. Different membrane remodeling events are required, which are orchestrated by the distinct autophagy machinery. An important player among these autophagy proteins is the small lipid-modifier Atg8. Atg8 proteins facilitate various aspects of autophagosome formation and serve as a binding platform for autophagy factors. Also Rab GTPases have been implicated in autophagosome biogenesis. As Atg8 proteins interact with several Rab GTPase regulators, they provide a possible link between autophagy progression and Rab GTPase activity. Here, we review central aspects in membrane dynamics during autophagosome biogenesis with a focus on Atg8 proteins and selected Rab GTPases.
    Keywords:  Atg8 proteins; Rab GTPases; autophagy; membrane dynamics
    DOI:  https://doi.org/10.1016/j.bbamcr.2021.119064
  5. J Cell Sci. 2021 May 26. pii: jcs.253781. [Epub ahead of print]
    Atg32 dependent mitophagy sustains spermidine and nitric oxide required for heat stress tolerance in S. cerevisiae.
    Jasvinder Kaur, Juliet Goldsmith, Alexandra Tankka, Sofía Bustamante Eguiguren, Alfredo A Gimenez, Lance Vick, Jayanta Debnath, Ariadne Vlahakis.
      In Saccharomyces cerevisiae, the selective autophagic degradation of mitochondria, termed mitophagy, is critically regulated by the adapter protein, Atg32. Despite our knowledge about the molecular mechanisms by which Atg32 controls mitophagy, its physiological roles in yeast survival and fitness remains less clear. Here, we demonstrate a requirement for Atg32 in promoting spermidine production during respiratory growth and heat-induced mitochondrial stress. During respiratory growth, mitophagy-deficient yeast exhibit profound heat-stress induced defects in growth and viability due to impaired biosynthesis of spermidine and its biosynthetic precursor S-Adenosyl-Methionine (SAM). Moreover, spermidine production is crucial for the induction of cytoprotective nitric oxide (NO) during heat stress. Hence, the re-addition of spermidine to Atg32 mutant yeast is sufficient to both enhance NO production and restore respiratory growth during heat stress. Our findings uncover a previously unrecognized physiological role for yeast mitophagy in spermidine metabolism and illuminate new interconnections between mitophagy, polyamine biosynthesis and NO signaling.
    Keywords:  ATG32; Autophagy; Mitophagy; Nitric Oxide; S-Adenosyl-Methionine; Spermidine
    DOI:  https://doi.org/10.1242/jcs.253781
  6. Biochem Biophys Res Commun. 2021 May 20. pii: S0006-291X(21)00792-0. [Epub ahead of print]561 158-164
    Cdc14 phosphatase downmodulates ESCRT-0 complex formation on vacuolar membranes and microautophagy after TORC1 inactivation.
    Tasnuva Sharmin, Shamsul Morshed, Most Naoshia Tasnin, Tsuneyuki Takuma, Takashi Ushimaru.
      Remodeling of vacuolar membranes mediated by endosomal sorting complex required for transport (ESCRT) is critical for microautophagy induction in budding yeast. Nutrient depletion and inactivation of target of rapamycin complex 1 (TORC1) protein kinase elicit recruitment of the ESCRT-0 complex (Vps27-Hse1) onto vacuolar membranes and ESCRT-mediated microautophagy induction. Mitotic protein phosphatase Cdc14 antagonizes TORC1-mediated phosphorylation in macroautophagy induction after nutrient starvation and TORC1 inactivation. Here, we report that Cdc14 downregulates microautophagy induction after TORC1 inactivation. Cdc14 dysfunction stimulated the vacuolar membrane recruitment of Hse1, but not Vps27, after TORC1 inactivation, promoting ESCRT-0 complex formation. Conversely, overexpression of CDC14 compromises Hse1 recruitment on vacuolar membranes and microautophagy induction after TORC1 inactivation. Thus, Cdc14 phosphatase regulates the fluxes of two types of autophagy in the opposite directions, namely, it elicits macroautophagy and attenuates microautophagy.
    Keywords:  Cdc14; ESCRT; Hse1; Microautophagy; TORC1; Vps27
    DOI:  https://doi.org/10.1016/j.bbrc.2021.05.021
  7. Methods Mol Biol. 2021 ;2322 81-92
    Monitoring PINK1-Parkin Signaling Using Dopaminergic Neurons from iPS Cells.
    Kahori Shiba-Fukushima, Yuzuru Imai.
      The physiological importance of mitochondrial quality control has been uncovered by the finding that genes for early onset Parkinson's disease (PD), PINK1 and Parkin, regulate mitochondrial autophagy, called mitophagy, and motility. Dopaminergic neurons derived from human-induced pluripotent stem (iPS) cells are a useful tool for analyzing the pathogenesis caused by defects in mitochondrial quality control and for screening candidate drugs for PD. Moreover, dopaminergic neurons could provide new findings not obtained in other cells. In this chapter, we will describe our method for monitoring PINK1-Parkin signaling using iPS cell-derived dopaminergic neurons.
    Keywords:  Autophagy; Dopaminergic neuron; Immunocytochemistry; Mitochondria; PINK1; Parkin; Ubiquitin; Western blot; iPS cells
    DOI:  https://doi.org/10.1007/978-1-0716-1495-2_9
  8. Cell Discov. 2020 May 26. 6(1): 32
    Emerging roles of ATG proteins and membrane lipids in autophagosome formation.
    Taki Nishimura, Sharon A Tooze.
      Autophagosome biogenesis is a dynamic membrane event, which is executed by the sequential function of autophagy-related (ATG) proteins. Upon autophagy induction, a cup-shaped membrane structure appears in the cytoplasm, then elongates sequestering cytoplasmic materials, and finally forms a closed double membrane autophagosome. However, how this complex vesicle formation event is strictly controlled and achieved is still enigmatic. Recently, there is accumulating evidence showing that some ATG proteins have the ability to directly interact with membranes, transfer lipids between membranes and regulate lipid metabolism. A novel role for various membrane lipids in autophagosome formation is also emerging. Here, we highlight past and recent key findings on the function of ATG proteins related to autophagosome biogenesis and consider how ATG proteins control this dynamic membrane formation event to organize the autophagosome by collaborating with membrane lipids.
    DOI:  https://doi.org/10.1038/s41421-020-0161-3
  9. Autophagy. 2021 May 28. 1-3
    A unique COPII population in plant autophagy.
    Yonglun Zeng, Liwen Jiang.
      Increasing evidence supports the bona fide function of the coat protein complex II (COPII) machinery in regulating autophagosomes biogenesis during macroautophagy/autophagy induced by nutrient starvation. However, the participation of the COPII machinery in the plant autophagy pathway remains elusive. We recently identified a unique population of COPII vesicles containing AT3G62560/AtSar1d-AT1G02130/AtRabD2a that functions in modulating autuphagosome biogenesis in Arabidopsis thaliana. Proteomic analysis identified the mechanistic connection between autophagy-related (ATG) proteins and a subset of specific COPII paralogs, including AtSar1d. Mutants of AtSar1d affect autophagosome progression and display starvation-related phenotypes. AtSar1d interacts with ATG8 by a non-canonical motif. Cellular and genetic analysis demonstrated that a plant-unique RAB1/Ypt1 homolog AtRabD2a coordinates with AtSar1d to mediate the specific COPII functions in the autophagy pathway. This study identified a plant-specific nexus in regulating autophagosome biogenesis.
    Keywords:  Arabidopsis; COPII; GTPase; autophagy; stress
    DOI:  https://doi.org/10.1080/15548627.2021.1933298
  10. Neuropathol Appl Neurobiol. 2021 May 28.
    TDP-43 proteinopathy occurs independently of autophagic substrate accumulation and underlies nuclear defects in Niemann-Pick C disease.
    Elaine A Liu, Erika Mori, Fuko Hamasaki, Andrew P Lieberman.
      AIMS: Neuronal cytoplasmic inclusions of TDP-43 are a pathological hallmark of diverse neurodegenerative disorders, yet the processes that mediate their formation and their functional significance remain incompletely understood. Both dysfunction in autophagy and neuroinflammation have been linked to TDP-43 mislocalisation. Here, we investigate TDP-43 proteinopathy in Niemann-Pick type C disease (NPC), an autosomal recessive lysosomal storage disease (LSD) distinguished by the accumulation of unesterified cholesterol within late endosomes and lysosomes. NPC is characterized by neurodegeneration, neuroinflammation and multifocal disruption of the autophagy pathway.METHODS: We utilized immunohistochemistry, confocal microscopy, electron microscopy, and biochemical and gene expression studies to characterize TDP-43 pathology and autophagic substrate accumulation in Npc1 deficient mice.
    RESULTS: In the NPC brain, cytoplasmic TDP-43 mislocalisation was independent of autophagic substrate accumulation. These pathologies occurred in distinct neuronal subtypes, as brainstem cholinergic neurons were more susceptible to TDP-43 mislocalisation while glutamatergic neurons exhibited hallmarks of autophagic dysfunction. Furthermore, TDP-43 mislocalisation did not co-localise with markers of stress granules or progress to ubiquitinated aggregates over months in vivo, indicating a stable, early stage in the aggregation process. Neither microgliosis nor neuroinflammation were sufficient to drive TDP-43 proteinopathy in the NPC brain. Notably, cytoplasmic TDP-43 co-localised with the nuclear import factor importin α, and TDP-43 mislocalised neurons demonstrated nuclear membrane abnormalities and disruption of nucleocytoplasmic transport.
    CONCLUSION: Our findings highlight the relationship between LSDs and TDP-43 proteinopathy, define its functional importance in NPC by triggering nuclear dysfunction, and expand the spectrum of TDP-43 pathology in the diseased brain.
    Keywords:  Niemann-Pick type C; TDP-43; autophagy; lysosomal diseases; nucleocytoplasmic transport
    DOI:  https://doi.org/10.1111/nan.12738
  11. Biochim Biophys Acta Gen Subj. 2021 May 19. pii: S0304-4165(21)00090-8. [Epub ahead of print]1865(8): 129932
    Yeast mitophagy: Unanswered questions.
    Yuxiang J Huang, Daniel J Klionsky.
      Superfluous and damaged mitochondria need to be efficiently repaired or removed. Mitophagy is a selective type of autophagy that can engulf a portion of mitochondria within a double-membrane structure, called a mitophagosome, and deliver it to the vacuole for degradation. Mitophagy has significant physiological functions from yeast to human, and recent advances in yeast mitophagy shed light on the molecular mechanisms of mitophagy, especially the regulation of mitophagy induction. This review summarizes our current knowledge about yeast mitophagy and considers several unsolved questions, with a particular focus on Saccharomyces cerevisiae.
    Keywords:  Autophagy; Degradation; Lysosome; Stress; Vacuole
    DOI:  https://doi.org/10.1016/j.bbagen.2021.129932
  12. Nat Commun. 2021 May 25. 12(1): 3091
    The P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2.
    Dipankar Ash, Varadarajan Sudhahar, Seock-Won Youn, Mustafa Nazir Okur, Archita Das, John P O'Bryan, Maggie McMenamin, Yali Hou, Jack H Kaplan, Tohru Fukai, Masuko Ushio-Fukai.
      VEGFR2 (KDR/Flk1) signaling in endothelial cells (ECs) plays a central role in angiogenesis. The P-type ATPase transporter ATP7A regulates copper homeostasis, and its role in VEGFR2 signaling and angiogenesis is entirely unknown. Here, we describe the unexpected crosstalk between the Copper transporter ATP7A, autophagy, and VEGFR2 degradation. The functional significance of this Copper transporter was demonstrated by the finding that inducible EC-specific ATP7A deficient mice or ATP7A-dysfunctional ATP7Amut mice showed impaired post-ischemic neovascularization. In ECs, loss of ATP7A inhibited VEGF-induced VEGFR2 signaling and angiogenic responses, in part by promoting ligand-induced VEGFR2 protein degradation. Mechanistically, VEGF stimulated ATP7A translocation from the trans-Golgi network to the plasma membrane where it bound to VEGFR2, which prevented autophagy-mediated lysosomal VEGFR2 degradation by inhibiting autophagic cargo/adapter p62/SQSTM1 binding to ubiquitinated VEGFR2. Enhanced autophagy flux due to ATP7A dysfunction in vivo was confirmed by autophagy reporter CAG-ATP7Amut -RFP-EGFP-LC3 transgenic mice. In summary, our study uncovers a novel function of ATP7A to limit autophagy-mediated degradation of VEGFR2, thereby promoting VEGFR2 signaling and angiogenesis, which restores perfusion recovery and neovascularization. Thus, endothelial ATP7A is identified as a potential therapeutic target for treatment of ischemic cardiovascular diseases.
    DOI:  https://doi.org/10.1038/s41467-021-23408-1
  13. Cell Rep. 2021 May 25. pii: S2211-1247(21)00529-5. [Epub ahead of print]35(8): 109184
    The autophagy protein Becn1 improves insulin sensitivity by promoting adiponectin secretion via exocyst binding.
    Kenta Kuramoto, Yoon-Jin Kim, Jung Hwa Hong, Congcong He.
      Autophagy dysregulation is implicated in metabolic diseases, including type 2 diabetes. However, the mechanism by which the autophagy machinery regulates metabolism is largely unknown. Autophagy is generally considered a degradation process via lysosomes. Here, we unveil a metabolically important non-cell-autonomous, non-degradative mechanism regulated by the essential autophagy protein Becn1 in adipose tissue. Upon high-fat diet challenge, autophagy-hyperactive Becn1F121A mice show systemically improved insulin sensitivity and enhanced activation of AMP-activated protein kinase (AMPK), a central regulator of energy homeostasis, via a non-cell-autonomous mechanism mediated by adiponectin, an adipose-derived metabolic hormone. Adipose-specific Becn1F121A expression is sufficient to activate AMPK in non-adipose tissues and improve systemic insulin sensitivity by increasing adiponectin secretion. Further, Becn1 enhances adiponectin secretion by interacting with components of the exocyst complex via the coiled-coil domain. Together, our study demonstrates that Becn1 improves insulin sensitivity by facilitating adiponectin secretion through binding the exocyst in adipose tissue.
    Keywords:  AMPK; Becn1; Sec6; adiponectin; adipose tissue; autophagy; exocyst; glucose tolerance; insulin sensitivity
    DOI:  https://doi.org/10.1016/j.celrep.2021.109184
  14. Ageing Res Rev. 2021 May 20. pii: S1568-1637(21)00114-8. [Epub ahead of print] 101367
    Cellular functions regulated by deubiquitinating enzymes in neurodegenerative diseases.
    Hyeon-Ah Do, Kwang-Hyun Baek.
      Neurodegenerative diseases are one of the most common diseases in mankind. Although there are reports of several candidates that cause neurodegenerative diseases, the exact mechanism of pathogenesis is poorly understood. The ubiquitin-proteasome system (UPS) is an important posttranslational modification for protein degradation and control of homeostasis. Enzymes such as E1, E2, E3 ligases, and deubiquitinating enzymes (DUBs) participating in UPS, regulate disease-inducing proteins by controlling the degree of ubiquitination. Therefore, the development of treatments targeting enzymes for degenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), is emerging as an attractive perspective. In particular, as DUBs are able to regulate one or more degenerative disease-related proteins, the potential as a therapeutic target is even more evident. DUBs influence the regulation of toxic proteins that cause neurodegenerative diseases by not only their removal, but also by regulating signals associated with mitophagy, autophagy, and endoplasmic reticulum-associated degradation (ERAD). In this review, we analyze not only the cellular processes of DUBs, which control neurodegenerative disease-inducing proteins, but also their potentials as a therapeutic agent for neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Deubiquitination; Huntington’s chorea; Parkinson’s disease; Ubiquitination
    DOI:  https://doi.org/10.1016/j.arr.2021.101367
  15. Nat Chem Biol. 2021 Jun;17(6): 653-664
    Small molecule probes for targeting autophagy.
    Thomas Whitmarsh-Everiss, Luca Laraia.
      Autophagy is implicated in a wide range of (patho)physiological processes including maintenance of cellular homeostasis, neurodegenerative disorders, aging and cancer. As such, small molecule autophagy modulators are in great demand, both for their ability to act as tools to better understand this essential process and as potential therapeutics. Despite substantial advances in the field, major challenges remain in the development and comprehensive characterization of probes that are specific to autophagy. In this Review, we discuss recent developments in autophagy-modulating small molecules, including the specific challenges faced in the development of activators and inhibitors, and recommend guidelines for their use. Finally, we discuss the potential to hijack the process for targeted protein degradation, an area of great importance in chemical biology and drug discovery.
    DOI:  https://doi.org/10.1038/s41589-021-00768-9
  16. Biochem J. 2021 May 28. 478(10): 1879-1883
    Casting iron into the cell fate mold.
    Or Kakhlon.
      This commentary discusses general concepts introduced in the article 'Bulk autophagy induction and life extension is achieved when iron is the only limited nutrient in Saccharomyces cerevisiae' by Montella-Manuel et al. (Biochem J (2021) 478: 811-837). Montella-Manuel et al. show that like central carbon metabolism, iron metabolism is also closely implicated in autophagy-mediated life extension via the TORC2 activator Ypk1p and the iron regulator Aft1p. While not being an iron-sulfur cluster protein, Aft1p interacts with such proteins and thus senses the redox status of the cell, which, similar to amino acids and AMP, reports its energetic status. Furthermore, glucose and iron deficiencies are interrelated as the diauxic shift in glucose depleted cells requires iron uptake for activating respiration in the absence of fermentation.
    DOI:  https://doi.org/10.1042/BCJ20210108
  17. J Cell Biol. 2021 Aug 02. pii: e202007061. [Epub ahead of print]220(8):
    The Rab7 effector WDR91 promotes autophagy-lysosome degradation in neurons by regulating lysosome fusion.
    Ruxiao Xing, Hejiang Zhou, Youli Jian, Lingling Li, Min Wang, Nan Liu, Qiuyuan Yin, Ziqi Liang, Weixiang Guo, Chonglin Yang.
      The effectors of the Rab7 small GTPase play multiple roles in Rab7-dependent endosome-lysosome and autophagy-lysosome pathways. However, it is largely unknown how distinct Rab7 effectors coordinate to maintain the homeostasis of late endosomes and lysosomes to ensure appropriate endolysosomal and autolysosomal degradation. Here we report that WDR91, a Rab7 effector required for early-to-late endosome conversion, is essential for lysosome function and homeostasis. Mice lacking Wdr91 specifically in the central nervous system exhibited behavioral defects and marked neuronal loss in the cerebral and cerebellar cortices. At the cellular level, WDR91 deficiency causes PtdIns3P-independent enlargement and dysfunction of lysosomes, leading to accumulation of autophagic cargoes in mouse neurons. WDR91 competes with the VPS41 subunit of the HOPS complex, another Rab7 effector, for binding to Rab7, thereby facilitating Rab7-dependent lysosome fusion in a controlled manner. WDR91 thus maintains an appropriate level of lysosome fusion to guard the normal function and survival of neurons.
    DOI:  https://doi.org/10.1083/jcb.202007061
  18. J Biol Chem. 2021 May 20. pii: S0021-9258(21)00608-6. [Epub ahead of print] 100813
    Enrichment of NPC1-deficient cells with the lipid LBPA stimulates autophagy, improves lysosomal function, and reduces cholesterol storage.
    Olga Ilnytska, Kimberly Lai, Kirill Gorshkov, Mark L Schultz, Bruce Nguyen Tran, Maciej Jeziorek, Thaddeus J Kunkel, Ruth D Azaria, Hayley S McLoughlin, Miriam Waghalter, Yang Xu, Michael Schlame, Nihal Altan-Bonnet, Wei Zheng, Andrew P Lieberman, Radek Dobrowolski, Judith Storch.
      Niemann-Pick C (NPC) is an autosomal recessive disorder characterized by mutations in the NPC1 or NPC2 genes encoding endo-lysosomal lipid transport proteins, leading to cholesterol accumulation and autophagy dysfunction. We have previously shown that enrichment of NPC1-deficient cells with the anionic lipid lysobisphosphatidic acid (LBPA; also called bis(monoacylglycerol)phosphate, BMP) via treatment with its precursor phosphatidylglycerol (PG) results in a dramatic decrease in cholesterol storage. However, the mechanisms underlying this reduction are unknown. In the present study, we showed using biochemical and imaging approaches in both NPC1-deficient cellular models and an NPC1 mouse model that PG incubation/LBPA enrichment significantly improved the compromised autophagic flux associated with NPC1 disease, providing a route for NPC1-independent endo-lysosomal cholesterol mobilization. PG/LBPA enrichment specifically enhanced the late stages of autophagy, and effects were mediated by activation of the lysosomal enzyme acid sphingomyelinase (ASM). PG incubation also led to robust and specific increases in LBPA species with polyunsaturated acyl chains, potentially increasing the propensity for membrane fusion events, which are critical for late-stage autophagy progression. Finally, we demonstrated that PG/LBPA treatment efficiently cleared cholesterol and toxic protein aggregates in Purkinje neurons of the NPC1I1061T mouse model. Collectively, these findings provide a mechanistic basis supporting cellular LBPA as a potential new target for therapeutic intervention in NPC disease.
    Keywords:  Niemann-Pick type C disease; acid sphingomyelinase; autophagy; cholesterol; lysobisphosphatidic acid
    DOI:  https://doi.org/10.1016/j.jbc.2021.100813
  19. Mol Cell Oncol. 2021 ;8(3): 1919006
    A mTORC1-mediated cyst(e)ine sensing mechanism governing GPX4 synthesis and ferroptosis.
    Yuelong Yan, Guang Lei, Boyi Gan.
      Ferroptosis is a cell death mechanism triggered by lipid peroxidation. Our recent study linked cyst(e)ine availability with glutathione peroxidase 4 (GPX4) protein synthesis and ferroptosis mitigation via a Rag-mechanistic target of rapamycin complex 1 (mTORC1) axis, and proposed that co-targeting mTORC1 and ferroptosis is a promising strategy for cancer therapy.
    Keywords:  GPX4; SLC7A11; cancer therapy; cysteine; cystine; ferroptosis; lipid peroxidation; mTORC1
    DOI:  https://doi.org/10.1080/23723556.2021.1919006
  20. Autophagy. 2021 May 26.
    Cell type-specific YAP1-WWTR1/TAZ transcriptional responses after autophagy perturbations are determined by levels of α-catenins (CTNNA1 and CTNNA3).
    Mariana Pavel, So Jung Park, Radu Tanasa, David gnmC Rubinsztein.
      The YAP1-WWTR1/TAZ transcription co-factors are key determinants of cell growth that are perturbed in many cancers. Previous studies have reported divergent responses in YAP1-WWTR1/TAZ activities after autophagy perturbations in different contexts. Recently, we identified that α-catenin levels determine whether YAP1-WWTR1/TAZ signalling will be increased or decreased after macroautophagy/autophagy inhibition/induction. CTNNA1/α-catenin can act as a switch in this pathway, as it is an autophagy substrate and a negative regulator of YAP1-WWTR1/TAZ. However, YAP1-WWTR1/TAZ are also directly degraded by autophagy and there is a feedback loop where YAP1-WWTR1/TAZ positively regulate autophagy. These features were integrated into a mathematical numerical model based on a set of differential equations in order to clarify the integrated output on YAP1-WWTR1/TAZ activity at a given time-point of autophagy perturbation in cells with distinct initial levels of α-catenins (CTNNA1 and CTNNA3). Our theoretical and experimental data allow an understanding of cell-type specific and time-dependent responses to autophagy manipulations that may be relevant in many contexts, including different types of cancer.
    Keywords:  Hippo signalling; YAP1-WWTR1/TAZ; autophagy; mathematical model; α-catenin
    DOI:  https://doi.org/10.1080/15548627.2021.1934273
  21. Neurobiol Dis. 2021 May 25. pii: S0969-9961(21)00154-6. [Epub ahead of print] 105405
    CERKL, a retinal dystrophy gene, regulates mitochondrial function and dynamics in the mammalian retina.
    Serena Mirra, Rocío García Arroyo, Elena B Domènech, Aleix Gavaldà-Navarro, Carlos Herrera-Úbeda, Clara Oliva, Jordi Garcia-Fernàndez, Rafael Artuch, Francesc Villarroya, Gemma Marfany.
      The retina is a highly active metabolic organ that displays a particular vulnerability to genetic and environmental factors causing stress and homeostatic imbalance. Mitochondria constitute a bioenergetic hub that coordinates stress response and cellular homeostasis, therefore structural and functional regulation of the mitochondrial dynamic network is essential for the mammalian retina. CERKL (ceramide kinase like) is a retinal degeneration gene whose mutations cause Retinitis Pigmentosa in humans, a visual disorder characterized by photoreceptors neurodegeneration and progressive vision loss. CERKL produces multiple isoforms with a dynamic subcellular localization. Here we show that a pool of CERKL isoforms localizes at mitochondria in mouse retinal ganglion cells. The depletion of CERKL levels in CerklKD/KO(knockdown/knockout) mouse retinas cause increase of autophagy, mitochondrial fragmentation, alteration of mitochondrial distribution, and dysfunction of mitochondrial-dependent bioenergetics and metabolism. Our results support CERKL as a regulator of autophagy and mitochondrial biology in the mammalian retina.
    Keywords:  CERKL; Mitochondrial dysfunction; Retinal dystrophies; Retinitis pigmentosa
    DOI:  https://doi.org/10.1016/j.nbd.2021.105405
  22. Mol Cell Oncol. 2021 ;8(3): 1915076
    Regulation of autophagy by VPS34 branched ubiquitination controls proteostasis and liver metabolism.
    Yu-Hsuan Chen, Ruey-Hwa Chen.
      Ubiquitin-proteasome system and autophagy are the two major recycling processes. Our recent work uncovers a K29/K48 branched ubiquitination on the phosphatidylinositol 3-kinase catalytic subunit type 3 (PI3KC3, best known as VPS34). This ubiquitination is positively or negatively regulated under pathophysiological conditions to influence on autophagy, proteostasis and lipid homeostasis.
    Keywords:  Autophagy; branched ubiquitination; liver steatosis; protein quality control; vps34
    DOI:  https://doi.org/10.1080/23723556.2021.1915076
  23. J Cell Sci. 2021 May 15. pii: jcs257485. [Epub ahead of print]134(10):
    TORC2 inhibition of α-arrestin Aly3 mediates cell surface persistence of S. pombe Ght5 glucose transporter in low glucose.
    Yusuke Toyoda, Saeko Soejima, Fumie Masuda, Shigeaki Saitoh.
      In the fission yeast, Schizosaccharomyces pombe, the high-affinity hexose transporter, Ght5, must be transcriptionally upregulated and localized to the cell surface for cell division under limited glucose. Although cell-surface localization of Ght5 depends on Target of rapamycin complex 2 (TORC2), the molecular mechanisms by which TORC2 ensures proper localization of Ght5 remain unknown. We performed genetic screening for gene mutations that restore Ght5 localization on the cell surface in TORC2-deficient mutant cells, and identified a gene encoding an uncharacterized α-arrestin-like protein, Aly3/SPCC584.15c. α-arrestins are thought to recruit a ubiquitin ligase to membrane-associated proteins. Consistently, Ght5 is ubiquitylated in TORC2-deficient cells, and this ubiquitylation is dependent on Aly3. TORC2 supposedly enables cell-surface localization of Ght5 by preventing Aly3-dependent ubiquitylation and subsequent ubiquitylation-dependent translocation of Ght5 to vacuoles. Surprisingly, nitrogen starvation, but not glucose depletion, triggers Aly3-dependent transport of Ght5 to vacuoles in S. pombe, unlike budding yeast hexose transporters, vacuolar transport of which is initiated upon changes in hexose concentration. This study provides new insights into the molecular mechanisms controlling the subcellular localization of hexose transporters in response to extracellular stimuli.
    Keywords:  Arrestin; Glucose limitation; Hexose transporter; Nitrogen starvation; Target of rapamycin complex; Ubiquitylation
    DOI:  https://doi.org/10.1242/jcs.257485
  24. Mol Cell Oncol. 2021 ;8(3): 1903291
    The role of OFD1 in selective autophagy.
    Brunella Franco, Manuela Morleo.
      Autophagy is a cellular self-degradative pathway. Our study unveiled a novel mechanism mediated by OFD1, the protein mutated in Oral-Facial-Digital type I syndrome, based on selective degradation of autophagic proteins, which enables cells to calibrate their self-degradation. We demonstrated that unrestrained autophagy contributes to renal cysts observed in Ofd1 mutants.
    Keywords:  OFD1; Oral-Facial-Digital type I syndrome; autophagy receptor; renal cystic disease; selective autophagy
    DOI:  https://doi.org/10.1080/23723556.2021.1903291
  25. Environ Toxicol. 2021 May 26.
    Compound essential oils relieve oxidative stress caused by PM2 .5 exposure by inhibiting autophagy through the AMPK/mTOR pathway.
    Fei Ren, Xin Xu, Jingbin Xu, Yuhui Mei, Jiahua Zhang, Xuguang Wang, Fasheng Li.
      Fine particulate matter (PM2.5 ) potentially damages the respiratory system and causes respiratory diseases. Compound essential oils (CEOs) have been shown to alleviate the damage to the lung and macrophages caused by PM2.5 . However, the effect of PM2.5 exposure on the brain has rarely been investigated. When oxidative stress occurs in the brain, it readily causes neurological diseases. Autophagy is intimately involved in many physiological processes, especially processes important for the brain. Blocked or excessive autophagy causes a series of brain diseases, such as cerebral ischemia and stroke. This study investigated whether CEOs regulate excessive autophagy and reduce the oxidative stress caused by PM2.5 in the brain and BV2 microglial cells. PM2.5 increased the levels of ROS, Nox2, NF-κB and MDA while decreasing superoxide dismutase and HO-1 levels, which led to oxidative stress in the brain. The increased LC3 level and decreased P62 level suggested that PM2.5 exposure increased the level of autophagy. After exposure to PM2.5 , the levels of 5'-adenosine monophosphate-activated protein kinase (AMPK) increased, while the levels of mammalian target of rapamycin (mTOR) decreased, suggesting that PM2.5 might induce autophagy by activating the AMPK/mTOR pathway. In addition, CEOs alleviated oxidative stress and autophagy induced by PM2.5 . Therefore, we concluded that CEOs reduce oxidative stress induced by PM2.5 exposure by inhibiting autophagy via the AMPK/mTOR signaling pathway, and these findings provide new opportunities for the prevention of PM2.5 -induced brain diseases.
    Keywords:  AMPK/mTOR pathway; PM2.5; autophagy; compound essential oils; oxidative stress
    DOI:  https://doi.org/10.1002/tox.23297
  26. Autophagy. 2021 May 24. 1-23
    Transcription- and phosphorylation-dependent control of a functional interplay between XBP1s and PINK1 governs mitophagy and potentially impacts Parkinson disease pathophysiology.
    Wejdane El Manaa, Eric Duplan, Thomas Goiran, Inger Lauritzen, Loan Vaillant Beuchot, Sandra Lacas-Gervais, Vanessa Alexandra Morais, Han You, Ling Qi, Mario Salazar, Umut Ozcan, Mounia Chami, Frédéric Checler, Cristine Alves da Costa.
      Parkinson disease (PD)-affected brains show consistent endoplasmic reticulum (ER) stress and mitophagic dysfunctions. The mechanisms underlying these perturbations and how they are directly linked remain a matter of questions. XBP1 is a transcription factor activated upon ER stress after unconventional splicing by the nuclease ERN1/IREα thereby yielding XBP1s, whereas PINK1 is a kinase considered as the sensor of mitochondrial physiology and a master gatekeeper of mitophagy process. We showed that XBP1s transactivates PINK1 in human cells, primary cultured neurons and mice brain, and triggered a pro-mitophagic phenotype that was fully dependent of endogenous PINK1. We also unraveled a PINK1-dependent phosphorylation of XBP1s that conditioned its nuclear localization and thereby, governed its transcriptional activity. PINK1-induced XBP1s phosphorylation occurred at residues reminiscent of, and correlated to, those phosphorylated in substantia nigra of sporadic PD-affected brains. Overall, our study delineated a functional loop between XBP1s and PINK1 governing mitophagy that was disrupted in PD condition.Abbreviations: 6OHDA: 6-hydroxydopamine; baf: bafilomycin A1; BECN1: beclin 1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CASP3: caspase 3; CCCP: carbonyl cyanide chlorophenylhydrazone; COX8A: cytochrome c oxidase subunit 8A; DDIT3/CHOP: DNA damage inducible transcript 3; EGFP: enhanced green fluorescent protein; ER: endoplasmic reticulum; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FACS: fluorescence-activated cell sorting; HSPD1/HSP60: heat shock protein family D (Hsp60) member 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFN2: mitofusin 2; OPTN: optineurin; PD: Parkinson disease; PINK1: PTEN-induced kinase 1; PCR: polymerase chain reaction:; PRKN: parkin RBR E3 ubiquitin protein ligase; XBP1s [p-S61A]: XBP1s phosphorylated at serine 61; XBP1s [p-T48A]: XBP1s phosphorylated at threonine 48; shRNA: short hairpin RNA, SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TM: tunicamycin; TMRM: tetramethyl rhodamine methylester; TOMM20: translocase of outer mitochondrial membrane 20; Toy: toyocamycin; TP: thapsigargin; UB: ubiquitin; UB (S65): ubiquitin phosphorylated at serine 65; UPR: unfolded protein response, XBP1: X-box binding protein 1; XBP1s: spliced X-box binding protein 1.
    Keywords:  Mitophagy; PINK1; Parkinson disease; XBP1; phosphorylation; transcription; unfolded protein response
    DOI:  https://doi.org/10.1080/15548627.2021.1917129
  27. Autophagy. 2021 May 24. 1-20
    HMGB1 downregulation in retinal pigment epithelial cells protects against diabetic retinopathy through the autophagy-lysosome pathway.
    Lujia Feng, Liang Liang, Shaochong Zhang, Jinglu Yang, Yanan Yue, Xuedong Zhang.
      Diabetic retinopathy (DR) is a serious complication of diabetes mellitus and currently one of the major causes of blindness. Several previous studies have demonstrated that autophagy, which is regulated by HMGB1 (high mobility group box 1), is involved in DR development. However, the role of autophagy in DR is quite complicated in that it promotes pericyte survival in early DR, whereas excessive autophagy causes excess stress and leads to necrosis. Therefore, this study aimed to investigate the relationship between HMGB1, the macroautophagy/autophagy-lysosome pathway, and DR, as well as their underlying molecular mechanisms. In brief, the relationship between high glucose (HG) and the autophagy-lysosome pathway was examined in retinal pigment epithelial (RPE) cells. The relationship was studied by detecting classical autophagic features, and siRNAs targeting HMGB1 and pharmacological regulators were used to explore the role of the autophagy-lysosome pathway in DR development. The results demonstrated that HG inhibited autophagy and diminished the degradative capacity of autophagy due to lysosome membrane permeabilization (LMP). In addition, HMGB1 was found to be involved in LMP via the CTSB (cathepsin B)-dependent pathway, but not the CTSL (cathepsin L)-dependent pathway. Knockdown of HMGB1 expression rescued LMP, restored the degradative capacity of autophagy, decreased the expression of inflammatory factors and VEGF (vascular endothelial growth factor), and protected against apoptosis in RPE cells in the early stages of DR.
    Keywords:  Autophagy; HMGB1; RPE; diabetic retinopathy; lysosome
    DOI:  https://doi.org/10.1080/15548627.2021.1926655
  28. Free Radic Biol Med. 2021 May 21. pii: S0891-5849(21)00306-3. [Epub ahead of print]
    Advanced oxidation protein products impair autophagic flux in macrophage by inducing lysosomal dysfunction via activation of PI3K-Akt-mTOR pathway in Crohn's disease.
    Yan Liao, Jiahui Xu, Biyan Qin, Jie Shi, Caolitao Qin, Fang Xie, Shiyu Ou, Jing Tang, Weidong Wang, Fengfei Wu, Lan Bai.
      Dysfunction in macrophages is involved in the pathogenesis of various diseases, including Crohn's disease (CD). Previously, we found that advanced oxidation protein products (AOPPs) were predominantly deposited in macrophages in the intestinal lamina propria of CD patients. However, whether AOPPs contributes to macrophage dysfunction in CD and the underlying mechanism remains unknown. This study aimed to investigate the effects of AOPPs on macrophages functions in CD. In the present study, we discovered increased AOPPs levels were positively correlated with impaired autophagy in macrophages of CD patients. AOPPs could impair autophagic flux by inducing lysosomal dysfunction in RAW264.7 cell line and macrophages in AOPPs-treated mice, evidenced by increased number of autophagosomes, blocked degradation of autophagy-related proteins (LC3B-II and SQSTM1/p62), and decreased activity of lysosomal proteolytic enzymes after AOPPs challenge. Besides, AOPPs could also promote M1 polarization in RAW264.7 cells and bone marrow derived macrophages (BMDMs) in AOPPs-treated mice. In addition, our study revealed that PI3K-AKT-mTOR-TFEB pathway was activated by AOPPs in macrophages. Inhibition of the PI3K pathway effectively alleviated AOPPs-induced autophagy impairment and M1 polarization both in vitro and in vivo, thus reducing intestinal inflammation in AOPPs-challenged mice. Together, this study demonstrates that AOPPs-induced autophagy impairment in macrophages is crucial for CD progression.
    Keywords:  Crohn’s disease; M1 polarization; advanced oxidation protein products; autophagy; macrophage
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.05.018
  29. Biochem J. 2021 May 28. 478(10): 1959-1976
    Understanding amphisomes.
    Dhasarathan Ganesan, Qian Cai.
      Amphisomes are intermediate/hybrid organelles produced through the fusion of endosomes with autophagosomes within cells. Amphisome formation is an essential step during a sequential maturation process of autophagosomes before their ultimate fusion with lysosomes for cargo degradation. This process is highly regulated with multiple protein machineries, such as SNAREs, Rab GTPases, tethering complexes, and ESCRTs, are involved to facilitate autophagic flux to proceed. In neurons, autophagosomes are robustly generated in axonal terminals and then rapidly fuse with late endosomes to form amphisomes. This fusion event allows newly generated autophagosomes to gain retrograde transport motility and move toward the soma, where proteolytically active lysosomes are predominantly located. Amphisomes are not only the products of autophagosome maturation but also the intersection of the autophagy and endo-lysosomal pathways. Importantly, amphisomes can also participate in non-canonical functions, such as retrograde neurotrophic signaling or autophagy-based unconventional secretion by fusion with the plasma membrane. In this review, we provide an updated overview of the recent discoveries and advancements on the molecular and cellular mechanisms underlying amphisome biogenesis and the emerging roles of amphisomes. We discuss recent developments towards the understanding of amphisome regulation as well as the implications in the context of major neurodegenerative diseases, with a comparative focus on Alzheimer's disease and Parkinson's disease.
    Keywords:  amphisome; autophagy; late endosome; neurodegeneration; neurotrophic signaling; retrograde axonal transport
    DOI:  https://doi.org/10.1042/BCJ20200917
  30. EMBO Rep. 2021 May 27. e53232
    Lysosome positioning and mTOR activity in Lowe syndrome.
    Cansu Karabiyik, Sung Min Son, David C Rubinsztein.
      Lowe syndrome is a rare, developmental disorder caused by mutations in the phosphatase, OCRL. A study in this issue of EMBO Reports shows that OCRL is required for microtubule nucleation and that mutations in this protein lead to an inability to activate mTORC1 signaling and consequent cell proliferation in the presence of nutrients. These defects are the result of impaired microtubule-dependent lysosomal trafficking to the cell periphery and are independent of OCRL phosphatase activity.
    DOI:  https://doi.org/10.15252/embr.202153232
  31. Biochem Biophys Res Commun. 2021 May 22. pii: S0006-291X(21)00813-5. [Epub ahead of print]562 36-42
    A conserved klo-1-mpk-1 pathway regulates autophagy and modulates longevity in Caenorhabditis elegans.
    Jie Tang, Jian-Fan Zhang, Rui-Qiu Yang, Yuan-Li Chen, Baosen Ni.
      There are six different longevity models in Caenorhabditis elegans. Previous studies have identified several convergence points, such as hlh-30, daf-16, and klf-3, required for lifespan extension in these longevity models. However, it is not clear whether there other such convergence points. In this study, based on analysis of transcriptome data, we found that the expression of klo-1/klotho was elevated in several longevity models. klo-1 was required for lifespan extension in the glp-1(e2141) and isp-1(qm150) mutants. klo-1 extended the lifespan of glp-1(e2141) and isp-1(qm150) worms by activating extracellular-signal-regulated kinase (ERK). In addition, klo-1 and mpk-1 (the homologous gene encoding ERK) regulated autophagy in glp-1(e2141) mutants, suggesting that klo-1 regulates lifespan by activating autophagy.
    Keywords:  Autophagy; Klo-1; Longevity; Mpk-1; RNA sequencing
    DOI:  https://doi.org/10.1016/j.bbrc.2021.05.042
  32. FEBS Open Bio. 2021 May 29.
    The mitochondrial fission factor FIS1 promotes stemness of human lung cancer stem cells via mitophagy.
    Doudou Liu, Zhiwei Sun, Ting Ye, Jingyuan Li, Bin Zeng, Qiting Zhao, Jianyu Wang, H Rosie Xing.
      Mitophagy, a form of autophagy, plays a role in cancer development, progression and recurrence. Cancer stem cells (CSCs) also play a key role in these processes, but it is unknown whether mitophagy can regulate the stemness of CSCs. Here, we employed the A549-SD human non-small cell lung adenocarcinoma CSC model that we have developed and characterized to investigate the effect of mitophagy on the stemness of CSCs. We observed a positive relationship between mitophagic activity and the stemness of lung CSCs. At the mechanistic level, our results suggest that augmentation of mitophagy in lung CSCs can be induced by FIS1 through mitochondrial fission. In addition, we assessed the clinical relevance of FIS1 in lung adenocarcinoma by using the TCGA database. An elevation in FIS1, when observed together with other prognostic markers for lung cancer progression, was found to correlate with shorter overall survival.
    Keywords:  FIS1; cancer stem cell; mitochondrial fission; mitophagy; stemness
    DOI:  https://doi.org/10.1002/2211-5463.13207
  33. Mol Cell Oncol. 2021 Mar 25. 8(3): 1902250
    Targeting one-carbon metabolism requires mTOR inhibition: a new therapeutic approach in osteosarcoma.
    Richa Rathore, Brian Van Tine.
      The rate-limiting enzyme of serine biosynthesis, 3-phosphoglycerate dehydrogenase (PHGDH), contributes to rapid growth and proliferation when it is overexpressed in cancer. We recently described the metabolic adaptations that occur upon PHGDH inhibition in osteosarcoma. PHGDH inhibition causes metabolite accumulation that activates the mechanistic target of rapamycin (mTOR) signaling, sensitizing osteosarcoma to non-rapalog mTOR inhibition.
    Keywords:  PHGDH; mTORC1; methotrexate; osteosarcoma; perhexiline; serine
    DOI:  https://doi.org/10.1080/23723556.2021.1902250
  34. Plant J. 2021 May 26.
    Autophagy-related genes serve as heat shock protein 90 co-chaperones in disease resistance against cassava bacterial blight.
    Yunxie Wei, Hongqiu Zeng, Wen Liu, Xiao Cheng, Binbin Zhu, Jingru Guo, Haitao Shi.
      Heat shock protein 90 (HSP90) is involved in plant growth and various stress responses via regulating protein homeostasis. Autophagy keeps cellular homeostasis by recycling the cellular cytoplasmic constituents components. Although they have similar effects on cellular protein homeostasis, the direct association between HSP90 and autophagy signaling remain unclear in plants, especially in tropical crops. In this study, the correlation between HSP90 and autophagy signaling was systematically analyzed by protein-protein interaction in cassava, one of the most important economy fruit in tropic. In addition, their effects on plant disease response and underlying mechanisms in cassava were investigated by functional genomics and genetic phenotype assay. The potential MeHSP90.9-MeSGT1-MeRAR1 chaperone complex interacts with MeATGs and subsequently triggers autophagy signaling, conferring improved disease resistance to cassava bacterial blight (CBB). On the contrary, HSP90 inhibitor and autophagy inhibitor decreased disease resistance against CBB in cassava, and autophagy may be involved in the potential MeHSP90.9-MeSGT1-MeRAR1 chaperone complex-mediated multiple immune responses. This study highlights the precise modulation of autophagy signaling by potential MeHSP90.9-MeSGT1-MeRAR1 chaperone complex in autophagy-mediated disease resistance to CBB.
    Keywords:  Autophagy; cassava (Manihot esculenta); cassava bacterial blight; heat shock protein 90; protein-protein interaction
    DOI:  https://doi.org/10.1111/tpj.15355
  35. Trends Endocrinol Metab. 2021 May 22. pii: S1043-2760(21)00115-6. [Epub ahead of print]
    The ubiquitin-proteasome system and autophagy: self-digestion for metabolic health.
    Jia Liang Sun-Wang, Alex Yarritu-Gallego, Saška Ivanova, Antonio Zorzano.
      Type 2 diabetes mellitus (T2DM) is a global health challenge. Therefore, understanding the molecular mechanisms underlying the pathophysiology of T2DM is key to improving current therapies. Loss of protein homeostasis leads to the accumulation of damaged proteins in cells, which results in tissue dysfunction. The elimination of damaged proteins occurs through the ubiquitin-proteasome system (UPS) and autophagy. In this review, we describe the mutual regulation between the UPS and autophagy and the involvement of these two proteolytic systems in metabolic dysregulation, insulin resistance, and T2DM. We propose that alterations in the UPS or autophagy contribute to triggering insulin resistance and the development of T2DM. In addition, these two pathways emerge as promising therapeutic targets for improving insulin resistance.
    Keywords:  E3-ubiquitin ligases; UPS-autophagy crosstalk; autophagy; proteaphagy; proteasome
    DOI:  https://doi.org/10.1016/j.tem.2021.04.015
  36. iScience. 2021 May 21. 24(5): 102434
    Chronic cold exposure induces autophagy to promote fatty acid oxidation, mitochondrial turnover, and thermogenesis in brown adipose tissue.
    Winifred W Yau, Kiraely Adam Wong, Jin Zhou, Nivetha Kanakaram Thimmukonda, Yajun Wu, Boon-Huat Bay, Brijesh Kumar Singh, Paul Michael Yen.
      Autophagy plays an important role in lipid breakdown, mitochondrial turnover, and mitochondrial function during brown adipose tissue (BAT) activation by thyroid hormone, but its role in BAT during adaptive thermogenesis remains controversial. Here, we examined BAT from mice exposed to 72 h of cold challenge as well as primary brown adipocytes treated with norepinephrine and found increased autophagy as well as increased β-oxidation, mitophagy, mitochondrial turnover, and mitochondrial activity. To further understand the role of autophagy of BAT in vivo, we generated BAT-specific Atg5 knockout (Atg5cKO) mice and exposed them to cold for 72 h. Interestingly, BAT-specific Atg5cKO mice were unable to maintain body temperature after chronic cold exposure and displayed deranged mitochondrial morphology and reactive oxygen species damage in their BAT. Our findings demonstrate the critical role of autophagy in adaptive thermogenesis, fatty acid metabolism, and mitochondrial function in BAT during chronic cold exposure.
    Keywords:  Cell Biology; Endocrine System Physiology; Molecular Physiology
    DOI:  https://doi.org/10.1016/j.isci.2021.102434
  37. J Adv Res. 2021 May;30 1-13
    The therapeutic effect of TBK1 in intervertebral disc degeneration via coordinating selective autophagy and autophagic functions.
    Sunli Hu, Liang Chen, Abdullah Al Mamun, Libin Ni, Weiyang Gao, Yan Lin, Haiming Jin, Xiaolei Zhang, Xiangyang Wang.
      Introduction: While its innate immune function has been known, recent works of literature have focused on the role of Tank binding kinase 1 (TBK1) in regulating autophagy and it is unknown whether TBK1 protects against intervertebral disc degeneration (IVDD) through affecting autophagy.Objectives: Here, we aim to explore whether TBK1 is implicated in the pathogenesis of IVDD, and investigated the potential mechanism.
    Methods: Western blotting and immunohistochemistry were used to detect the TBK1 expression in human and rat NP tissue. After TBK1 overexpression in NP cells with lentivirus transfection, autophagic flux, apoptosis and senescence percentage were assessed. Si-RNA , a utophagy inhibitors and protein phosphatase inhibitors were applied to study the mechanism of autophagy regulation. In vivo study, we further evaluated the therapeutic action of lentivirus-TBK1(Lv-TBK1)injection in a rodent IVDD model.
    Results: The TBK1 level was reduced in rat and human NP tissue. TBK1 overexpression protected against apoptosis and premature senescence. These functions of TBK1 were abolished by chloroquine-medicated autophagy inhibition.P-TBK1, an activation form of TBK, is involved in selective autophagy through directly phosphorylating P62 at Ser 403, and the activation of TBK1 is also dependent on Parkin manner. TBK1 also activated NPCs autophagy to relieve puncture injury in vivo.
    Conclusion: We demonstrated that TBK1 overexpression attenuated senescence and apoptosis and promoted NPCs survival via upregulating autophagy. TBK1 represents a promising avenue for IVDD treatment.
    Keywords:  Apoptosis; IVDD; Selective autophagy; Senescence; TBK1
    DOI:  https://doi.org/10.1016/j.jare.2020.08.011
  38. Cell Mol Life Sci. 2021 May 27.
    Dual regulation of fatty acid synthase (FASN) expression by O-GlcNAc transferase (OGT) and mTOR pathway in proliferating liver cancer cells.
    Sadia Raab, Alexis Gadault, Ninon Very, Amélie Decourcelle, Steffi Baldini, Céline Schulz, Marlène Mortuaire, Quentin Lemaire, Stéphan Hardivillé, Vanessa Dehennaut, Ikram El Yazidi-Belkoura, Anne-Sophie Vercoutter-Edouart, Ganna Panasyuk, Tony Lefebvre.
      Fatty acid synthase (FASN) participates in many fundamental biological processes, including energy storage and signal transduction, and is overexpressed in many cancer cells. We previously showed in a context of lipogenesis that FASN is protected from degradation by its interaction with O-GlcNAc transferase (OGT) in a nutrient-dependent manner. We and others also reported that OGT and O-GlcNAcylation up-regulate the PI3K/AKT/mTOR pathway that senses mitogenic signals and nutrient availability to drive cell cycle. Using biochemical and microscopy approaches, we show here that FASN co-localizes with OGT in the cytoplasm and, to a lesser extent, in the membrane fraction. This interaction occurs in a cell cycle-dependent manner, following the pattern of FASN expression. Moreover, we show that FASN expression depends on OGT upon serum stimulation. The level of FASN also correlates with the activation of the PI3K/AKT/mTOR pathway in hepatic cell lines, and in livers of obese mice and in a chronically activated insulin and mTOR signaling mouse model (PTEN-null mice). These results indicate that FASN is under a dual control of O-GlcNAcylation and mTOR pathways. In turn, blocking FASN with the small-molecule inhibitor C75 reduces both OGT and O-GlcNAcylation levels, and mTOR activation, highlighting a novel reciprocal regulation between these actors. In addition to the role of O-GlcNAcylation in tumorigenesis, our findings shed new light on how aberrant activity of FASN and mTOR signaling may promote the emergence of hepatic tumors.
    Keywords:  Cell proliferation; Ob/ob mice; Protein interactions; Proximity ligation assay; siRNA
    DOI:  https://doi.org/10.1007/s00018-021-03857-z
  39. Nat Commun. 2021 May 24. 12(1): 3055
    In vivo genome-wide CRISPR screen reveals breast cancer vulnerabilities and synergistic mTOR/Hippo targeted combination therapy.
    Meiou Dai, Gang Yan, Ni Wang, Girija Daliah, Ashlin M Edick, Sophie Poulet, Julien Boudreault, Suhad Ali, Sergio A Burgos, Jean-Jacques Lebrun.
      Triple negative breast cancer (TNBC) patients exhibit poor survival outcomes and lack effective targeted therapies. Using unbiased in vivo genome-wide CRISPR screening, we interrogated cancer vulnerabilities in TNBC and identified an interplay between oncogenic and tumor suppressor pathways. This study reveals tumor regulatory functions for essential components of the mTOR and Hippo pathways in TNBC. Using in vitro drug matrix synergy models and in vivo patient-derived xenografts, we further establish the therapeutic relevance of our findings and show that pharmacological inhibition of mTORC1/2 and oncoprotein YAP efficiently reduces tumorigenesis in TNBC. At the molecular level, we find that while verteporfin-induced YAP inhibition leads to apoptosis, torin1-mediated mTORC1/2 inhibition promotes macropinocytosis. Torin1-induced macropinocytosis further facilitates verteporfin uptake, thereby greatly enhancing its pro-apoptotic effects in cancer cells. Overall, our study underscores the power and robustness of in vivo CRISPR genome-wide screens in identifying clinically relevant and innovative therapeutic modalities in cancer.
    DOI:  https://doi.org/10.1038/s41467-021-23316-4
  40. Autophagy. 2021 May 26. 1-15
    Acetylation-dependent regulation of TPD52 isoform 1 modulates chaperone-mediated autophagy in prostate cancer.
    Yizeng Fan, Tao Hou, Yang Gao, Weichao Dan, Tianjie Liu, Bo Liu, Yule Chen, Hongjun Xie, Zhao Yang, Jiaqi Chen, Jin Zeng, Lei Li.
      Aberrant chaperone-mediated autophagy (CMA) activation has been suggested as a tumorigenesis-promoting event in various cancers, although its roles in prostate cancer (PCa) remain elusive. Emerging evidence indicates that TPD52 isoform 1, a prostate-specific and androgen-responsive gene, contributes to the malignant progression of PCa. Here, we demonstrate that TPD52 enhances CMA activation by interacting with HSPA8/HSC70 and enhancing substrate degradation in PCa. Elevation of TPD52 is essential for CMA-induced PCa cell proliferation and stress resistance in vitro and in vivo. Furthermore, TPD52 is acetylated by KAT2B at K163, which is a process that can be antagonized by HDAC2. Inactivation of HDAC2 results in elevated TPD52 acetylation, which compromises the interaction between TPD52 and HSPA8, leading to impaired CMA function and tumor growth in vivo. Taken together, our findings reveal that acetylation-dependent regulation of TPD52 modulates CMA oncogenic function in PCa, thereby suggesting the possibility of targeting the TPD52-mediated CMA pathway to control the progression of PCa.Abbreviations: CMA: chaperone-mediated autophagy; HDAC2: histone deacetylase 2; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KAT2B: lysine acetyltransferase 2B; LAMP2A: lysosomal associated membrane protein 2A; PCa: prostate cancer; TPD52: tumor protein D52.
    Keywords:  Chaperone-mediated autophagy; HDAC2; HSPA8; KAT2B; TPD52 isoform 1; prostate cancer
    DOI:  https://doi.org/10.1080/15548627.2021.1917130
  41. JCI Insight. 2021 May 25. pii: 149271. [Epub ahead of print]
    Placental mTOR-Complex1 regulates fetal programming of obesity and insulin resistance in mice.
    Brian Akhaphong, Daniel C Baumann, Megan Beetch, Amber D Lockridge, Seokwon Jo, Alicia Wong, Tate Zemanovic, Ramkumar Mohan, Danica L Fondevilla, Michelle Sia, Maria Rb Pineda-Cortel, Emilyn U Alejandro.
      Fetal growth restriction, or low birthweight is a strong determinant for eventual obesity and Type 2 diabetes. Clinical studies suggest placental mechanistic target of rapamycin (mTOR) signaling regulate fetal birthweight and the metabolic health trajectory of the offspring. In the current study, we used genetic model with loss of placental mTOR function (mTORKOPlacenta) to test the direct role of mTOR signaling on birthweight and the metabolic health in the adult offspring. mTORKOPlacenta animals displayed reduced placental area and total weight, as well as fetal bodyweight at embryonic day (e) 17.5. Birthweight and serum insulin levels were reduced; however, β-cell mass was normal in mTORKOPlacenta newborns. Adult mTORKOPlacenta offspring, under a metabolic high-fat challenge, displayed exacerbated obesity and metabolic dysfunction compared to littermate controls. Subsequently, we tested whether enhancing placental mTOR complex 1 (mTORC1) signaling, via genetic ablation of TSC2, in utero would improve glucose homeostasis in the offspring. Indeed, increased placental mTORC1 conferred protection from a diet-induced obesity in the offspring. In conclusion, placental mTORC1 serves as a mechanistic link between placental function and programming of obesity and insulin resistance in the adult offspring.
    Keywords:  Diabetes; Endocrinology; Islet cells; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/jci.insight.149271
  42. Prog Mol Subcell Biol. 2021 ;59 99-114
    Endoplasmic Reticulum (ER) and ER-Phagy.
    Marisa Loi, Alessandro Marazza, Maurizio Molinari.
      The endoplasmic reticulum (ER) is a biosynthetic organelle in eukaryotic cells. Its capacity to produce proteins, lipids and oligosaccharides responds to physiologic and pathologic demand. The transcriptional and translational unfolded protein response (UPR) programs increase ER size and activity. In contrast, ER-phagy programs in all their flavors select ER subdomains for lysosomal clearance. These programs are activated by nutrient deprivation, accumulation of excess ER (recov-ER-phagy), production of misfolded proteins that cannot be degraded by ER-associated degradation and that are removed from cells by the so-called ER-to-lysosome-associated degradation (ERLAD). Selection of ER subdomains to be cleared from cells relies on ER-phagy receptors, a class of membrane-bound proteins displaying cytosolic domains that engage the cytosolic ubiquitin-like protein LC3. Mechanistically, ER clearance proceeds via macro-ER-phagy, micro-ER-phagy and LC3-regulated vesicular delivery.
    Keywords:  Autophagy; ER-phagy receptors; ERLAD; Endoplasmic reticulum; LC3; Macro-ER-phagy and micro-ER-phagy; Vesicular transport
    DOI:  https://doi.org/10.1007/978-3-030-67696-4_5
  43. Front Mol Biosci. 2021 ;8 681237
    Mitochondrial Fusion Protein Mfn2 and Its Role in Heart Failure.
    Lei Chen, Bilin Liu, Yuan Qin, Anqi Li, Meng Gao, Hanyu Liu, Guohua Gong.
      Mitofusin 2 (Mfn2) is a transmembrane GTPase located on the mitochondrial outer membrane that contributes to mitochondrial network regulation. It is an essential multifunctional protein that participates in various biological processes under physical and pathological conditions, including mitochondrial fusion, reticulum-mitochondria contacts, mitochondrial quality control, and apoptosis. Mfn2 dysfunctions have been found to contribute to cardiovascular diseases, such as ischemia-reperfusion injury, heart failure, and dilated cardiomyopathy. Here, this review mainly focuses on what is known about the structure and function of Mfn2 and its crucial role in heart failure.
    Keywords:  Mfn2; endoplasmic reticulum–mitochondria contacts; heart failure; mitochondria fusion; mitophagy
    DOI:  https://doi.org/10.3389/fmolb.2021.681237
  44. Mol Cell Oncol. 2021 ;8(3): 1896348
    Regulation of nuclear mTORC1.
    Xin Zhou, Yanghao Zhong, Jin Zhang.
      mTORC1 integrates diverse upstream signals to control cell growth and metabolism. We previously showed that mTORC1 activity is spatially compartmentalized to ensure its signaling specificity. In a recently published study, we demonstrated the existence of mTORC1 activity in the nucleus and identified a unique mode of its regulation in the nuclear compartment.
    Keywords:  RAPTOR; nuclear translocation; protein kinase; signaling specificity; spatial compartmentalization
    DOI:  https://doi.org/10.1080/23723556.2021.1896348
  45. Front Cardiovasc Med. 2021 ;8 670222
    AMPK: Potential Therapeutic Target for Vascular Calcification.
    Yi Lu, Tan Yuan, Xinjia Min, Zhen Yuan, Zhejun Cai.
      Vascular calcification (VC) is an urgent worldwide health issue with no available medical treatment. It is an active cell-driven process by osteogenic differentiation of vascular cells with complex mechanisms. The AMP-activated protein kinase (AMPK) serves as the master sensor of cellular energy status. Accumulating evidence reveals the vital role of AMPK in VC progression. AMPK is involved in VC in various ways, including inhibiting runt-related transcription factor 2 signaling pathways, triggering autophagy, attenuating endoplasmic reticulum stress and dynamic-related protein 1-mediated mitochondrial fission, and activating endothelial nitric oxide synthase. AMPK activators, like metformin, are associated with reduced calcification deposits in certain groups of patients, indicating that AMPK is a potential therapeutic target for VC.
    Keywords:  AMP-activated protein kinase; autophagy; endoplasmic reticulum stress; runt-related transcription factor 2; vascular calcification
    DOI:  https://doi.org/10.3389/fcvm.2021.670222
  46. Aging (Albany NY). 2021 May 24. 13
    Autophagy deficiency downregulates O6methylguanine-DNA methyltransferase and increases chemosensitivity of liver cancer cells.
    Xiaojuan Hou, Changchun Shao, Kai Sun, Rong Li, Lu Gao, Yan Meng, Yingying Jing, Lixin Wei.
      It is known that autophagy-deficient cells are prone to DNA damage, but the specific role of autophagy in DNA damage repair is not fully known. Here, we show that autophagy-deficient liver cancer cells exhibit increased DNA damage caused by the chemotherapeutic agent epirubicin. Autophagy deficiency promotes downregulation of the DNA repair enzyme O6methylguanine-DNA methyltransferase (MGMT) in liver cancer cells. However, autophagy induction with epirubicin had no impact on MGMT gene or protein expression in liver cancer cells. In the absence of autophagy, the chemosensitivity of liver cancer cells was increased, but this was reversed by MGMT overexpression, indicating that autophagy mediates resistance to chemotherapy in liver cancer cells via MGMT. These findings demonstrate a direct link between autophagy, MGMT, and DNA damage repair in liver cancer cells, and show that MGMT not only regulates chemosensitivity to alkylating agents, but may also be involved in other DNA damage repair processes in autophagy-deficient cells.
    Keywords:  DNA damage; O6methylguanine-DNA methyltransferase (MGMT); autophagy deficiency; chemosensitivity; liver cancer
    DOI:  https://doi.org/10.18632/aging.203044
  47. Nat Chem Biol. 2021 Jun;17(6): 626
    Compromised autophagy.
    Caitlin Deane.
      
    DOI:  https://doi.org/10.1038/s41589-021-00809-3
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