bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2022‒01‒16
sixty-one papers selected by
Viktor Korolchuk, Newcastle University
  1. PP2A-dependent TFEB activation is blocked by PIKfyve-induced mTORC1 activity.
  2. RABEP1/Rabaptin5: a link between autophagy and early endosome homeostasis.
  3. Mechanism of Atg9 recruitment by Atg11 in the cytoplasm-to-vacuole targeting pathway.
  4. Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis.
  5. Tributyltin inhibits autophagy by decreasing lysosomal acidity in SH-SY5Y cells.
  6. GAK and PRKCD kinases regulate basal mitophagy.
  7. Molecular Mechanisms and Regulation of Mammalian Mitophagy.
  8. Alternative mitophagy is a major form of mitophagy in the chronically stressed heart.
  9. Degradation of the NOTCH intracellular domain by elevated autophagy in osteoblasts promotes osteoblast differentiation and alleviates osteoporosis.
  10. Links between autophagy and lipid droplet dynamics.
  11. Mosaic dysfunction of mitophagy in mitochondrial muscle disease.
  12. Autophagy mediates the clearance of oligodendroglial SNCA/alpha-synuclein and TPPP/p25A in multiple system atrophy models.
  13. Autophagy: a molecular switch to regulate adipogenesis and lipolysis.
  14. Ulk1-dependent alternative mitophagy plays a protective role during pressure overload in the heart.
  15. The exploitation of host autophagy and ubiquitin machinery by Mycobacterium tuberculosis in shaping immune responses and host defense during infection.
  16. Novel and conventional inhibitors of canonical autophagy differently affect LC3-associated phagocytosis.
  17. The complex interplay between autophagy and cell death pathways.
  18. Targeting mTOR Signaling in Type 2 Diabetes Mellitus and Diabetes Complications.
  19. Ceramide-induced mitophagy impairs ß-oxidation-linked energy production in PINK1 deficiency.
  20. GATOR2 complex-mediated amino acid signaling regulates brain myelination.
  21. Novel molecular insights into the autophagy-virus arms race.
  22. Emerging Lysosomal Functions for Photoreceptor Cell Homeostasis and Survival.
  23. Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia.
  24. Autophagy and Glycative Stress: A Bittersweet Relationship in Neurodegeneration.
  25. A Journey towards Understanding the Molecular Pathology and Developing Therapies for Lysosomal Storage Disorders.
  26. EBV LMP1-activated mTORC1 and mTORC2 Coordinately Promote Nasopharyngeal Cancer Stem Cell Properties.
  27. Surface Chemistry- and Intracellular Trafficking-Dependent Autophagy Induction by Iron Oxide Nanoparticles.
  28. RNA binding protein HuD promotes autophagy and tumor stress survival by suppressing mTORC1 activity and augmenting ARL6IP1 levels.
  29. Dysregulated Autophagy and Mitophagy in a Mouse Model of Duchenne Muscular Dystrophy Remain Unchanged Following Heme Oxygenase-1 Knockout.
  30. Caffeine prevents restenosis and inhibits vascular smooth muscle cell proliferation through the induction of autophagy.
  31. The Intricate Interplay between Cell Cycle Regulators and Autophagy in Cancer.
  32. Broad activation of the Parkin pathway induces synaptic mitochondrial deficits in early tauopathy.
  33. Gut Microbiome Regulation of Autophagic Flux and Neurodegenerative Disease Risks.
  34. Inhibition of Autophagy via Lysosomal Impairment Enhances Cytotoxicity of Fullerenol under Starvation Condition.
  35. Dysregulation of the Retromer Complex in Brain Endothelial Cells Results in Accumulation of Phosphorylated Tau.
  36. Targeted protein degradation: from small molecules to complex organelles-a Keystone Symposia report.
  37. Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis.
  38. Autophagy and ncRNAs: Dangerous Liaisons in the Crosstalk between the Tumor and Its Microenvironment.
  39. Plant virus infection disrupts vacuolar acidification and autophagic degradation for the effective infection.
  40. Mitochondrial Homeostasis in Neurodegeneration and Ageing.
  41. Matrix Stiffness Regulates Chemosensitivity, Stemness Characteristics, and Autophagy in Breast Cancer Cells.
  42. Synergistic effects of autophagy/mitophagy inhibitors and magnolol promote apoptosis and antitumor efficacy.
  43. Translational and post-translational control of human naïve versus primed pluripotency.
  44. CDC42 controlled apical-basal polarity regulates intestinal stem cell to transit amplifying cell fate transition via YAP-EGF-mTOR signaling.
  45. Chronic lithium administration in a mouse model for Krabbe disease.
  46. Down-regulation of TRPM2 attenuates hepatic ischemia/reperfusion injury through activation of autophagy and inhibition of NLRP3 inflammasome pathway.
  47. Pharmacological agents targeting autophagy and their effects on lipolysis in human adipocytes.
  48. NUMB facilitates autophagy initiation through targeting SCFβ-TrCP2 complex.
  49. Autophagy and Polyphenols in Osteoarthritis: A Focus on Epigenetic Regulation.
  50. Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy.
  51. Translational Activation of ATF4 through Mitochondrial Anaplerotic Metabolic Pathways Is Required for DLBCL Growth and Survival.
  52. Abnormal activation of yap/Taz contributes to the pathogenesis of tuberous sclerosis complex.
  53. The Metabolism Reprogramming of microRNA Let-7-Mediated Glycolysis Contributes to Autophagy and Tumor Progression.
  54. Phosphorylated tau as a toxic agent in synaptic mitochondria: implications in aging and Alzheimer's disease.
  55. Secretory Autophagy Forges a Therapy Resistant Microenvironment in Melanoma.
  56. The complexity of biological control systems: An autophagy case study.
  57. A dynamically evolving war between autophagy and pathogenic microorganisms.
  58. Autophagy Modulation and Cancer Combination Therapy: A Smart Approach in Cancer Therapy.
  59. The Tubulin Code and Tubulin-Modifying Enzymes in Autophagy and Cancer.
  60. Autophagy and Endoplasmic Reticulum Stress during Onset and Progression of Arrhythmogenic Cardiomyopathy.
  61. Annexin A6 and NPC1 regulate LDL-inducible cell migration and distribution of focal adhesions.
  1. Mol Biol Cell. 2022 Jan 12. mbcE21060309
    PP2A-dependent TFEB activation is blocked by PIKfyve-induced mTORC1 activity.
    Junya Hasegawa, Emi Tokuda, Yao Yao, Takehiko Sasaki, Ken Inoki, Lois S Weisman.
      Transcriptional factor EB (TFEB) is a master regulator of genes required for autophagy and lysosomal function. The nuclear localization of TFEB is blocked by the mechanistic target of rapamycin complex 1 (mTORC1)-dependent phosphorylation of TFEB at multiple sites including Ser-211. Here we show that inhibition of PIKfyve, which produces phosphatidylinositol 3,5-bisphosphate on endosomes and lysosomes, causes a loss of Ser-211 phosphorylation and concomitant nuclear localization of TFEB. We found that while mTORC1 activity toward S6K1, as well as other major mTORC1 substrates, is not impaired, PIKfyve inhibition specifically impedes the interaction of TFEB with mTORC1. This suggests that mTORC1 activity on TFEB is selectively inhibited due to loss of mTORC1 access to TFEB. In addition, we found that TFEB activation during inhibition of PIKfyve relies on the ability of protein phosphatase 2A (PP2A) but not calcineurin/PPP3, to dephosphorylate TFEB Ser-211. Thus, when PIKfyve is inhibited, PP2A is dominant over mTORC1 for control of TFEB phosphorylation at Ser-S211. Together these findings suggest that mTORC1 and PP2A have opposing roles on TFEB via phosphorylation and dephosphorylation of Ser-211, respectively, and further, that PIKfyve inhibits TFEB activity by facilitating mTORC1-dependent phosphorylation of TFEB.
    DOI:  https://doi.org/10.1091/mbc.E21-06-0309
  2. Autophagy. 2022 Jan 09. 1-2
    RABEP1/Rabaptin5: a link between autophagy and early endosome homeostasis.
    Valentina Millarte, Martin Spiess.
      Selective autophagy of damaged organelles assures maintenance of cellular homeostasis in eukaryotes. While the mechanisms by which cells selectively remove dysfunctional mitochondria, lysosomes, endoplasmic reticulum and other organelles has been well characterized, little is known about specific autophagy of damaged early endosomes. In our recent study, we uncovered a new role for RABEP1/Rabaptin5, a long-established regulator of early endosome function, in targeting the autophagy machinery to early endosomes damaged by chloroquine or by internalized Salmonella via interaction with RB1CC1/FIP200 and ATG16L1.
    Keywords:  ATG16L1; FIP200; Rabaptin5; Salmonella; autophagy; early endosome
    DOI:  https://doi.org/10.1080/15548627.2021.2021497
  3. J Biol Chem. 2022 Jan 07. pii: S0021-9258(22)00013-8. [Epub ahead of print] 101573
    Mechanism of Atg9 recruitment by Atg11 in the cytoplasm-to-vacuole targeting pathway.
    Nicolas Coudevylle, Bartłomiej Banaś, Verena Baumann, Martina Schuschnig, Anna Zawadzka-Kazimierczuk, Wiktor Koźmiński, Sascha Martens.
      Autophagy is a lysosomal degradation pathway for the removal of damaged and superfluous cytoplasmic material. This is achieved by the sequestration of this cargo material within double membrane vesicles termed autophagosomes. Autophagosome formation is mediated by the conserved autophagy machinery. In selective autophagy this machinery including the transmembrane protein Atg9 is recruited to specific cargo material via cargo receptors and the Atg11/FIP200 scaffold protein. The molecular details of the interaction between Atg11 and Atg9 are unclear and it is still unknown how the recruitment of Atg9 is regulated. Here we employ NMR spectroscopy of the N-terminal disordered domain of Atg9 (Atg9-NTD) to map its interaction with Atg11 revealing that it involves two short peptides both containing a PLF motif. We show that the Atg9-NTD binds to Atg11 with an affinity of about 1 micromolar and that both PLF motifs contribute to the interaction. Mutation of the PLF motifs abolishes the interaction of Atg9-NTD with Atg11, reduces the recruitment of Atg9 to the precursor aminopeptidase 1 (prApe1) cargo and blocks prApe1 transport into the vacuole by the selective autophagy-like cytoplasm-to-vacuole (Cvt) targeting pathway while not affecting bulk autophagy. Our results provide mechanistic insights into the interaction of the Atg11 scaffold with the Atg9 transmembrane protein in selective autophagy and suggest a model where only clustered Atg11 when bound to the prApe1 cargo is able to efficiently recruit Atg9 vesicles.
    Keywords:  Autophagy; Intrinsically disordered proteins; Isothermal titration calorimetry; Nuclear magnetic resonance; yeast metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2022.101573
  4. Cells. 2021 Dec 23. pii: 30. [Epub ahead of print]11(1):
    Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis.
    Roberto Iorio, Giuseppe Celenza, Sabrina Petricca.
      Mitochondria are multifunctional subcellular organelles essential for cellular energy homeostasis and apoptotic cell death. It is, therefore, crucial to maintain mitochondrial fitness. Mitophagy, the selective removal of dysfunctional mitochondria by autophagy, is critical for regulating mitochondrial quality control in many physiological processes, including cell development and differentiation. On the other hand, both impaired and excessive mitophagy are involved in the pathogenesis of different ageing-associated diseases such as neurodegeneration, cancer, myocardial injury, liver disease, sarcopenia and diabetes. The best-characterized mitophagy pathway is the PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent pathway. However, other Parkin-independent pathways are also reported to mediate the tethering of mitochondria to the autophagy apparatuses, directly activating mitophagy (mitophagy receptors and other E3 ligases). In addition, the existence of molecular mechanisms other than PINK1-mediated phosphorylation for Parkin activation was proposed. The adenosine5'-monophosphate (AMP)-activated protein kinase (AMPK) is emerging as a key player in mitochondrial metabolism and mitophagy. Beyond its involvement in mitochondrial fission and autophagosomal engulfment, its interplay with the PINK1-Parkin pathway is also reported. Here, we review the recent advances in elucidating the canonical molecular mechanisms and signaling pathways that regulate mitophagy, focusing on the early role and spatial specificity of the AMPK/ULK1 axis.
    Keywords:  AMPK; E3 ligases; PINK1–Parkin pathway; Parkin activation; ULK1; mitochondria; mitophagy; mitophagy receptors; ubiquitin
    DOI:  https://doi.org/10.3390/cells11010030
  5. Biochem Biophys Res Commun. 2022 Jan 04. pii: S0006-291X(21)01769-1. [Epub ahead of print]592 31-37
    Tributyltin inhibits autophagy by decreasing lysosomal acidity in SH-SY5Y cells.
    Shunichi Hatamiya, Masatsugu Miyara, Yaichiro Kotake.
      Tributyltin (TBT) is an environmental pollutant that remains in marine sediments and is toxic to mammals. For example, TBT elicits neurotoxic and immunosuppressive effects on rats. However, it is not entirely understood how TBT causes toxicity. Autophagy plays a pivotal role in protein quality control and eliminates aggregated proteins and damaged organelles. We previously reported that TBT dephosphorylates mammalian target of rapamycin (mTOR), which may be involved in enhancement of autophagosome synthesis, in primary cultures of cortical neurons. Autophagosomes can accumulate due to enhancement of autophagosome synthesis or inhibition of autophagic degradation, and we did not clarify whether TBT alters autophagic flux. Here, we investigated the mechanism by which TBT causes accumulation of autophagosomes in SH-SY5Y cells. TBT inhibited autophagy without affecting autophagosome-lysosome fusion before it caused cell death. TBT dramatically decreased the acidity of lysosomes without affecting lysosomal membrane integrity. TBT decreased the mature protein level of cathepsin B, and this may be related to the decrease in lysosomal acidity. These results suggest that TBT inhibits autophagic degradation by decreasing lysosomal acidity. Autophagy impairment may be involved in the mechanism underlying neuronal death and/or T-cell-dependent thymus atrophy induced by TBT.
    Keywords:  Autophagy; Lysosome; Tributyltin
    DOI:  https://doi.org/10.1016/j.bbrc.2021.12.118
  6. Autophagy. 2022 Jan 09. 1-3
    GAK and PRKCD kinases regulate basal mitophagy.
    Michael J Munson, Benan J Mathai, Matthew Yoke Wui Ng, Laura Trachsel-Moncho, Laura R de la Ballina, Anne Simonsen.
      The removal of mitochondria in a programmed or stress-induced manner is essential for maintaining cellular homeostasis. To date, much research has focused upon stress-induced mitophagy that is largely regulated by the E3 ligase PRKN, with limited insight into the mechanisms regulating basal "housekeeping" mitophagy levels in different model organisms. Using iron chelation as an inducer of PRKN-independent mitophagy, we recently screened an siRNA library of lipid-binding proteins and determined that two kinases, GAK and PRKCD, act as positive regulators of PRKN-independent mitophagy. We demonstrate that PRKCD is localized to mitochondria and regulates recruitment of ULK1-ATG13 upon induction of mitophagy. GAK activity, by contrast, modifies the mitochondrial network and lysosomal morphology that compromise efficient transport of mitochondria for degradation. Impairment of either kinase in vivo blocks basal mitophagy, demonstrating the biological relevance of our findings.Abbreviations: CCCP: carbonyl cyanide-m-chlorophenyl hydrazone; DFP: deferiprone; GAK: cyclin G associated kinase; HIF1A: hypoxia inducible factor 1 subunit alpha; PRKC/PKC: protein kinase C; PRKCD: protein kinase C delta; PRKN: parkin RBR E3 ubiquitin protein ligase.
    Keywords:  Cyclin-G-associated kinase; GAK; PKC; PRKCD; PRKN; mitophagy; protein kinase C
    DOI:  https://doi.org/10.1080/15548627.2021.2015154
  7. Cells. 2021 Dec 23. pii: 38. [Epub ahead of print]11(1):
    Molecular Mechanisms and Regulation of Mammalian Mitophagy.
    Vinay Choubey, Akbar Zeb, Allen Kaasik.
      Mitochondria in the cell are the center for energy production, essential biomolecule synthesis, and cell fate determination. Moreover, the mitochondrial functional versatility enables cells to adapt to the changes in cellular environment and various stresses. In the process of discharging its cellular duties, mitochondria face multiple types of challenges, such as oxidative stress, protein-related challenges (import, folding, and degradation) and mitochondrial DNA damage. They mitigate all these challenges with robust quality control mechanisms which include antioxidant defenses, proteostasis systems (chaperones and proteases) and mitochondrial biogenesis. Failure of these quality control mechanisms leaves mitochondria as terminally damaged, which then have to be promptly cleared from the cells before they become a threat to cell survival. Such damaged mitochondria are degraded by a selective form of autophagy called mitophagy. Rigorous research in the field has identified multiple types of mitophagy processes based on targeting signals on damaged or superfluous mitochondria. In this review, we provide an in-depth overview of mammalian mitophagy and its importance in human health and diseases. We also attempted to highlight the future area of investigation in the field of mitophagy.
    Keywords:  BNIP3; FUNDC1; PARKIN; PINK1; Parkinson’s disease; autophagy; cardiolipin; mitophagy; quality control
    DOI:  https://doi.org/10.3390/cells11010038
  8. Autophagy. 2022 Jan 13. 1-2
    Alternative mitophagy is a major form of mitophagy in the chronically stressed heart.
    Junichi Sadoshima.
      Mitochondrial dysfunction is a key determinant of the development of cardiomyopathy in patients with obesity and diabetes. We recently reported that mitophagy is activated in the mouse heart during the chronic phase of high-fat diet (HFD) consumption, despite downregulation of general macroautophagy/autophagy. This form of mitophagy is mediated by a mechanism distinct from that of conventional autophagy and is termed alternative mitophagy. We here discuss the underlying mechanisms of alternative mitophagy and its functional significance in heart disease.
    Keywords:  Mitophagy; Rab9; cardiomyopathy; diabetes; heart; obesity
    DOI:  https://doi.org/10.1080/15548627.2022.2025573
  9. Autophagy. 2022 Jan 13. 1-10
    Degradation of the NOTCH intracellular domain by elevated autophagy in osteoblasts promotes osteoblast differentiation and alleviates osteoporosis.
    Gota Yoshida, Tsuyoshi Kawabata, Hyota Takamatsu, Shotaro Saita, Shuhei Nakamura, Keizo Nishikawa, Mari Fujiwara, Yusuke Enokidani, Tadashi Yamamuro, Keisuke Tabata, Maho Hamasaki, Masaru Ishii, Atsushi Kumanogoh, Tamotsu Yoshimori.
      Maintenance of bone integrity is mediated by the balanced actions of osteoblasts and osteoclasts. Because macroautophagy/autophagy regulates osteoblast mineralization, osteoclast differentiation, and their secretion from osteoclast cells, autophagy deficiency in osteoblasts or osteoclasts can disrupt this balance. However, it remains unclear whether upregulation of autophagy becomes beneficial for suppression of bone-associated diseases. In this study, we found that genetic upregulation of autophagy in osteoblasts facilitated bone formation. We generated mice in which autophagy was specifically upregulated in osteoblasts by deleting the gene encoding RUBCN/Rubicon, a negative regulator of autophagy. The rubcnflox/flox;Sp7/Osterix-Cre mice showed progressive skeletal abnormalities in femur bones. Consistent with this, RUBCN deficiency in osteoblasts resulted in elevated differentiation and mineralization, as well as an increase in the elevated expression of key transcription factors involved in osteoblast function such as Runx2 and Bglap/Osteocalcin. Furthermore, RUBCN deficiency in osteoblasts accelerated autophagic degradation of NOTCH intracellular domain (NICD) and downregulated the NOTCH signaling pathway, which negatively regulates osteoblast differentiation. Notably, osteoblast-specific deletion of RUBCN alleviated the phenotype in a mouse model of osteoporosis. We conclude that RUBCN is a key regulator of bone homeostasis. On the basis of these findings, we propose that medications targeting RUBCN or autophagic degradation of NICD could be used to treat age-related osteoporosis and bone fracture.Abbreviations: ALPL: alkaline phosphatase, liver/bone/kidney; BCIP/NBT: 5-bromo-4-chloro-3'-indolyl phosphate/nitro blue tetrazolium; BMD: bone mineral density; BV/TV: bone volume/total bone volume; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NICD: NOTCH intracellular domain; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; SERM: selective estrogen receptor modulator; TNFRSF11B/OCIF: tumor necrosis factor receptor superfamily, member 11b (osteoprotegerin).
    Keywords:  Bone remodeling; NICD; RUBCN; Rubicon; differentiation; mineralization; osteoblast
    DOI:  https://doi.org/10.1080/15548627.2021.2017587
  10. J Exp Bot. 2022 Jan 10. pii: erac003. [Epub ahead of print]
    Links between autophagy and lipid droplet dynamics.
    Changcheng Xu, Jilian Fan.
      Autophagy is a catabolic process in which cytoplasmic components are delivered to vacuoles or lysosomes for degradation and nutrient recycling. Autophagy-mediated degradation of membrane lipids provides a source of fatty acids for the synthesis of energy-rich, storage lipid esters such as triacylglycerol (TAG). In eukaryotes, storage lipids are packaged into dynamic subcellular organelles, lipid droplets (LDs). In times of energy scarcity, LDs can be degraded via autophagy in a process termed lipophagy to release fatty acids for energy production via fatty acid β-oxidation. On the other hand, emerging evidence suggests that LDs are required for the efficient execution of autophagic processes. Here, we review recent advances in our understanding of metabolic interactions between autophagy and TAG storage and discuss mechanisms of lipophagy. Free fatty acids are cytotoxic due to their detergent-like properties and their incorporation into lipid intermediates that are toxic at high levels, therefore, the third part of this review deals with how cells manage lipotoxic stresses during autophagy-mediated mobilization of fatty acids from LDs and organellar membranes for energy generation.
    Keywords:  autophagy; fatty acid; lipid droplet; lipid homeostasis; lipophagy; lipotoxicity
    DOI:  https://doi.org/10.1093/jxb/erac003
  11. Cell Metab. 2022 Jan 07. pii: S1550-4131(21)00636-7. [Epub ahead of print]
    Mosaic dysfunction of mitophagy in mitochondrial muscle disease.
    Takayuki Mito, Amy E Vincent, Julie Faitg, Robert W Taylor, Nahid A Khan, Thomas G McWilliams, Anu Suomalainen.
      Mitophagy is a quality control mechanism that eliminates damaged mitochondria, yet its significance in mammalian pathophysiology and aging has remained unclear. Here, we report that mitophagy contributes to mitochondrial dysfunction in skeletal muscle of aged mice and human patients. The early disease stage is characterized by muscle fibers with central nuclei, with enhanced mitophagy around these nuclei. However, progressive mitochondrial dysfunction halts mitophagy and disrupts lysosomal homeostasis. Interestingly, activated or halted mitophagy occur in a mosaic manner even in adjacent muscle fibers, indicating cell-autonomous regulation. Rapamycin restores mitochondrial turnover, indicating mTOR-dependence of mitochondrial recycling in advanced disease stage. Our evidence suggests that (1) mitophagy is a hallmark of age-related mitochondrial pathology in mammalian muscle, (2) mosaic halting of mitophagy is a mechanism explaining mosaic respiratory chain deficiency and accumulation of pathogenic mtDNA variants in adult-onset mitochondrial diseases and normal aging, and (3) augmenting mitophagy is a promising therapeutic approach for muscle mitochondrial dysfunction.
    Keywords:  SBFSEM; centrally nucleated fibers; lysosome; mito-QC; mitochondrial disease; mitochondrial myopathy; mitophagy; patient; ragged-red fibers
    DOI:  https://doi.org/10.1016/j.cmet.2021.12.017
  12. Autophagy. 2022 Jan 09. 1-30
    Autophagy mediates the clearance of oligodendroglial SNCA/alpha-synuclein and TPPP/p25A in multiple system atrophy models.
    Panagiota Mavroeidi, Fedra Arvanitaki, Maria Vetsi, Stefan Becker, Dimitrios Vlachakis, Poul Henning Jensen, Leonidas Stefanis, Maria Xilouri.
      Accumulation of the neuronal protein SNCA/alpha-synuclein and of the oligodendroglial phosphoprotein TPPP/p25A within the glial cytoplasmic inclusions (GCIs) represents the key histophathological hallmark of multiple system atrophy (MSA). Even though the levels/distribution of both oligodendroglial SNCA and TPPP/p25A proteins are critical for disease pathogenesis, the proteolytic mechanisms involved in their turnover in health and disease remain poorly understood. Herein, by pharmacological and molecular modulation of the autophagy-lysosome pathway (ALP) and the proteasome we demonstrate that the endogenous oligodendroglial SNCA and TPPP/p25A are degraded mainly by the ALP in murine primary oligodendrocytes and oligodendroglial cell lines under basal conditions. We also identify a KFERQ-like motif in the TPPP/p25A sequence that enables its effective degradation via chaperone-mediated autophagy (CMA) in an in vitro system of rat brain lysosomes. Furthermore, in a MSA-like setting established by addition of human recombinant SNCA pre-formed fibrils (PFFs) as seeds of pathological SNCA, we thoroughly characterize the contribution of CMA and macroautophagy in particular, in the removal of the exogenously added and the seeded oligodendroglial SNCA pathological assemblies. We also show that PFF treatment impairs autophagic flux and that TPPP/p25A exerts an inhibitory effect on macroautophagy, while at the same time CMA is upregulated to remove the pathological SNCA species formed within oligodendrocytes. Finally, augmentation of CMA or macroautophagy accelerates the removal of the engendered pathological SNCA conformations further suggesting that autophagy targeting may represent a successful approach for the clearance of pathological SNCA and/or TPPP/p25A in the context of MSA.Abbreviations: 3MA: 3-methyladenine; ACTB: actin, beta; ALP: autophagy-lysosome pathway; ATG5: autophagy related 5; AR7: atypical retinoid 7; CMA: chaperone-mediated autophagy; CMV: cytomegalovirus; CTSD: cathepsin D; DAPI: 4',6-diamidino-2-phenylindole; DMEM: Dulbecco's modified Eagle's medium; Epox: epoxomicin; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GCIs: glial cytoplasmic inclusions; GFP: green fluorescent protein; HMW: high molecular weight; h: hours; HSPA8/HSC70: heat shock protein 8; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; mcherry: monomeric cherry; MFI: mean fluorescence intensity; mRFP: monomeric red fluorescent protein; MSA: multiple system atrophy; OLN: oligodendrocytes; OPCs: oligodendroglial progenitor cells; PBS: phosphate-buffered saline; PC12: pheochromocytoma cell line; PD: Parkinson disease; PFFs: pre-formed fibrils; PIs: protease inhibitors; PSMB5: proteasome (prosome, macropain) subunit, beta type 5; Rap: rapamycin; RFP: red fluorescent protein; Scr: scrambled; SDS: sodium dodecyl sulfate; SE: standard error; siRNAs: small interfering RNAs; SNCA: synuclein, alpha; SQSTM1: sequestosome 1; TPPP: tubulin polymerization promoting protein; TUBA: tubulin, alpha; UPS: ubiquitin-proteasome system; WT: wild type.
    Keywords:  Chaperone-mediated autophagy; fibrils; inclusions; macroautophagy; oligodendrocytes; proteasome; seeding
    DOI:  https://doi.org/10.1080/15548627.2021.2016256
  13. Mol Cell Biochem. 2022 Jan 13.
    Autophagy: a molecular switch to regulate adipogenesis and lipolysis.
    Mouliganesh Sekar, Kavitha Thirumurugan.
      Obesity is a complex epidemic disease caused by an imbalance of adipose tissue function that results in hyperglycemia, hyperlipidemia and insulin resistance which further develop into type 2 diabetes, cardiovascular disease and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Adipose tissue is responsible for fat storage; white adipose tissue stores excess energy as fat for availability during starvation, whereas brown adipose tissue regulates thermogenesis through fat oxidation using uncoupling protein 1. However, hypertrophic fat storage results in inflammation and increase the chances for obesity which triggers autophagy genes and lipolytic enzymes to regulate lipid metabolism. Autophagy degrades cargo molecule with the help of lysosome and redistributes the energy back to the cell. Autophagy regulates adipocyte differentiation by modulating master regulators of adipogenesis. Adipogenesis is the process which stores excessive energy in the form of lipid droplets. Lipid droplets (LD) are dynamic cellular organelles that store toxic free-fatty acids into neutral triglycerides in adipose tissue. LD activates both lipolysis and lipophagy to degrade excess triglycerides. In obese tissue, autophagy is activated via pro-inflammatory cytokines produced by surplus fat stored in the adipose tissue. This review focused on the process of autophagy and adipogenesis and the transcription factors that regulate lipogenesis and lipolysis in the adipose tissue. We have also discussed about the importance of autophagic regulation within adipose tissue which controls the onset of obesity and its associated diseases.
    Keywords:  Adipose tissue; Autophagy; Lipolysis; Lipophagy; Obesity; Transcription factors
    DOI:  https://doi.org/10.1007/s11010-021-04324-w
  14. Cardiovasc Res. 2022 Jan 09. pii: cvac003. [Epub ahead of print]
    Ulk1-dependent alternative mitophagy plays a protective role during pressure overload in the heart.
    Jihoon Nah, Akihiro Shirakabe, Risa Mukai, Peiyong Zhai, Eun-Ah Sung, Andreas Ivessa, Wataru Mizushima, Yasuki Nakada, Toshiro Saito, Chengchen Hu, Yong-Keun Jung, Junichi Sadoshima.
      AIMS: Well-controlled mitochondrial homeostasis, including a mitochondria-specific form of autophagy (hereafter referred to as mitophagy), is essential for maintaining cardiac function. The molecular mechanism mediating mitophagy during PO is poorly understood. We have shown previously that mitophagy in the heart is mediated primarily by Atg5/Atg7-independent mechanisms, including Unc-51-like kinase1 (Ulk1)-dependent alternative mitophagy, during myocardial ischemia. Here, we investigated the role of alternative mitophagy in the heart during PO-induced hypertrophy.METHODS AND RESULTS: Mitophagy was observed in the heart in response to transverse aortic constriction (TAC), peaking at 3-5 days. Whereas mitophagy is transiently upregulated by TAC through an Atg7-dependent mechanism in the heart, peaking at 1 day, it is also activated more strongly and with a delayed time course through an Ulk1-dependent mechanism. TAC induced more severe cardiac dysfunction, hypertrophy and fibrosis in ulk1 cardiac specific knock-out (cKO) mice than in wild type mice. Delayed activation of mitophagy was characterized by the co-localization of Rab9 dots and mitochondria and phosphorylation of Rab9 at Ser179, major features of alternative mitophagy. Furthermore, TAC-induced decreases in the mitochondrial aspect ratio were abolished and the irregularity of mitochondrial cristae was exacerbated, suggesting that mitochondrial quality control mechanisms are impaired in ulk1 cKO mice in response to TAC. TAT-Beclin 1 activates mitophagy even in Ulk1-deficient conditions. TAT-Beclin 1 treatment rescued mitochondrial dysfunction and cardiac dysfunction in ulk1 cKO mice during PO.
    CONCLUSIONS: Ulk1-mediated alternative mitophagy is a major mechanism mediating mitophagy in response to PO and plays an important role in mediating mitochondrial quality control mechanisms and protecting the heart against cardiac dysfunction.
    TRANSLATIONAL PERSPECTIVE: Heart failure is often accompanied by mitochondrial dysfunction in cardiomyocytes. Elimination of dysfunctional mitochondria by mitochondria-specific forms of autophagy, termed mitophagy, is a crucial mechanism for maintaining mitochondrial function in the stressed heart. We discovered that an unconventional form of mitophagy mediated through an Atg7-independent and Ulk1- and Rab9-dependent mechanism is a predominant form of mitophagy in the heart in response to pressure overload. Interventions to restore mitophagy by stimulating the signaling mechanism of the Ulk1-Rab9-dependent mitophagy should delay the development of heart failure in patients with increased afterload.
    Keywords:  Cardiac hypertrophy; Rab9; Ulk1; mitochondria; mitophagy; pressure overload
    DOI:  https://doi.org/10.1093/cvr/cvac003
  15. Autophagy. 2022 Jan 09. 1-22
    The exploitation of host autophagy and ubiquitin machinery by Mycobacterium tuberculosis in shaping immune responses and host defense during infection.
    Mohd Shariq, Neha Quadir, Anwar Alam, Sheeba Zarin, Javaid A Sheikh, Neha Sharma, Jasmine Samal, Uzair Ahmad, Indu Kumari, Seyed E Hasnain, Nasreen Z Ehtesham.
      Intracellular pathogens have evolved various efficient molecular armaments to subvert innate defenses. Cellular ubiquitination, a normal physiological process to maintain homeostasis, is emerging one such exploited mechanism. Ubiquitin (Ub), a small protein modifier, is conjugated to diverse protein substrates to regulate many functions. Structurally diverse linkages of poly-Ub to target proteins allow enormous functional diversity with specificity being governed by evolutionarily conserved enzymes (E3-Ub ligases). The Ub-binding domain (UBD) and LC3-interacting region (LIR) are critical features of macroautophagy/autophagy receptors that recognize Ub-conjugated on protein substrates. Emerging evidence suggests that E3-Ub ligases unexpectedly protect against intracellular pathogens by tagging poly-Ub on their surfaces and targeting them to phagophores. Two E3-Ub ligases, PRKN and SMURF1, provide immunity against Mycobacterium tuberculosis (M. tb). Both enzymes conjugate K63 and K48-linked poly-Ub to M. tb for successful delivery to phagophores. Intriguingly, M. tb exploits virulence factors to effectively dampen host-directed autophagy utilizing diverse mechanisms. Autophagy receptors contain LIR-motifs that interact with conserved Atg8-family proteins to modulate phagophore biogenesis and fusion to the lysosome. Intracellular pathogens have evolved a vast repertoire of virulence effectors to subdue host-immunity via hijacking the host ubiquitination process. This review highlights the xenophagy-mediated clearance of M. tb involving host E3-Ub ligases and counter-strategy of autophagy inhibition by M. tb using virulence factors. The role of Ub-binding receptors and their mode of autophagy regulation is also explained. We also discuss the co-opting and utilization of the host Ub system by M. tb for its survival and virulence.Abbreviations: APC: anaphase promoting complex/cyclosome; ATG5: autophagy related 5; BCG: bacille Calmette-Guerin; C2: Ca2+-binding motif; CALCOCO2: calcium binding and coiled-coil domain 2; CUE: coupling of ubiquitin conjugation to ER degradation domains; DUB: deubiquitinating enzyme; GABARAP: GABA type A receptor-associated protein; HECT: homologous to the E6-AP carboxyl terminus; IBR: in-between-ring fingers; IFN: interferon; IL1B: interleukin 1 beta; KEAP1: kelch like ECH associated protein 1; LAMP1: lysosomal associated membrane protein 1; LGALS: galectin; LIR: LC3-interacting region; MAPK11/p38: mitogen-activated protein kinase 11; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MAPK8/JNK: mitogen-activated protein kinase 8; MHC-II: major histocompatibility complex-II; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; NFKB1/p50: nuclear factor kappa B subunit 1; OPTN: optineurin; PB1: phox and bem 1; PE/PPE: proline-glutamic acid/proline-proline-glutamic acid; PknG: serine/threonine-protein kinase PknG; PRKN: parkin RBR E3 ubiquitin protein ligase; RBR: RING-in between RING; RING: really interesting new gene; RNF166: RING finger protein 166; ROS: reactive oxygen species; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TNF: tumor necrosis factor; TRAF6: TNF receptor associated factor 6; Ub: ubiquitin; UBA: ubiquitin-associated; UBAN: ubiquitin-binding domain in ABIN proteins and NEMO; UBD: ubiquitin-binding domain; UBL: ubiquitin-like; ULK1: unc-51 like autophagy activating kinase 1.
    Keywords:  Autophagy; E3-Ub ligase; LC3; intracellular pathogens; phagolysosome; ubiquitin-binding receptors; virulence effectors; xenophagy
    DOI:  https://doi.org/10.1080/15548627.2021.2021495
  16. FEBS Lett. 2022 Jan 10.
    Novel and conventional inhibitors of canonical autophagy differently affect LC3-associated phagocytosis.
    Femmy C Stempels, Maaike H Janssens, Martin Ter Beest, Rob J Mesman, Natalia H Revelo, Melina Ioannidis, Geert van den Bogaart.
      In autophagy, LC3-positive autophagophores fuse and encapsulate the autophagic cargo in a double-membrane structure. In contrast, lipidated LC3 (LC3-II) is directly formed at the phagosomal membrane in LC3-associated phagocytosis (LAP). In this study, we dissected the effects of autophagy inhibitors on LAP. SAR405, an inhibitor of VPS34, reduced levels of LC3-II and inhibited LAP. In contrast, the inhibitors of endosomal acidification bafilomycin A1 and chloroquine increased levels of LC3-II, due to reduced degradation in acidic lysosomes. However, while bafilomycin A1 inhibited LAP, chloroquine did not. Finally, EACC, which inhibits the fusion of autophagosomes with lysosomes, promoted LC3 degradation possibly by the proteasome. Targeting LAP with small molecule inhibitors is important given its emerging role in infectious and autoimmune diseases.
    Keywords:  EACC; LAP; LC3-associated phagocytosis; SAR405; autophagy; bafilomycin A1; chloroquine
    DOI:  https://doi.org/10.1002/1873-3468.14280
  17. Biochem J. 2022 Jan 14. 479(1): 75-90
    The complex interplay between autophagy and cell death pathways.
    Christina Ploumi, Margarita-Elena Papandreou, Nektarios Tavernarakis.
      Autophagy is a universal cellular homeostatic process, required for the clearance of dysfunctional macromolecules or organelles. This self-digestion mechanism modulates cell survival, either directly by targeting cell death players, or indirectly by maintaining cellular balance and bioenergetics. Nevertheless, under acute or accumulated stress, autophagy can also contribute to promote different modes of cell death, either through highly regulated signalling events, or in a more uncontrolled inflammatory manner. Conversely, apoptotic or necroptotic factors have also been implicated in the regulation of autophagy, while specific factors regulate both processes. Here, we survey both earlier and recent findings, highlighting the intricate interaction of autophagic and cell death pathways. We, Furthermore, discuss paradigms, where this cross-talk is disrupted, in the context of disease.
    Keywords:  apoptosis; autophagic cell death; autophagy; cancer; necroptosis; neurodegeneration
    DOI:  https://doi.org/10.1042/BCJ20210450
  18. Curr Drug Targets. 2022 Jan 11.
    Targeting mTOR Signaling in Type 2 Diabetes Mellitus and Diabetes Complications.
    Lin Yang, Zhixin Zhang, Doudou Wang, Yu Jiang, Ying Liu.
      The mechanistic target of rapamycin (mTOR) is a pivotal regulator of cell metabolism and growth. In the form of two different multi-protein complexes, mTORC1 and mTORC2, mTOR integrates cellular energy, nutrient and hormonal signals to regulate cellular metabolic homeostasis. In type 2 diabetes mellitus (T2DM) aberrant mTOR signaling underlies its pathological conditions and end-organ complications. Substantial evidence suggests that two mTOR-mediated signaling schemes, mTORC1-p70S6 kinase 1 (S6K1) and mTORC2-protein kinase B (AKT), play a critical role in insulin sensitivity and that their dysfunction contributes to development of T2DM. This review summaries our current understanding of the role of mTOR signaling in T2DM and its associated complications, as well as the potential use of mTOR inhibitors in treatment of T2DM.
    Keywords:  diabetes complications; mTOR inhibitor; mTORC1; mTORC2; type 2 diabetes mellitus
    DOI:  https://doi.org/10.2174/1389450123666220111115528
  19. Autophagy. 2022 Jan 14. 1-2
    Ceramide-induced mitophagy impairs ß-oxidation-linked energy production in PINK1 deficiency.
    Melissa Vos, Christine Klein.
      Mitophagy and energy production are two functionalities in which PINK1 plays a key role. Loss of PINK1 is one of the genetic causes of Parkinson disease (PD), suggesting both processes are important in PD pathogenesis. Nonetheless, it remains unclear whether these processes are connected or independent of one another. Sphingolipids, including ceramide, have recently emerged as an important new player in the development of PD, however, how alterations in ceramide levels are mechanistically linked to PD remained elusive. In a recently published study, we demonstrated that ceramide accumulates in mitochondria and initiates ceramide-induced mitophagy, thereby compensating for the lack of PINK1-dependent mitophagy upon PINK1 deficiency. However, ceramide accumulation negatively affects ß-oxidation, further aggravating the electron transport chain (ETC) defect caused by PINK1 deficiency and resulting in an additional requirement for mitophagy. Thus, we showed that ceramide serves as a link between the ETC and mitophagy upon PINK1 deficiency. Interruption of this vicious cycle via stimulation of ß-oxidation or reduction of ceramide levels can provide a novel therapeutic target in the treatment of PINK1-related PD.
    Keywords:  PINK1; Parkinson’s disease; ceramide; mitophagy; ß-oxidation
    DOI:  https://doi.org/10.1080/15548627.2022.2027193
  20. Proc Natl Acad Sci U S A. 2022 Jan 18. pii: e2110917119. [Epub ahead of print]119(3):
    GATOR2 complex-mediated amino acid signaling regulates brain myelination.
    Zongyan Yu, Zhiwen Yang, Guoru Ren, Yingjie Wang, Xiang Luo, Feiyan Zhu, Shouyang Yu, Lanlan Jia, Mina Chen, Paul F Worley, Bo Xiao.
      Amino acids are essential for cell growth and metabolism. Amino acid and growth factor signaling pathways coordinately regulate the mechanistic target of rapamycin complex 1 (mTORC1) kinase in cell growth and organ development. While major components of amino acid signaling mechanisms have been identified, their biological functions in organ development are unclear. We aimed to understand the functions of the critically positioned amino acid signaling complex GAP activity towards Rags 2 (GATOR2) in brain development. GATOR2 mediates amino acid signaling to mTORC1 by directly linking the amino acid sensors for arginine and leucine to downstream signaling complexes. Now, we report a role of GATOR2 in oligodendrocyte myelination in postnatal brain development. We show that the disruption of GATOR2 complex by genetic deletion of meiosis regulator for oocyte development (Mios, encoding a component of GATOR2) selectively impairs the formation of myelinating oligodendrocytes, thus brain myelination, without apparent effects on the formation of neurons and astrocytes. The loss of Mios impairs cell cycle progression of oligodendrocyte precursor cells, leading to their reduced proliferation and differentiation. Mios deletion manifests a cell type-dependent effect on mTORC1 in the brain, with oligodendroglial mTORC1 selectively affected. However, the role of Mios/GATOR2 in oligodendrocyte formation and myelination involves mTORC1-independent function. This study suggests that GATOR2 coordinates amino acid and growth factor signaling to regulate oligodendrocyte myelination.
    Keywords:  GATOR2; Mios; amino acid signaling; myelination; oligodendrocytes
    DOI:  https://doi.org/10.1073/pnas.2110917119
  21. Trends Microbiol. 2022 Jan 07. pii: S0966-842X(21)00317-6. [Epub ahead of print]
    Novel molecular insights into the autophagy-virus arms race.
    Christophe Viret, Mathias Faure.
      Autophagy can restrict virus replication so efficiently that viruses have evolved means to avoid or oppose the autophagic response. Two recent studies (Ames et al. and Martin-Sancho et al.) have revealed that the autophagy receptor optineurin restricts HSV-1 replication in neurons and have elucidated how the M2 protein of IAV inhibits the completion of autophagy.
    Keywords:  autophagy; autophagy receptor; coevolution; virophagy; viruses
    DOI:  https://doi.org/10.1016/j.tim.2021.12.010
  22. Cells. 2021 Dec 26. pii: 60. [Epub ahead of print]11(1):
    Emerging Lysosomal Functions for Photoreceptor Cell Homeostasis and Survival.
    Manuela Santo, Ivan Conte.
      Lysosomes are membrane-bound cell organelles that respond to nutrient changes and are implicated in cell homeostasis and clearance mechanisms, allowing effective adaptation to specific cellular needs. The relevance of the lysosome has been elucidated in a number of different contexts. Of these, the retina represents an interesting scenario to appreciate the various functions of this organelle in both physiological and pathological conditions. Growing evidence suggests a role for lysosome-related mechanisms in retinal degeneration. Abnormal lysosomal activation or inhibition has dramatic consequences on photoreceptor cell homeostasis and impacts extensive cellular function, which in turn affects vision. Based on these findings, a series of therapeutic methods targeting lysosomal processes could offer treatment for blindness conditions. Here, we review the recent findings on membrane trafficking, subcellular organization, mechanisms by which lysosome/autophagy pathway impairment affects photoreceptor cell homeostasis and the recent advances on developing efficient lysosomal-based therapies for retinal disorders.
    Keywords:  autophagy; lysosome; membrane trafficking; photoreceptors; retinal degeneration
    DOI:  https://doi.org/10.3390/cells11010060
  23. Aging Cell. 2022 Jan 13. e13549
    Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia.
    Patricia Gomez-Suaga, Gábor M Mórotz, Andrea Markovinovic, Sandra M Martín-Guerrero, Elisavet Preza, Natalia Arias, Keith Mayl, Afra Aabdien, Vesela Gesheva, Agnes Nishimura, Ambra Annibali, Younbok Lee, Jacqueline C Mitchell, Selina Wray, Christopher Shaw, Wendy Noble, Christopher C J Miller.
      Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which the expansions cause disease are not properly understood but a favoured route involves its translation into dipeptide repeat (DPR) polypeptides, some of which are neurotoxic. However, the precise targets for mutant C9orf72 and DPR toxicity are not fully clear, and damage to several neuronal functions has been described. Many of these functions are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. ER-mitochondria signalling requires close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 'tethering' proteins. Here, we show that ER-mitochondria signalling and the VAPB-PTPIP51 tethers are disrupted in neurons derived from induced pluripotent stem (iPS) cells from patients carrying ALS/FTD pathogenic C9orf72 expansions and in affected neurons in mutant C9orf72 transgenic mice. In these mice, disruption of the VAPB-PTPIP51 tethers occurs prior to disease onset suggesting that it contributes to the pathogenic process. We also show that neurotoxic DPRs disrupt the VAPB-PTPIP51 interaction and ER-mitochondria contacts and that this may involve activation of glycogen synthase kinases-3β (GSK3β), a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that these DPRs disrupt delivery of Ca2+ from ER stores to mitochondria, which is a primary function of the VAPB-PTPIP51 tethers. This delivery regulates a number of key neuronal functions that are damaged in ALS/FTD including bioenergetics, autophagy and synaptic function. Our findings reveal a new molecular target for mutant C9orf72-mediated toxicity.
    Keywords:   C9orf72 ; GSK3β; PTPIP51; VAPB; amyotrophic lateral sclerosis; endoplasmic reticulum; frontotemporal dementia; mitochondria
    DOI:  https://doi.org/10.1111/acel.13549
  24. Front Cell Dev Biol. 2021 ;9 790479
    Autophagy and Glycative Stress: A Bittersweet Relationship in Neurodegeneration.
    Olga Gómez, Giuliana Perini-Villanueva, Andrea Yuste, José Antonio Rodríguez-Navarro, Enric Poch, Eloy Bejarano.
      Autophagy is a fine-tuned proteolytic pathway that moves dysfunctional/aged cellular components into the lysosomal compartment for degradation. Over the last 3 decades, global research has provided evidence for the protective role of autophagy in different brain cell components. Autophagic capacities decline with age, which contributes to the accumulation of obsolete/damaged organelles and proteins and, ultimately, leads to cellular aging in brain tissues. It is thus well-accepted that autophagy plays an essential role in brain homeostasis, and malfunction of this catabolic system is associated with major neurodegenerative disorders. Autophagy function can be modulated by different types of stress, including glycative stress. Glycative stress is defined as a cellular status with abnormal and accelerated accumulation of advanced glycation end products (AGEs). It occurs in hyperglycemic states, both through the consumption of high-sugar diets or under metabolic conditions such as diabetes. In recent years, glycative stress has gained attention for its adverse impact on brain pathology. This is because glycative stress stimulates insoluble, proteinaceous aggregation that is linked to the malfunction of different neuropathological proteins. Despite the emergence of new literature suggesting that autophagy plays a major role in fighting glycation-derived damage by removing cytosolic AGEs, excessive glycative stress might also negatively impact autophagic function. In this mini-review, we provide insight on the status of present knowledge regarding the role of autophagy in brain physiology and pathophysiology, with an emphasis on the cytoprotective role of autophagic function to ameliorate the adverse effects of glycation-derived damage in neurons, glia, and neuron-glia interactions.
    Keywords:  AGEs; aging; autophagy; glycation; neurodegeneration
    DOI:  https://doi.org/10.3389/fcell.2021.790479
  25. Cells. 2021 Dec 23. pii: 36. [Epub ahead of print]11(1):
    A Journey towards Understanding the Molecular Pathology and Developing Therapies for Lysosomal Storage Disorders.
    Ritva Tikkanen.
      Lysosomal storage disorders (LSDs) are rare, monogenic diseases characterized by aberrant lysosomes with storage material [...].
    DOI:  https://doi.org/10.3390/cells11010036
  26. J Virol. 2022 Jan 12. jvi0194121
    EBV LMP1-activated mTORC1 and mTORC2 Coordinately Promote Nasopharyngeal Cancer Stem Cell Properties.
    Nannan Zhu, Qian Wang, Zhidong Wu, Yan Wang, Mu-Sheng Zeng, Yan Yuan.
      Epstein-Barr Virus (EBV) is associated with several malignant diseases, including Burkitt's lymphoma, nasopharyngeal carcinoma (NPC), certain types of lymphomas, and a portion of gastric cancers. Virus-encoded oncoprotein LMP1 induces the epithelial-to-mesenchymal transition (EMT), leading to cancer stem cell formation. In the current study, we investigated how LMP1 contributes to cancer stem cell development in NPC. We found that LMP1 plays an essential role in acquiring CSC characteristics, including tumor initiation, metastasis, and therapeutic resistance by activating the PI3K/mTOR/Akt signaling pathway. We dissected the functions of distinct signaling (mTORC1 and mTORC2) in the acquisition of different CSC characteristics. Side population (SP) formation, which represents the chemotherapy resistance feature of CSC, requires mTORC1 signaling. Tumor initiation capability is mainly attributed to mTORC2, which confers on NPC the capabilities of proliferation and survival by activating mTORC2 downstream genes c-Myc. Both mTORC1 and mTORC2 enhance cell migration and invasion of NPC cells, suggesting that mTORC1/2 co-regulate metastasis of NPC. The revelation of the roles of the mTOR signaling pathways in distinct tumorigenic features provides a guideline for designing efficient therapies by choosing specific mTOR inhibitors targeting mTORC1, mTORC2, or both to achieve durable remission of NPC in patients. Importance LMP1 endows NPC to gain cancer stem cell characteristics through activating mTORC1 and mTORC2 pathways. The different mTOR pathways are responsible for distinct tumorigenic features. Rapamycin-insensitive mTORC1 is essential for CSC drug resistance. NPC tumor initiation capacity is mainly attributed to mTORC2 signaling. mTORC1 and mTORC2 co-regulate NPC cell migration and invasion. The revelation of the roles of mTOR signaling in NPC CSC establishment has implications for novel therapeutic strategies to treat relapsed and metastatic NPC and achieve durable remission.
    DOI:  https://doi.org/10.1128/jvi.01941-21
  27. ACS Appl Bio Mater. 2020 Sep 21. 3(9): 5974-5983
    Surface Chemistry- and Intracellular Trafficking-Dependent Autophagy Induction by Iron Oxide Nanoparticles.
    Prasanta Panja, Koushik Debnath, Nihar R Jana, Nikhil R Jana.
      Autophagy is a cellular self-clearance process for maintaining regular cytoplasmic function, and modulation of autophagy can influence cytotoxicity, apoptosis, and clearance of toxic amyloid fibril. In a recent work, functional nanoparticles are used to modulate autophagy. However, the role of nanoparticle uptake mechanisms and their intracellular processing on autophagy is vaguely understood. Here, we show that autophagy is influenced by nanoparticle surface chemistry-directed intracellular trafficking and localization. In particular, we have designed iron oxide nanoparticles functionalized with arginine/arginine methyl ester/octyl/oleyl/cholesterol with a high cell uptake property. We found that autophagy is induced by octyl/oleyl functionalization without appreciable cell death. Further study shows that enhanced cytosolic delivery over membrane localization and increased intracellular aggregation over homogeneous cytosolic distribution lead to autophagy induction via intracellular reactive oxygen species generation. The observed result can be used to design functional nanoparticles/nanodrugs for modulating cellular autophagy that can be used in various biomedical applications.
    Keywords:  autophagy; iron oxide; nanoparticle; reactive oxygen species; surface chemistry
    DOI:  https://doi.org/10.1021/acsabm.0c00640
  28. J Exp Clin Cancer Res. 2022 Jan 10. 41(1): 18
    RNA binding protein HuD promotes autophagy and tumor stress survival by suppressing mTORC1 activity and augmenting ARL6IP1 levels.
    Kausik Bishayee, Khadija Habib, Uddin Md Nazim, Jieun Kang, Aniko Szabo, Sung-Oh Huh, Ali Sadra.
      BACKGROUND: Neuronal-origin HuD (ELAVL4) is an RNA binding protein overexpressed in neuroblastoma (NB) and certain other cancers. The RNA targets of this RNA binding protein in neuroblastoma cells and their role in promoting cancer survival have been unexplored. In the study of modulators of mTORC1 activity under the conditions of optimal cell growth and starvation, the role of HuD and its two substrates were studied.METHODS: RNA immunoprecipitation/sequencing (RIP-SEQ) coupled with quantitative real-time PCR were used to identify substrates of HuD in NB cells. Validation of the two RNA targets of HuD was via reverse capture of HuD by synthetic RNA oligoes from cell lysates and binding of RNA to recombinant forms of HuD in the cell and outside of the cell. Further analysis was via RNA transcriptome analysis of HuD silencing in the test cells.
    RESULTS: In response to stress, HuD was found to dampen mTORC1 activity and allow the cell to upregulate its autophagy levels by suppressing mTORC1 activity. Among mRNA substrates regulated cell-wide by HuD, GRB-10 and ARL6IP1 were found to carry out critical functions for survival of the cells under stress. GRB-10 was involved in blocking mTORC1 activity by disrupting Raptor-mTOR kinase interaction. Reduced mTORC1 activity allowed lifting of autophagy levels in the cells required for increased survival. In addition, ARL6IP1, an apoptotic regulator in the ER membrane, was found to promote cell survival by negative regulation of apoptosis. As a therapeutic target, knockdown of HuD in two xenograft models of NB led to a block in tumor growth, confirming its importance for viability of the tumor cells. Cell-wide RNA messages of these two HuD substrates and HuD and mTORC1 marker of activity significantly correlated in NB patient populations and in mouse xenografts.
    CONCLUSIONS: HuD is seen as a novel means of promoting stress survival in this cancer type by downregulating mTORC1 activity and negatively regulating apoptosis.
    Keywords:  ARL6IP1; Cancer cell survival; ELAVL4; GRB-10; mTORC1
    DOI:  https://doi.org/10.1186/s13046-021-02203-2
  29. Int J Mol Sci. 2021 Dec 31. pii: 470. [Epub ahead of print]23(1):
    Dysregulated Autophagy and Mitophagy in a Mouse Model of Duchenne Muscular Dystrophy Remain Unchanged Following Heme Oxygenase-1 Knockout.
    Olga Mucha, Katarzyna Kaziród, Paulina Podkalicka, Kinga Rusin, Józef Dulak, Agnieszka Łoboda.
      Dysregulation of autophagy may contribute to the progression of various muscle diseases, including Duchenne muscular dystrophy (DMD). Heme oxygenase-1 (HO-1, encoded by Hmox1), a heme-degrading enzyme, may alleviate symptoms of DMD, inter alia, through anti-inflammatory properties. In the present study, we determined the role of HO-1 in the regulation of autophagy and mitophagy in mdx animals, a commonly used mouse model of the disease. In the gastrocnemius of 6-week-old DMD mice, the mRNA level of mitophagy markers: Bnip3 and Pink1, as well as autophagy regulators, e.g., Becn1, Map1lc3b, Sqstm1, and Atg7, was decreased. In the dystrophic diaphragm, changes in the latter were less prominent. In older, 12-week-old dystrophic mice, diminished expressions of Pink1 and Sqstm1 with upregulation of Atg5, Atg7, and Lamp1 was depicted. Interestingly, we demonstrated higher protein levels of autophagy regulator, LC3, in dystrophic muscles. Although the lack of Hmox1 in mdx mice influenced blood cell count and the abundance of profibrotic proteins, no striking differences in mRNA and protein levels of autophagy and mitophagy markers were found. In conclusion, we demonstrated complex, tissue, and age-dependent dysregulation of mitophagic and autophagic markers in DMD mice, which are not affected by the additional lack of Hmox1.
    Keywords:  DMD; Duchenne muscular dystrophy; HO-1; autophagy; heme oxygenase-1; mdx; mitophagy
    DOI:  https://doi.org/10.3390/ijms23010470
  30. Autophagy. 2022 Jan 11. 1-11
    Caffeine prevents restenosis and inhibits vascular smooth muscle cell proliferation through the induction of autophagy.
    Madhulika Tripathi, Brijesh Kumar Singh, Elisa A Liehn, Sheau Yng Lim, Keziah Tikno, David Castano-Mayan, Chutima Rattanasopa, Pakhwan Nilcham, Siti Aishah Binte Abdul Ghani, Zihao Wu, Syaza Hazwany Azhar, Jin Zhou, Sauri Hernández-Resèndiz, Gustavo E Crespo-Avilan, Rohit Anthony Sinha, Benjamin Livingston Farah, Kyaw Thu Moe, Deidre Anne De Silva, Veronique Angeli, Manvendra K Singh, Roshni R Singaraja, Derek J Hausenloy, Paul Michael Yen.
      Caffeine is among the most highly consumed substances worldwide, and it has been associated with decreased cardiovascular risk. Although caffeine has been shown to inhibit the proliferation of vascular smooth muscle cells (VSMCs), the mechanism underlying this effect is unknown. Here, we demonstrated that caffeine decreased VSMC proliferation and induced macroautophagy/autophagy in an in vivo vascular injury model of restenosis. Furthermore, we studied the effects of caffeine in primary human and mouse aortic VSMCs and immortalized mouse aortic VSMCs. Caffeine decreased cell proliferation, and induced autophagy flux via inhibition of MTOR signaling in these cells. Genetic deletion of the key autophagy gene Atg5, and the Sqstm1/p62 gene encoding a receptor protein, showed that the anti-proliferative effect by caffeine was dependent upon autophagy. Interestingly, caffeine also decreased WNT-signaling and the expression of two WNT target genes, Axin2 and Ccnd1 (cyclin D1). This effect was mediated by autophagic degradation of a key member of the WNT signaling cascade, DVL2, by caffeine to decrease WNT signaling and cell proliferation. SQSTM1/p62, MAP1LC3B-II and DVL2 were also shown to interact with each other, and the overexpression of DVL2 counteracted the inhibition of cell proliferation by caffeine. Taken together, our in vivo and in vitro findings demonstrated that caffeine reduced VSMC proliferation by inhibiting WNT signaling via stimulation of autophagy, thus reducing the vascular restenosis. Our findings suggest that caffeine and other autophagy-inducing drugs may represent novel cardiovascular therapeutic tools to protect against restenosis after angioplasty and/or stent placement.
    Keywords:  Aortic smooth muscle cell proliferation; WNT signaling; autophagy; caffeine; vascular injury model
    DOI:  https://doi.org/10.1080/15548627.2021.2021494
  31. Cancers (Basel). 2021 Dec 29. pii: 153. [Epub ahead of print]14(1):
    The Intricate Interplay between Cell Cycle Regulators and Autophagy in Cancer.
    Dorian V Ziegler, Katharina Huber, Lluis Fajas.
      In the past decade, cell cycle regulators have extended their canonical role in cell cycle progression to the regulation of various cellular processes, including cellular metabolism. The regulation of metabolism is intimately connected with the function of autophagy, a catabolic process that promotes the efficient recycling of endogenous components from both extrinsic stress, e.g., nutrient deprivation, and intrinsic sub-lethal damage. Mediating cellular homeostasis and cytoprotection, autophagy is found to be dysregulated in numerous pathophysiological contexts, such as cancer. As an adaptative advantage, the upregulation of autophagy allows tumor cells to integrate stress signals, escaping multiple cell death mechanisms. Nevertheless, the precise role of autophagy during tumor development and progression remains highly context-dependent. Recently, multiple articles has suggested the importance of various cell cycle regulators in the modulation of autophagic processes. Here, we review the current clues indicating that cell-cycle regulators, including cyclin-dependent kinase inhibitors (CKIs), cyclin-dependent kinases (CDKs), and E2F transcription factors, are intrinsically linked to the regulation of autophagy. As an increasing number of studies highlight the importance of autophagy in cancer progression, we finally evoke new perspectives in therapeutic avenues that may include both cell cycle inhibitors and autophagy modulators to synergize antitumor efficacy.
    Keywords:  CDKs; CKI; E2F; autophagy; cancer; cell cycle regulators
    DOI:  https://doi.org/10.3390/cancers14010153
  32. Brain. 2022 Jan 12. pii: awab243. [Epub ahead of print]
    Broad activation of the Parkin pathway induces synaptic mitochondrial deficits in early tauopathy.
    Yu Young Jeong, Sinsuk Han, Nuo Jia, Mingyang Zhang, Preethi Sheshadri, Prasad Tammineni, Jasmine Cheung, Marialaina Nissenbaum, Sindhuja S Baskar, Kelvin Kwan, David J Margolis, Peng Jiang, Alexander Kusnecov, Qian Cai.
      Mitochondrial defects are a hallmark of early pathophysiology in Alzheimer's disease, with pathologically phosphorylated tau reported to induce mitochondrial toxicity. Mitophagy constitutes a key pathway in mitochondrial quality control by which damaged mitochondria are targeted for autophagy. However, few details are known regarding the intersection of mitophagy and pathologies in tauopathy. Here, by applying biochemical and cell biological approaches including time-lapse confocal imaging in live tauopathy neurons, combined with gene rescue experiments via stereotactic injections of adeno-associated virus particles into tauopathy mouse brains, electrophysiological recordings and behavioural tests, we demonstrate for the first time that mitochondrial distribution deficits at presynaptic terminals are an early pathological feature in tauopathy brains. Furthermore, Parkin-mediated mitophagy is extensively activated in tauopathy neurons, which accelerates mitochondrial Rho GTPase 1 (Miro1) turnover and consequently halts Miro1-mediated mitochondrial anterograde movement towards synaptic terminals. As a result, mitochondrial supply at tauopathy synapses is disrupted, impairing synaptic function. Strikingly, increasing Miro1 levels restores the synaptic mitochondrial population by enhancing mitochondrial anterograde movement and thus reverses tauopathy-associated synaptic failure. In tauopathy mouse brains, overexpression of Miro1 markedly elevates synaptic distribution of mitochondria and protects against synaptic damage and neurodegeneration, thereby counteracting impairments in learning and memory as well as synaptic plasticity. Taken together, our study reveals that activation of the Parkin pathway triggers an unexpected effect-depletion of mitochondria from synaptic terminals, a characteristic feature of early tauopathy. We further provide new mechanistic insights into how parkin activation-enhanced Miro1 degradation and impaired mitochondrial anterograde transport drive tauopathy-linked synaptic pathogenesis and establish a foundation for future investigations into new therapeutic strategies to prevent synaptic deterioration in Alzheimer's disease and other tauopathies.
    Keywords:  Alzheimer’s disease; Parkin-mediated mitophagy; mitochondrial anterograde transport; synaptic mitochondrial deficits; tauopathy
    DOI:  https://doi.org/10.1093/brain/awab243
  33. Front Microbiol. 2021 ;12 817433
    Gut Microbiome Regulation of Autophagic Flux and Neurodegenerative Disease Risks.
    Andrew P Shoubridge, Célia Fourrier, Jocelyn M Choo, Christopher G Proud, Timothy J Sargeant, Geraint B Rogers.
      The gut microbiome-brain axis exerts considerable influence on the development and regulation of the central nervous system. Numerous pathways have been identified by which the gut microbiome communicates with the brain, falling largely into the two broad categories of neuronal innervation and immune-mediated mechanisms. We describe an additional route by which intestinal microbiology could mediate modifiable risk for neuropathology and neurodegeneration in particular. Autophagy, a ubiquitous cellular process involved in the prevention of cell damage and maintenance of effective cellular function, acts to clear and recycle cellular debris. In doing so, autophagy prevents the accumulation of toxic proteins and the development of neuroinflammation, both common features of dementia. Levels of autophagy are influenced by a range of extrinsic exposures, including nutrient deprivation, infection, and hypoxia. These relationships between exposures and rates of autophagy are likely to be mediated, as least in part, by the gut microbiome. For example, the suppression of histone acetylation by microbiome-derived short-chain fatty acids appears to be a major contributor to upregulation of autophagic function. We discuss the potential contribution of the microbiome-autophagy axis to neurological health and examine the potential of exploiting this link to predict and prevent neurodegenerative diseases.
    Keywords:  autophagy; dementia; microbiome; neurodegenerative; pathway; risk exposure
    DOI:  https://doi.org/10.3389/fmicb.2021.817433
  34. ACS Appl Bio Mater. 2020 Feb 17. 3(2): 977-985
    Inhibition of Autophagy via Lysosomal Impairment Enhances Cytotoxicity of Fullerenol under Starvation Condition.
    Liyun Yang, Siyu Hua, Junpeng Fan, Zhiqiang Zhou, Guanchao Wang, Fenglei Jiang, Zhixiong Xie, Qi Xiao, Yi Liu.
      Autophagy is well-known as a common cellular response to nanomaterials. As one of the most comprehensively studied carbon-based nanomaterials, fullerene and its derivatives have been reported to bring about autophagic features in various cell lines, but little is known about the role of fullerenol (C60(OH)44) on the modulation of autophagy in human gastric tumor cell line SGC-7901. Fullerenol treatment led to the accumulation of autophagosomes, as evidenced by the increased fluorescent intensity of monodansylcadaverine (MDC) staining cells, an elevated level of LC3 protein, and the observation of auotphagosomes in cytoplasm. Subsequent results of the p62 level demonstrated that the accumulation of autophagosomes resulted from the blockade of autophagic flux rather than the activation of autophagy. Fullerenol disrupted autophagic flux by impairing lysosomal function, including lysosome membrane permeabilization (LMP), alkaline of lysosomes, and reduced activity of capthesin B. Interestingly, fullerenol treatment was noncytotoxic under a nutrient-rich condition. When serum was deprived, cytotoxicity occurred in a concentration- and time-dependent manner, along with massive vacuoles in cytoplasm, a large amount of ROS generation, and finally cell death, which can be ascribed to the disruption of essential autophagy in cells. Taken together, understanding this autophagy-lysosome pathway will shed light on the potential anticancer application of fullerenol.
    Keywords:  autophagy; cytotoxicity; fullerenol; lysosomal dysfunction; starvation
    DOI:  https://doi.org/10.1021/acsabm.9b01001
  35. J Inflamm Res. 2021 ;14 7455-7465
    Dysregulation of the Retromer Complex in Brain Endothelial Cells Results in Accumulation of Phosphorylated Tau.
    Alessia Filippone, Tiffany Smith, Domenico Pratico.
      Introduction: Transport through endothelial cells of the blood-brain barrier (BBB) involves a complex group of structures of the endo-lysosome system such as early and late endosomes, and the retromer complex system. Studies show that neuronal dysregulation of the vacuolar protein sorting 35 (VPS35), the main component of the retromer complex recognition core, results in altered protein trafficking and degradation and is involved in neurodegeneration. Since the functional role of VPS35 in endothelial cells has not been fully investigated, in the present study we aimed at characterizing the effect of its downregulation on these pathways.Methods: Genetic silencing of VPS35 in human brain endothelial cells; measurement of retromer complex system proteins, autophagy and ubiquitin-proteasome systems.
    Results: VPS35-downregulated endothelial cells had increased expression of LC3B2/1 and more ubiquitinated products, markers of autophagy flux and impaired proteasome activity, respectively. Additionally, compared with controls VPS35 downregulation resulted in significant accumulation of tau protein and its phosphorylated isoforms.
    Discussion: Our findings demonstrate that in brain endothelial cells retromer complex dysfunction by influencing endosome-lysosome degradation pathways results in altered proteostasis. Restoration of the retromer complex system function should be considered a novel therapeutic approach to rescue endothelial protein transport.
    Keywords:  Alzheimer’s disease; autophagy; brain endothelial cells; endosomal trafficking; retromer complex; tau protein; ubiquitin-proteasome
    DOI:  https://doi.org/10.2147/JIR.S342096
  36. Ann N Y Acad Sci. 2022 Jan 08.
    Targeted protein degradation: from small molecules to complex organelles-a Keystone Symposia report.
    Jennifer Cable, Eilika Weber-Ban, Tim Clausen, Kylie J Walters, Michal Sharon, Daniel J Finley, Yangnan Gu, John Hanna, Yue Feng, Sascha Martens, Anne Simonsen, Malene Hansen, Hong Zhang, Jonathan M Goodwin, Alessio Reggio, Chunmei Chang, Liang Ge, Brenda A Schulman, Raymond J Deshaies, Ivan Dikic, J Wade Harper, Ingrid E Wertz, Nicolas H Thomä, Mikołaj Słabicki, Judith Frydman, Ursula Jakob, Della C David, Eric J Bennett, Carolyn R Bertozzi, Richa Sardana, Vinay V Eapen, Serena Carra.
      Targeted protein degradation is critical for proper cellular function and development. Protein degradation pathways, such as the ubiquitin proteasomes system, autophagy, and endosome-lysosome pathway, must be tightly regulated to ensure proper elimination of misfolded and aggregated proteins and regulate changing protein levels during cellular differentiation, while ensuring that normal proteins remain unscathed. Protein degradation pathways have also garnered interest as a means to selectively eliminate target proteins that may be difficult to inhibit via other mechanisms. On June 7 and 8, 2021, several experts in protein degradation pathways met virtually for the Keystone eSymposium "Targeting protein degradation: from small molecules to complex organelles." The event brought together researchers working in different protein degradation pathways in an effort to begin to develop a holistic, integrated vision of protein degradation that incorporates all the major pathways to understand how changes in them can lead to disease pathology and, alternatively, how they can be leveraged for novel therapeutics.
    Keywords:  aggregation; autophagy; lysophagy; proteasome; protein degradation; ubiquitin
    DOI:  https://doi.org/10.1111/nyas.14745
  37. Front Neurosci. 2021 ;15 783624
    Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis.
    Bridget C Benson, Pamela J Shaw, Mimoun Azzouz, J Robin Highley, Guillaume M Hautbergue.
      Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. As with the majority of neurodegenerative diseases, the pathological hallmarks of ALS involve proteinopathies which lead to the formation of various polyubiquitylated protein aggregates in neurons and glia. ALS is a highly heterogeneous disease, with both familial and sporadic forms arising from the convergence of multiple disease mechanisms, many of which remain elusive. There has been considerable research effort invested into exploring these disease mechanisms and in recent years dysregulation of RNA metabolism and mitochondrial function have emerged as of crucial importance to the onset and development of ALS proteinopathies. Widespread alterations of the RNA metabolism and post-translational processing of proteins lead to the disruption of multiple biological pathways. Abnormal mitochondrial structure, impaired ATP production, dysregulation of energy metabolism and calcium homeostasis as well as apoptosis have been implicated in the neurodegenerative process. Dysfunctional mitochondria further accumulate in ALS motor neurons and reflect a wider failure of cellular quality control systems, including mitophagy and other autophagic processes. Here, we review the evidence for RNA and mitochondrial dysfunction as some of the earliest critical pathophysiological events leading to the development of ALS proteinopathies, explore their relative pathological contributions and their points of convergence with other key disease mechanisms. This review will focus primarily on mutations in genes causing four major types of ALS (C9ORF72, SOD1, TARDBP/TDP-43, and FUS) and in protein homeostasis genes (SQSTM1, OPTN, VCP, and UBQLN2) as well as sporadic forms of the disease. Finally, we will look to the future of ALS research and how an improved understanding of central mechanisms underpinning proteinopathies might inform research directions and have implications for the development of novel therapeutic approaches.
    Keywords:  RNA metabolism alteration; amyotrophic lateral sclerosis; impaired proteostasis; mitochondrial dysfunction; proteinopathies
    DOI:  https://doi.org/10.3389/fnins.2021.783624
  38. Cancers (Basel). 2021 Dec 21. pii: 20. [Epub ahead of print]14(1):
    Autophagy and ncRNAs: Dangerous Liaisons in the Crosstalk between the Tumor and Its Microenvironment.
    Gracie Wee Ling Eng, Yilong Zheng, Dominic Wei Ting Yap, Andrea York Tiang Teo, Jit Kong Cheong.
      Autophagy is a fundamental cellular homeostasis mechanism known to play multifaceted roles in the natural history of cancers over time. It has recently been shown that autophagy also mediates the crosstalk between the tumor and its microenvironment by promoting the export of molecular payloads such as non-coding RNA (ncRNAs) via LC3-dependent Extracellular Vesicle loading and secretion (LDELS). In turn, the dynamic exchange of exosomal ncRNAs regulate autophagic responses in the recipient cells within the tumor microenvironment (TME), for both tumor and stromal cells. Autophagy-dependent phenotypic changes in the recipient cells further enhance tumor growth and metastasis, through diverse biological processes, including nutrient supplementation, immune evasion, angiogenesis, and therapeutic resistance. In this review, we discuss how the feedforward autophagy-ncRNA axis orchestrates vital communications between various cell types within the TME ecosystem to promote cancer progression.
    Keywords:  autophagy; cancer; metastasis; ncRNAs
    DOI:  https://doi.org/10.3390/cancers14010020
  39. Autophagy. 2022 Jan 14. 1-2
    Plant virus infection disrupts vacuolar acidification and autophagic degradation for the effective infection.
    Meng Yang, Yan Wang, Dawei Li, Yule Liu.
      Vacuoles are the largest compartments in plant cells and are involved in plant development and response to abiotic and biotic stresses. Vacuolar acidification is essential for vacuoles in various physiological functions. However, its role in plant defense, and whether and how pathogens affect vacuolar acidification to promote infection have never been reported. In this autophagy punctum, we discuss our recent findings about how plant viruses suppress vacuolar acidification and the degradation of autophagic bodies by directly interacting with a component of the V-ATPase to promote virus infection.
    Keywords:  Autophagic degradation; V-ATPase; autophagy; defense; vacuolar acidification; virus
    DOI:  https://doi.org/10.1080/15548627.2022.2027194
  40. Adv Exp Med Biol. 2021 ;1339 381-382
    Mitochondrial Homeostasis in Neurodegeneration and Ageing.
    Nektarios Tavernarakis.
      Ageing is driven by the inexorable and stochastic accumulation of damage in biomolecules vital for proper cellular function. Although this process is fundamentally haphazard and uncontrollable, senescent decline and ageing is broadly influenced by genetic and extrinsic factors. Numerous gene mutations and treatments have been shown to extend the lifespan of diverse organisms ranging from the unicellular Saccharomyces cerevisiae to primates. It is becoming increasingly apparent that most such interventions ultimately interface with cellular stress response mechanisms, suggesting that longevity is intimately related to the ability of the organism to effectively cope with both intrinsic and extrinsic stress. Key determinants of this capacity are the molecular mechanisms that link ageing to main stress response pathways and mediate age-related changes in the effectiveness of the response to stress. How each pathway contributes to modulate the ageing process is not fully elucidated. A better understanding of the dynamics and reciprocal interplay between stress responses and ageing is critical for the development of novel therapeutic strategies that exploit endogenous stress combat pathways against age-associated pathologies.
    DOI:  https://doi.org/10.1007/978-3-030-78787-5_46
  41. ACS Appl Bio Mater. 2020 Jul 20. 3(7): 4474-4485
    Matrix Stiffness Regulates Chemosensitivity, Stemness Characteristics, and Autophagy in Breast Cancer Cells.
    Yan Li, Rotsiniaina Randriantsilefisoa, Jie Chen, Jose Luis Cuellar-Camacho, Wanjun Liang, Wenzhong Li.
      The biomechanical environment of natural or synthetic extracellular matrices (ECMs) is identified to play a considerable role in embryonic development in stem cell fate and also in cancer development and fibrotic diseases. However, rare evidence shows the impact of biomechanical signals such as ECM stiffness on cancer cell stemness and autophagy, which makes huge contributions to cancer and many developmental and physiological processes. Furthermore, the influence and mechanism of ECM stiffness on autophagy in cancer cells remains unclear. Herein, we employed fibronectin-coated polyacrylamide hydrogels as the substrates for culturing breast cancer cells. We found that a soft environment was beneficial for the maintenance of cancer stem cell (CSC) population in breast cancer cells, which likely led to aggravated chemoresistance. Conversely, nutritional deprivation-induced autophagy was elevated along with increasing matrix stiffness. In addition, we found that though the central regulator of mechanotransduction, the yes-associated protein, YAP, was beneficial for autophagy activation, unexpectedly, it was not the main cause of rigid substrate promoting autophagy. In contrast, the YAP was crucial for a compliant environment for maintaining breast cancer stem cells and promoting chemotherapeutic resistance. We also found that the Rho-ROCK-ERK signal pathway and actin cytoskeleton were essential for the regulation of autophagy by matrix stiffness. Taken together, our study showed the important influence of ECM stiffness on stemness and autophagy in breast cancer cells and revealed the possible signal pathway involved in the mechanotransduction in autophagy activation, which provides significant implications for the study of cancer progression and design of hydrogels for tissue engineering in clinical therapy.
    Keywords:  BCSCs; YAP; autophagy; breast cancer cells; chemosensitivity; matrix stiffness; stemness
    DOI:  https://doi.org/10.1021/acsabm.0c00448
  42. Acta Pharm Sin B. 2021 Dec;11(12): 3966-3982
    Synergistic effects of autophagy/mitophagy inhibitors and magnolol promote apoptosis and antitumor efficacy.
    Yancheng Tang, Liming Wang, Tao Yi, Jun Xu, Jigang Wang, Jiang-Jiang Qin, Qilei Chen, Ka-Man Yip, Yihang Pan, Peng Hong, Yingying Lu, Han-Ming Shen, Hu-Biao Chen.
      Mitochondria as a signaling platform play crucial roles in deciding cell fate. Many classic anticancer agents are known to trigger cell death through induction of mitochondrial damage. Mitophagy, one selective autophagy, is the key mitochondrial quality control that effectively removes damaged mitochondria. However, the precise roles of mitophagy in tumorigenesis and anticancer agent treatment remain largely unclear. Here, we examined the functional implication of mitophagy in the anticancer properties of magnolol, a natural product isolated from herbal Magnolia officinalis. First, we found that magnolol induces mitochondrial depolarization, causes excessive mitochondrial fragmentation, and increases mitochondrial reactive oxygen species (mtROS). Second, magnolol induces PTEN-induced putative kinase protein 1 (PINK1)‒Parkin-mediated mitophagy through regulating two positive feedforward amplification loops. Third, magnolol triggers cancer cell death and inhibits neuroblastoma tumor growth via the intrinsic apoptosis pathway. Moreover, magnolol prolongs the survival time of tumor-bearing mice. Finally, inhibition of mitophagy by PINK1/Parkin knockdown or using inhibitors targeting different autophagy/mitophagy stages significantly promotes magnolol-induced cell death and enhances magnolol's anticancer efficacy, both in vitro and in vivo. Altogether, our study demonstrates that magnolol can induce autophagy/mitophagy and apoptosis, whereas blockage of autophagy/mitophagy remarkably enhances the anticancer efficacy of magnolol, suggesting that targeting mitophagy may be a promising strategy to overcome chemoresistance and improve anticancer therapy.
    Keywords:  Apoptosis; Combination therapy; Magnolol; PINK1‒Parkin-mediated mitophagy; Tumor suppression
    DOI:  https://doi.org/10.1016/j.apsb.2021.06.007
  43. iScience. 2022 Jan 21. 25(1): 103645
    Translational and post-translational control of human naïve versus primed pluripotency.
    Cheng Chen, Xiaobing Zhang, Yisha Wang, Xinyu Chen, Wenjie Chen, Songsong Dan, Shiqi She, Weiwei Hu, Jie Dai, Jianwen Hu, Qingyi Cao, Qianyu Liu, Yinghua Huang, Baoming Qin, Bo Kang, Ying-Jie Wang.
      Deciphering the regulatory network for human naive and primed pluripotency is of fundamental theoretical and applicable significance. Here, by combining quantitative proteomics, phosphoproteomics, and acetylproteomics analyses, we revealed RNA processing and translation as the most differentially regulated processes between naive and primed human embryonic stem cells (hESCs). Although glycolytic primed hESCs rely predominantly on the eukaryotic initiation factor 4E (eIF4E)-mediated cap-dependent pathway for protein translation, naive hESCs with reduced mammalian target of rapamycin complex (mTORC1) activity are more tolerant to eIF4E inhibition, and their bivalent metabolism allows for translating selective mRNAs via both eIF4E-dependent and eIF4E-independent/eIF4A2-dependent pathways to form a more compact naive proteome. Globally up-regulated proteostasis and down-regulated post-translational modifications help to further refine the naive proteome that is compatible with the more rapid cycling of naive hESCs, where CDK1 plays an indispensable coordinative role. These findings may assist in better understanding the unrestricted lineage potential of naive hESCs and in further optimizing conditions for future clinical applications.
    Keywords:  Molecular biology; Proteomics; Stem cells research
    DOI:  https://doi.org/10.1016/j.isci.2021.103645
  44. Cell Rep. 2022 Jan 11. pii: S2211-1247(21)01487-X. [Epub ahead of print]38(2): 110009
    CDC42 controlled apical-basal polarity regulates intestinal stem cell to transit amplifying cell fate transition via YAP-EGF-mTOR signaling.
    Zheng Zhang, Feng Zhang, Ashley Kuenzi Davis, Mei Xin, Gerd Walz, Weidong Tian, Yi Zheng.
      Epithelial polarity is controlled by a polarity machinery that includes Rho GTPase CDC42 and Scribble/PAR. By using intestinal stem cell (ISC)-specific deletion of CDC42 in olfactomedin-4 (Olfm4)-internal ribosome entry site (IRES)-EGFP/CreERT2;CDC42flox/flox mice, we find that CDC42 loss initiated in the ISCs causes a drastic hyperproliferation of transit amplifying (TA) cells and disrupts epithelial polarity. CDC42-null crypts display expanded TA cell and diminished ISC populations, accompanied by elevated Hippo signaling via YAP/TAZ-Ereg (yes-associated protein/WW domain-containing transcription regulator protein 1-epiregulin) and mechanistic target of rapamycin (mTOR) activation, independent from canonical Wnt signaling. YAP/TAZ conditional knockout (KO) restores the balance of ISC/TA cell populations and crypt proliferation but does not rescue the polarity in CDC42-null small intestine. mTOR or epidermal growth factor receptor (EGFR) inhibitor treatment of CDC42 KO mice exhibits similar rescuing effects without affecting YAP/TAZ signaling. Inducible ablation of Scribble in intestinal epithelial cells mimics that of CDC42 KO defects, including crypt hyperplasia and Hippo signaling activation. Mammalian epithelial polarity regulates ISC/TA cell fate and proliferation via a Hippo-Ereg-mTOR cascade.
    Keywords:  Cdc42; Hippo signaling; cell fate; intestinal stem cells; mTOR signaling; mouse model; polarity
    DOI:  https://doi.org/10.1016/j.celrep.2021.110009
  45. JIMD Rep. 2022 Jan;63(1): 50-65
    Chronic lithium administration in a mouse model for Krabbe disease.
    Ambra Del Grosso, Gabriele Parlanti, Lucia Angella, Nadia Giordano, Ilaria Tonazzini, Elisa Ottalagana, Sara Carpi, Roberto Maria Pellegrino, Husam B R Alabed, Carla Emiliani, Matteo Caleo, Marco Cecchini.
      Krabbe disease (KD; or globoid cell leukodystrophy) is an autosomal recessive lysosomal storage disorder caused by deficiency of the galactosylceramidase (GALC) enzyme. No cure is currently available for KD. Clinical applied treatments are supportive only. Recently, we demonstrated that two differently acting autophagy inducers (lithium and rapamycin) can improve some KD hallmarks in-vitro, laying the foundation for their in-vivo pre-clinical testing. Here, we test lithium carbonate in-vivo, in the spontaneous mouse model for KD, the Twitcher (TWI) mouse. The drug is administered ad libitum via drinking water (600 mg/L) starting from post natal day 20. We longitudinally monitor the mouse motor performance through the grip strength, the hanging wire and the rotarod tests, and a set of biochemical parameters related to the KD pathogenesis [i.e., GALC enzymatic activity, psychosine (PSY) accumulation and astrogliosis]. Additionally, we investigate the expression of some crucial markers related to the two pathways that could be altered by lithium: the autophagy and the β-catenin-dependent pathways. Results demonstrate that lithium has not a significant rescue effect on the TWI phenotype, although it can slightly and transiently improves muscle strength. We also show that lithium, with this administration protocol, is unable to stimulate autophagy in the TWI mice central nervous system, whereas results suggest that it can restore the β-catenin activation status in the TWI sciatic nerve. Overall, these data provide intriguing inputs for further evaluations of lithium treatment in TWI mice.
    Keywords:  Krabbe; Twitcher; autophagy; globoid cell leukodystrophy; lithium; psychosine
    DOI:  https://doi.org/10.1002/jmd2.12258
  46. Int Immunopharmacol. 2022 Jan 10. pii: S1567-5769(21)01079-1. [Epub ahead of print]104 108443
    Down-regulation of TRPM2 attenuates hepatic ischemia/reperfusion injury through activation of autophagy and inhibition of NLRP3 inflammasome pathway.
    Tao Zhang, Wenqi Huang, Yi Ma.
      AIM: Hepatic ischemia/reperfusion (I/R) injury is a significant pathological process that contributes to high morbidity and mortality rates, although the underlying mechanism is unknown. Recent studies have shown that transient receptor potential melastatin 2 (TRPM2) plays a critical role in organ I/R injury, but the exact mechanism is elusive. This study investigates the role and mechanism of TPRM2 in hepatic I/R injury and oxygen-glucosedeprivation/reoxygenation (OGD/R) induced hepatocyte injury.METHODS: We evaluated the effects of TRPM2 on hepatic I/R injury using a knockout mouse model of hepatic I/R. In a model of OGD/R in hepatocytes, we investigated the mechanism of TPRM2 in it using the autophagy agonist and inhibitor and an NLRP3 inhibitor.
    RESULTS: We discovered that knockout of TRPM2 protected against hepatic I/R accompanied by autophagy activation and NLRP3 inflammasome pathway inhibition. Furthermore, increasing autophagy attenuated OGD/R-induced cell injury and knockdown of TRPM2 alleviated the injury by activating autophagy. Additionally, we detected the expression of NLRP3 inflammasome pathway in the OGD/R-induced hepatocytes which had been treated with the autophagy agonist and inhibitor, and found that autophagy negatively regulated the NLRP3 inflammasome pathway. Moreover, we discovered that the administration of NLRP3-inhibitor INF39 increased cell viability and caused a decline in cell death in the OGD/R-treated hepatocytes.
    CONCLUSIONS: Downregulation of TRPM2 protected the liver against I/R injury and OGD/R induced injury, mediated by autophagy activation and inhibition of the NLRP3 inflammasome pathway, whereas autophagy negatively regulated the NLRP3 inflammasome pathway in this process.
    Keywords:  Autophagy; Hepatic ischemia/reperfusion injury; NLRP3 inflammasome; Transient receptor potential melastatin 2
    DOI:  https://doi.org/10.1016/j.intimp.2021.108443
  47. Mol Cell Endocrinol. 2022 Jan 11. pii: S0303-7207(22)00002-8. [Epub ahead of print] 111555
    Pharmacological agents targeting autophagy and their effects on lipolysis in human adipocytes.
    Qing Xu, Edwin Cm Mariman, Ellen E Blaak, Johan We Jocken.
      Adipose tissue of metabolically compromised humans with obesity is often characterized by impaired regulation of autophagy pathway. However, data on the role of autophagy in human adipocyte lipid catabolism is scarce. Therefore, we investigated the effect of pharmacological agents (including 3-methyladenine (3MA), bafilomycin A1 (BAF), chloroquine (CQ) and lalistat-2 (L-stat), that target different stages of the autophagy pathway on lipid hydrolysis in differentiated human multipotent adipose-derived stem cells (hMADs). Glycerol and fatty acid release were measured as marker of lipid hydrolysis following starvation and β-adrenergic stimulation. Microtubule-associated protein light chain 3 ratio (LC3II/LC3I) and HSL phosphorylation (pHSL) were analyzed by Western blot. Our data indicate that pharmacological inhibition of the autophagy pathway reduced lipid hydrolysis in human adipocytes, although to a limited extent (10-15%). However, further research is needed to reveal the exact mechanism of action of these pharmacological agents and their interplay with cytosolic lipid breakdown in human adipocytes.
    Keywords:  Autophagy; Human adipocyte; Lipolysis; Pharmacological inhibitors
    DOI:  https://doi.org/10.1016/j.mce.2022.111555
  48. Cell Death Differ. 2022 Jan 11.
    NUMB facilitates autophagy initiation through targeting SCFβ-TrCP2 complex.
    Hao Li, Shuangshuang Shu, Miaomiao Zhou, Ying Chen, An Xiao, Yuanyuan Ma, Fengxin Zhu, Zheng Hu, Jing Nie.
      Given the critical role of SCF E3 ligases in autophagy by modulating the protein stability of various autophagic components, the activity of SCF should be tightly controlled to maintain the autophagic flux. We here showed that Numb, a multifunctional adaptor protein, increased the protein abundance of DEPTOR, which is an inhibitor of mTORC1, leading to increased autophagy flux. In vitro ubiquitination assay demonstrated that Numb inhibited SCFβ-TrCP2 mediated ubiquitination of DEPTOR. Mechanistically, Numb interrupted the interaction between β-TrCP2 and SKP1 by directly binding with SKP1. In the presence of wild type β-TrCP2, Numb overexpression inhibited DEPTOR degradation. Whereas, in the presence of the mutant β-TrCP2 which lacks the F-box domain, Numb overexpression did not affect the protein abundance of DEPTOR. In mouse model of renal fibrosis induced by unilateral ureteral obstruction, the expression of Numb was significantly increased. Consistently, the upregulation of Numb was observed in renal fibrotic lesions of chronic kidney disease patients. Specifically depleting Numb in proximal renal tubules decreased the protein abundance of DEPTOR, attenuated autophagy in fibrotic lesions and protected the kidney from development of renal fibrosis in vivo. Taken together, both in vitro and in vivo data indicated that Numb functions as a novel regulator to fine tuning the activity of SCFβ-TrCP2 in modulating autophagy.
    DOI:  https://doi.org/10.1038/s41418-022-00930-3
  49. Int J Mol Sci. 2021 Dec 31. pii: 421. [Epub ahead of print]23(1):
    Autophagy and Polyphenols in Osteoarthritis: A Focus on Epigenetic Regulation.
    Consuelo Arias, Luis A Salazar.
      Autophagy is an intracellular mechanism that maintains cellular homeostasis in different tissues. This process declines in cartilage due to aging, which is correlated with osteoarthritis (OA), a multifactorial and degenerative joint disease. Several studies show that microRNAs regulate different steps of autophagy but only a few of them participate in OA. Therefore, epigenetic modifications could represent a therapeutic opportunity during the development of OA. Besides, polyphenols are bioactive components with great potential to counteract diseases, which could reverse altered epigenetic regulation and modify autophagy in cartilage. This review aims to analyze epigenetic mechanisms that are currently associated with autophagy in OA, and to evaluate whether polyphenols are used to reverse the epigenetic alterations generated by aging in the autophagy pathway.
    Keywords:  aging; autophagy; epigenetics; microRNAs; osteoarthritis; polyphenols
    DOI:  https://doi.org/10.3390/ijms23010421
  50. J Exp Clin Cancer Res. 2022 Jan 08. 41(1): 16
    Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy.
    Maria Saliakoura, Matteo Rossi Sebastiano, Ioanna Nikdima, Chiara Pozzato, Georgia Konstantinidou.
      BACKGROUND: KRAS is the predominant oncogene mutated in pancreatic ductal adenocarcinoma (PDAC), the fourth cause of cancer-related deaths worldwide. Mutant KRAS-driven tumors are metabolically programmed to support their growth and survival, which can be used to identify metabolic vulnerabilities. In the present study, we aimed to understand the role of extracellularly derived fatty acids in KRAS-driven pancreatic cancer.METHODS: To assess the dependence of PDAC cells on extracellular fatty acids we employed delipidated serum or RNAi-mediated suppression of ACSL3 (to inhibit the activation and cellular retention of extracellular fatty acids) followed by cell proliferation assays, qPCR, apoptosis assays, immunoblots and fluorescence microscopy experiments. To assess autophagy in vivo, we employed the KrasG12D/+;p53flox/flox;Pdx1-CreERT2 (KPC) mice crossed with Acsl3 knockout mice, and to assess the efficacy of the combination therapy of ACSL3 and autophagy inhibition we used xenografted human cancer cell-derived tumors in immunocompromised mice.
    RESULTS: Here we show that depletion of extracellularly derived lipids either by serum lipid restriction or suppression of ACSL3, triggers autophagy, a process that protects PDAC cells from the reduction of bioenergetic intermediates. Combined extracellular lipid deprivation and autophagy inhibition exhibits anti-proliferative and pro-apoptotic effects against PDAC cell lines in vitro and promotes suppression of xenografted human pancreatic cancer cell-derived tumors in mice. Therefore, we propose lipid deprivation and autophagy blockade as a potential co-targeting strategy for PDAC treatment.
    CONCLUSIONS: Our work unravels a central role of extracellular lipid supply in ensuring fatty acid provision in cancer cells, unmasking a previously unappreciated metabolic vulnerability of PDAC cells.
    Keywords:  Combination therapy; Extracellular lipids; Lipid metabolism; Pancreatic cancer; Tumor metabolic vulnerabilities
    DOI:  https://doi.org/10.1186/s13046-021-02231-y
  51. Blood Cancer Discov. 2022 Jan;3(1): 50-65
    Translational Activation of ATF4 through Mitochondrial Anaplerotic Metabolic Pathways Is Required for DLBCL Growth and Survival.
    Meng Li, Matthew R Teater, Jun Young Hong, Noel R Park, Cihangir Duy, Hao Shen, Ling Wang, Zhengming Chen, Leandro Cerchietti, Shawn M Davidson, Hening Lin, Ari M Melnick.
      Diffuse large B-cell lymphomas (DLBCL) are broadly dependent on anaplerotic metabolism regulated by mitochondrial SIRT3. Herein we find that translational upregulation of ATF4 is coupled with anaplerotic metabolism in DLBCLs due to nutrient deprivation caused by SIRT3 driving rapid flux of glutamine into the tricarboxylic acid (TCA) cycle. SIRT3 depletion led to ATF4 downregulation and cell death, which was rescued by ectopic ATF4 expression. Mechanistically, ATF4 translation is inhibited in SIRT3-deficient cells due to the increased pools of amino acids derived from compensatory autophagy and decreased glutamine consumption by the TCA cycle. Absence of ATF4 further aggravates this state through downregulation of its target genes, including genes for amino acid biosynthesis and import. Collectively, we identify a SIRT3-ATF4 axis required to maintain survival of DLBCL cells by enabling them to optimize amino acid uptake and utilization. Targeting ATF4 translation can potentiate the cytotoxic effect of SIRT3 inhibitor to DLBCL cells. SIGNIFICANCE: We discovered the link between SIRT3 and ATF4 in DLBCL cells, which connected lymphoma amino acid metabolism with ATF4 translation via metabolic stress signals. SIRT3-ATF4 axis is required in DLBCL cells regardless of subtype, which indicates a common metabolic vulnerability in DLBCLs and can serve as a therapeutic target.This article is highlighted in the In This Issue feature, p. 1.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-20-0183
  52. Hum Mol Genet. 2022 Jan 06. pii: ddab374. [Epub ahead of print]
    Abnormal activation of yap/Taz contributes to the pathogenesis of tuberous sclerosis complex.
    Bethany K Terry, Raehee Park, Seo-Hee Cho, Peter B Crino, Seonhee Kim.
      The multi-systemic genetic disorder tuberous sclerosis complex (TSC) impacts multiple neurodevelopmental processes including neuronal morphogenesis, neuronal migration, myelination, and gliogenesis. These alterations contribute to the development of cerebral cortex abnormalities and malformations. Although TSC is caused by mTORC1 hyperactivation, cognitive and behavioral impairments are not improved through mTORC1 targeting, making the study of the downstream effectors of this complex important for understanding the mechanisms underlying TSC. As mTORC1 has been shown to promote the activity of the transcriptional co-activator Yap, we hypothesized that altered Yap/Taz signaling contributes to the pathogenesis of TSC. We first observed that the level of Yap/Taz are increased in a human cortical tuber sample and in embryonic cortices of Tsc2 conditional knockout (cKO) mice. Next, to determine how abnormal upregulation of Yap/Taz impacts the neuropathology of TSC, we deleted Yap/Taz in Tsc2 cKO mice. Importantly, Yap/Taz/Tsc2 tcKO animals show reduced cortical thickness and cortical neuron cell size, despite the persistence of high mTORC1 activity, suggesting that Yap/Taz play a downstream role in cytomegaly. Furthermore, Yap/Taz/Tsc2 tcKO significantly restored cortical and hippocampal lamination defects and reduced hippocampal heterotopia formation. Finally, the loss of Yap/Taz increased the distribution of myelin basic protein in Tsc2 cKO animals, consistent with an improvement in myelination. Overall, our results indicate that targeting Yap/Taz lessens the severity of neuropathology in a TSC animal model. This study is the first to implicate Yap/Taz as contributors to cortical pathogenesis in TSC and therefore as potential novel targets in the treatment of this disorder.
    DOI:  https://doi.org/10.1093/hmg/ddab374
  53. Int J Mol Sci. 2021 Dec 22. pii: 113. [Epub ahead of print]23(1):
    The Metabolism Reprogramming of microRNA Let-7-Mediated Glycolysis Contributes to Autophagy and Tumor Progression.
    Chien-Hsiu Li, Chiao-Chun Liao.
      Cancer is usually a result of abnormal glucose uptake and imbalanced nutrient metabolization. The dysregulation of glucose metabolism, which controls the processes of glycolysis, gives rise to various physiological defects. Autophagy is one of the metabolic-related cellular functions and involves not only energy regeneration but also tumorigenesis. The dysregulation of autophagy impacts on the imbalance of metabolic homeostasis and leads to a variety of disorders. In particular, the microRNA (miRNA) Let-7 has been identified as related to glycolysis procedures such as tissue repair, stem cell-derived cardiomyocytes, and tumoral metastasis. In many cancers, the expression of glycolysis-related enzymes is correlated with Let-7, in which multiple enzymes are related to the regulation of the autophagy process. However, much recent research has not comprehensively investigated how Let-7 participates in glycolytic reprogramming or its links to autophagic regulations, mainly in tumor progression. Through an integrated literature review and omics-related profiling correlation, this review provides the possible linkage of the Let-7 network between glycolysis and autophagy, and its role in tumor progression.
    Keywords:  Let-7; autophagy; cancer; glycolysis; microRNA
    DOI:  https://doi.org/10.3390/ijms23010113
  54. Neural Regen Res. 2022 Aug;17(8): 1645-1651
    Phosphorylated tau as a toxic agent in synaptic mitochondria: implications in aging and Alzheimer's disease.
    Angie K Torres, Bastián I Rivera, Catalina M Polanco, Claudia Jara, Cheril Tapia-Rojas.
      During normal aging, there is a decline in all physiological functions in the organism. One of the most affected organs is the brain, where neurons lose their proper synaptic function leading to cognitive impairment. Aging is one of the main risk factors for the development of neurodegenerative diseases, such as Alzheimer's disease. One of the main responsible factors for synaptic dysfunction in aging and neurodegenerative diseases is the accumulation of abnormal proteins forming aggregates. The most studied brain aggregates are the senile plaques, formed by Aβ peptide; however, the aggregates formed by phosphorylated tau protein have gained relevance in the last years by their toxicity. It is reported that neurons undergo severe mitochondrial dysfunction with age, with a decrease in adenosine 5'-triphosphate production, loss of the mitochondrial membrane potential, redox imbalance, impaired mitophagy, and loss of calcium buffer capacity. Interestingly, abnormal tau protein interacts with several mitochondrial proteins, suggesting that it could induce mitochondrial dysfunction. Nevertheless, whether tau-mediated mitochondrial dysfunction occurs indirectly or directly is still unknown. A recent study of our laboratory shows that phosphorylated tau at Ser396/404 (known as PHF-1), an epitope commonly related to pathology, accumulates inside mitochondria during normal aging. This accumulation occurs preferentially in synaptic mitochondria, which suggests that it may contribute to the synaptic failure and cognitive impairment seen in aged individuals. Here, we review the main tau modifications promoting mitochondrial dysfunction, and the possible mechanism involved. Also, we discuss the evidence that supports the possibility that phosphorylated tau accumulation in synaptic mitochondria promotes synaptic and cognitive impairment in aging. Finally, we show evidence and argue about the presence of phosphorylated tau PHF-1 inside mitochondria in Alzheimer's disease, which could be considered as an early event in the neurodegenerative process. Thus, phosphorylated tau PHF-1 inside the mitochondria could be considered such a potential therapeutic target to prevent or attenuate age-related cognitive impairment.
    Keywords:  Alzheimer’s disease; PHF-1; age pathology; aging; hippocampus; memory; mitochondria; phosphorylated tau; synaptic mitochondria; tau
    DOI:  https://doi.org/10.4103/1673-5374.332125
  55. Cancers (Basel). 2022 Jan 04. pii: 234. [Epub ahead of print]14(1):
    Secretory Autophagy Forges a Therapy Resistant Microenvironment in Melanoma.
    Silvina Odete Bustos, Nathalia Leal Santos, Roger Chammas, Luciana Nogueira de Sousa Andrade.
      Melanoma is the most aggressive skin cancer characterized by high mutational burden and large heterogeneity. Cancer cells are surrounded by a complex environment, critical to tumor establishment and progression. Thus, tumor-associated stromal components can sustain tumor demands or impair cancer cell progression. One way to manage such processes is through the regulation of autophagy, both in stromal and tumor cells. Autophagy is a catabolic mechanism that provides nutrients and energy, and it eliminates damaged organelles by degradation and recycling of cellular elements. Besides this primary function, autophagy plays multiple roles in the tumor microenvironment capable of affecting cell fate. Evidence demonstrates the existence of novel branches in the autophagy system related to cytoplasmic constituent's secretion. Hence, autophagy-dependent secretion assembles a tangled network of signaling that potentially contributes to metabolism reprogramming, immune regulation, and tumor progression. Here, we summarize the current awareness regarding secretory autophagy and the intersection with exosome biogenesis and release in melanoma and their role in tumor resistance. In addition, we present and discuss data from public databases concerning autophagy and exosome-related genes as important mediators of melanoma behavior. Finally, we will present the main challenges in the field and strategies to translate most of the pre-clinical findings to clinical practice.
    Keywords:  exosomes; melanoma; secretion; secretory autophagy; tumor microenvironment; tumor resistance
    DOI:  https://doi.org/10.3390/cancers14010234
  56. Bioessays. 2022 Jan 14. e2100224
    The complexity of biological control systems: An autophagy case study.
    Mariana Pavel, Radu Tanasa, So Jung Park, David C Rubinsztein.
      Autophagy and YAP1-WWTR1/TAZ signalling are tightly linked in a complex control system of forward and feedback pathways which determine different cellular outcomes in differing cell types at different time-points after perturbations. Here we extend our previous experimental and modelling approaches to consider two possibilities. First, we have performed additional mathematical modelling to explore how the autophagy-YAP1 crosstalk may be controlled by posttranslational modifications of components of the pathways. Second, since analogous contrasting results have also been reported for autophagy as a regulator of other transduction pathways engaged in tumorigenesis (Wnt/β-catenin, TGF-β/Smads, NF-kB or XIAP/cIAPs), we have considered if such discrepancies may be explicable through situations involving competing pathways and feedback loops in different cell types, analogous to the autophagy-YAP/TAZ situation. Since distinct posttranslational modifications dominate those pathways in distinct cells, these need to be understood to enable appropriate cell type-specific therapeutic strategies for cancers and other diseases.
    Keywords:  YAP1 signalling; autophagy; cell heterogeneity; mathematical model; precision medicine; transduction pathways
    DOI:  https://doi.org/10.1002/bies.202100224
  57. J Zhejiang Univ Sci B. 2022 Jan 15. pii: 1673-1581(2022)01-0019-23. [Epub ahead of print]23(1): 19-41
    A dynamically evolving war between autophagy and pathogenic microorganisms.
    Qianqian Zheng, Liangwei Duan, Yang Zhang, Jiaoyang Li, Shiyu Zhang, Hui Wang.
      Autophagy is an intracellular degradation process that maintains cellular homeostasis. It is essential for protecting organisms from environmental stress. Autophagy can help the host to eliminate invading pathogens, including bacteria, viruses, fungi, and parasites. However, pathogens have evolved multiple strategies to interfere with autophagic signaling pathways or inhibit the fusion of autophagosomes with lysosomes to form autolysosomes. Moreover, host cell matrix degradation by different types of autophagy can be used for the proliferation and reproduction of pathogens. Thus, determining the roles and mechanisms of autophagy during pathogen infections will promote understanding of the mechanisms of pathogen‍‒‍host interactions and provide new strategies for the treatment of infectious diseases.
    Keywords:  Autophagy; Bacteria; Fungi; Parasite; Pathogenic microorganism; Virus
    DOI:  https://doi.org/10.1631/jzus.B2100285
  58. Cancer Treat Res Commun. 2022 Jan 07. pii: S2468-2942(22)00004-1. [Epub ahead of print]30 100512
    Autophagy Modulation and Cancer Combination Therapy: A Smart Approach in Cancer Therapy.
    Ali Salimi-Jeda, Soad Ghabeshi, Zeinab Gol Mohammad Pour, Ehsan Ollah Jazaeri, Mehrdad Araiinejad, Farzaneh Sheikholeslami, Mohsen Abdoli, Mahdi Edalat, Asghar Abdoli.
      The autophagy pathway is the process whereby cells keep cellular homeostasis and respond to stress via recycling their damaged cellular proteins, organelles, and other cellular components. In the context of cancer, autophagy is a dual-edge sword pro- and anti-tumorigenic role depending on the oncogenic context and stage of tumorigenesis. Cancer cells have a higher dependency on autophagy compared with normal cells because of cellular damages and high demands for energy. The carbon, nitrogen, and molecular oxygen are building blocks for highly proliferative cancer cells which extremely depend on glutaminolysis and aerobic glycolysis; when a cancer cell is restricted to glucose and glutamine, it initiates to activate a stress response pathway using autophagy. Oncogenic tyrosine kinases (OncTKs) and receptor tyrosine kinases (RTKs) activation result in autophagy modulation through activation of the PI3K/AKT/mTORC1 and RAS/MAPK signaling pathways. Targeted inhibition of tyrosine kinases (TKs) and RTKs have recently been considered as cancer therapy but drug resistance and cancer relapse continue to be a major limitation of tyrosine kinase inhibitors (TKIs). Manipulation of autophagy pathway along with TKIs may be a promising strategy to circumvent unknown existing drug-resistance mechanisms that may emerge in a treated patient. In this way, clinical trials are ongoing to modulate autophagy to treat cancer. This review aims to summarize the combination therapy of autophagy affecting compounds with anticancer drugs which target cell signaling pathways, metabolism mechanisms, and epigenetics modification to improve therapeutic efficacy against cancers.
    Keywords:  Autophagy modulation; Cancer therapy; Combination therapy
    DOI:  https://doi.org/10.1016/j.ctarc.2022.100512
  59. Cancers (Basel). 2021 Dec 21. pii: 6. [Epub ahead of print]14(1):
    The Tubulin Code and Tubulin-Modifying Enzymes in Autophagy and Cancer.
    Daniela Trisciuoglio, Francesca Degrassi.
      Microtubules are key components of the cytoskeleton of eukaryotic cells. Microtubule dynamic instability together with the "tubulin code" generated by the choice of different α- and β- tubulin isoforms and tubulin post-translational modifications have essential roles in the control of a variety of cellular processes, such as cell shape, cell motility, and intracellular trafficking, that are deregulated in cancer. In this review, we will discuss available evidence that highlights the crucial role of the tubulin code in determining different cancer phenotypes, including metastatic cell migration, drug resistance, and tumor vascularization, and the influence of modulating tubulin-modifying enzymes on cancer cell survival and aggressiveness. We will also discuss the role of post-translationally modified microtubules in autophagy-the lysosomal-mediated cellular degradation pathway-that exerts a dual role in many cancer types, either promoting or suppressing cancer growth. We will give particular emphasis to the role of tubulin post-translational modifications and their regulating enzymes in controlling the different stages of the autophagic process in cancer cells, and consider how the experimental modulation of tubulin-modifying enzymes influences the autophagic process in cancer cells and impacts on cancer cell survival and thereby represents a new and fruitful avenue in cancer therapy.
    Keywords:  acetylation; autophagy; cancer; microtubules; tubulin post-translational modifications; tubulin-modifying enzymes; tyrosination
    DOI:  https://doi.org/10.3390/cancers14010006
  60. Cells. 2021 Dec 29. pii: 96. [Epub ahead of print]11(1):
    Autophagy and Endoplasmic Reticulum Stress during Onset and Progression of Arrhythmogenic Cardiomyopathy.
    Mark Pitsch, Sebastian Kant, Corinna Mytzka, Rudolf E Leube, Claudia A Krusche.
      Arrhythmogenic cardiomyopathy (AC) is a heritable, potentially lethal disease without a causal therapy. AC is characterized by focal cardiomyocyte death followed by inflammation and progressive formation of connective tissue. The pathomechanisms leading to structural disease onset and progression, however, are not fully elucidated. Recent studies revealed that dysregulation of autophagy and endoplasmic/sarcoplasmic reticulum (ER/SR) stress plays an important role in cardiac pathophysiology. We therefore examined the temporal and spatial expression patterns of autophagy and ER/SR stress indicators in murine AC models by qRT-PCR, immunohistochemistry, in situ hybridization and electron microscopy. Cardiomyocytes overexpressing the autophagy markers LC3 and SQSTM1/p62 and containing prominent autophagic vacuoles were detected next to regions of inflammation and fibrosis during onset and chronic disease progression. mRNAs of the ER stress markers Chop and sXbp1 were elevated in both ventricles at disease onset. During chronic disease progression Chop mRNA was upregulated in right ventricles. In addition, reduced Ryr2 mRNA expression together with often drastically enlarged ER/SR cisternae further indicated SR dysfunction during this disease phase. Our observations support the hypothesis that locally altered autophagy and enhanced ER/SR stress play a role in AC pathogenesis both at the onset and during chronic progression.
    Keywords:  ARVC; Chop; ER stress; arrhythmogenic cardiomyopathy; autophagy; desmoglein
    DOI:  https://doi.org/10.3390/cells11010096
  61. Sci Rep. 2022 Jan 12. 12(1): 596
    Annexin A6 and NPC1 regulate LDL-inducible cell migration and distribution of focal adhesions.
    Jaimy Jose, Monira Hoque, Johanna Engel, Syed S Beevi, Mohamed Wahba, Mariya Ilieva Georgieva, Kendelle J Murphy, William E Hughes, Blake J Cochran, Albert Lu, Francesc Tebar, Andrew J Hoy, Paul Timpson, Kerry-Anne Rye, Carlos Enrich, Carles Rentero, Thomas Grewal.
      Cholesterol is considered indispensable for cell motility, but how physiological cholesterol pools enable cells to move forward remains to be clarified. The majority of cells obtain cholesterol from the uptake of Low-Density lipoproteins (LDL) and here we demonstrate that LDL stimulates A431 squamous epithelial carcinoma and Chinese hamster ovary (CHO) cell migration and invasion. LDL also potentiated epidermal growth factor (EGF) -stimulated A431 cell migration as well as A431 invasion in 3-dimensional environments, using organotypic assays. Blocking cholesterol export from late endosomes (LE), using Niemann Pick Type C1 (NPC1) mutant cells, pharmacological NPC1 inhibition or overexpression of the annexin A6 (AnxA6) scaffold protein, compromised LDL-inducible migration and invasion. Nevertheless, NPC1 mutant cells established focal adhesions (FA) that contain activated focal adhesion kinase (pY397FAK, pY861FAK), vinculin and paxillin. Compared to controls, NPC1 mutants display increased FA numbers throughout the cell body, but lack LDL-inducible FA formation at cell edges. Strikingly, AnxA6 depletion in NPC1 mutant cells, which restores late endosomal cholesterol export in these cells, increases their cell motility and association of the cholesterol biosensor D4H with active FAK at cell edges, indicating that AnxA6-regulated transport routes contribute to cholesterol delivery to FA structures, thereby improving NPC1 mutant cell migratory behaviour.
    DOI:  https://doi.org/10.1038/s41598-021-04584-y
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