bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2022‒07‒10
sixty papers selected by
Viktor Korolchuk, Newcastle University
  1. Secretory autophagy during lysosome inhibition (SALI).
  2. CHAPERONE-MEDIATED AUTOPHAGY PROTECTS AGAINST ATHEROSCLEROSIS.
  3. SQSTM1, lipid droplets and current state of their lipophagy affairs.
  4. Mitochondrial Quality Control Links Two Seemingly Unrelated Neurodegenerative Diseases.
  5. Hallmarks and Molecular Tools for the Study of Mitophagy in Parkinson's Disease.
  6. Expanding the view of the molecular mechanisms of autophagy pathway.
  7. Endosomal LC3C-pathway selectively targets plasma membrane cargo for autophagic degradation.
  8. mTOR-Dependent Autophagy Regulates Slit Diaphragm Density in Podocyte-like Drosophila Nephrocytes.
  9. GRASP55 regulates the unconventional secretion and aggregation of mutant huntingtin.
  10. Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling.
  11. Autophagy and its mediated mitochondrial quality control maintain pollen tube growth and male fertility in Arabidopsis.
  12. Role of Mitophagy in neurodegenerative Diseases and potential tagarts for Therapy.
  13. Is denervation-induced TFEB translocation hitting an mTOR nerve?
  14. The Function of Autophagy as a Regulator of Melanin Homeostasis.
  15. mTORC1 signaling in antigen-presenting cells of the skin restrains CD8+ T cell priming.
  16. Enriched Environment-Induced Neuroprotection against Cerebral Ischemia-Reperfusion Injury Might Be Mediated via Enhancing Autophagy Flux and Mitophagy Flux.
  17. The Social Network of TORC1 in plants.
  18. Systemic approaches using single cell transcriptome reveal that C/EBPγ regulates autophagy under amino acid starved condition.
  19. Multiparameter phenotypic screening for endogenous TFEB and TFE3 translocation identifies novel chemical series modulating lysosome function.
  20. Ubiquitin profiling of lysophagy identifies actin stabilizer CNN2 as a target of VCP/p97 and uncovers a link to HSPB1.
  21. mTOR-Dependent Spine Dynamics in Autism.
  22. Autophagy Loss Impedes Cancer-Associated Fibroblast Activation via Downregulating Proline Biosynthesis.
  23. Salmonella Promotes Its Own Survival in B Cells by Inhibiting Autophagy.
  24. Autophagy regulates organelle reorganization during spermiogenesis in the liverwort Marchantia polymorpha.
  25. The Ubiquitin-26S Proteasome System and Autophagy Relay Proteome Homeostasis Regulation During Silique Development.
  26. Degradation Mechanism of Autophagy-Related Proteins and Research Progress.
  27. The plant TOR kinase tunes autophagy and meristem activity for nutrient stress-induced developmental plasticity.
  28. Editorial: Molecular Mechanisms of Autophagy in Cancer.
  29. eIF4A1 Inhibitor Suppresses Hyperactive mTOR-Associated Tumors by Inducing Necroptosis and G2/M Arrest.
  30. Numb Promotes Autophagy through p53 Pathway in Acute Kidney Injury Induced by Cisplatin.
  31. A quantitative high throughput screen identifies compounds that lower expression of the SCA2- and ALS-associated gene ATXN2.
  32. A partial reduction of VDAC1 enhances mitophagy, autophagy, synaptic activities in a transgenic Tau mouse model.
  33. Tangshenning Attenuates High Glucose-Induced Podocyte Injury via Restoring Autophagy Activity through Inhibiting mTORC1 Activation.
  34. Lysosomal dysfunction is associated with NLRP3 inflammasome activation in chronic unpredictable mild stress-induced depressive mice.
  35. Current opinions on mitophagy in fungi.
  36. Seventy-Two-Hour LRRK2 Kinase Activity Inhibition Increases Lysosomal GBA Expression in H4, a Human Neuroglioma Cell Line.
  37. A pH-Driven Small-Molecule Nanotransformer Hijacks Lysosomes and Overcomes Autophagy-Induced Resistance in Cancer.
  38. Extracellular Vesicles from BMSCs Prevent Glucocorticoid-Induced BMECs Injury by Regulating Autophagy via the PI3K/Akt/mTOR Pathway.
  39. MiR-142-5p/FAM134B Axis Manipulates ER-Phagy to Control PRRSV Replication.
  40. Cornel Iridoid Glycoside and Its Effective Component Regulate ATPase Vps4A/JNK to Alleviate Autophagy Deficit with Autophagosome Accumulation.
  41. Activation of Autophagic Flux Maintains Mitochondrial Homeostasis during Cardiac Ischemia/Reperfusion Injury.
  42. Spermidine overrides INSR (insulin receptor)-IGF1R (insulin-like growth factor 1 receptor)-mediated inhibition of autophagy in the aging heart.
  43. Lack of Cathepsin D in the central nervous system results in microglia and astrocyte activation and the accumulation of proteinopathy-related proteins.
  44. Neuron-specific translational control shift ensures proteostatic resilience during ER stress.
  45. Role of SNAREs in Unconventional Secretion-Focus on the VAMP7-Dependent Secretion.
  46. Alkalization of cellular pH leads to cancer cell death by disrupting autophagy and mitochondrial function.
  47. AMPK's double-faced role in advanced stages of prostate cancer.
  48. The Interaction of mTOR and Nrf2 in Neurogenesis and Its Implication in Neurodegenerative Diseases.
  49. BRAF inhibition promotes ER stress-mediated cell death in uveal melanoma.
  50. Modulating mitofusins to control mitochondrial function and signaling.
  51. Transcription factor EB controls both motogenic and mitogenic cell activities.
  52. Cytoplasmic LMO2-LDB1 Complex Activates STAT3 Signaling through Interaction with gp130-JAK in Glioma Stem Cells.
  53. Mitochondrial Dynamics and Mitophagy in Cardiometabolic Disease.
  54. Marimastat alleviates oxidative stress induced cellular senescence by activating autophagy.
  55. A p53-phosphoinositide signalosome regulates nuclear AKT activation.
  56. Autophagic factors in Paget disease.
  57. Regulation of Cellular Ribonucleoprotein Granules: From Assembly to Degradation via Post-translational Modification.
  58. Sex-biased autophagy as a potential mechanism mediating sex differences in ischemic stroke outcome.
  59. Virus, Exosome, and MicroRNA: New Insights into Autophagy.
  60. Spatial regulation of AMPK signaling revealed by a sensitive kinase activity reporter.
  1. Autophagy. 2022 Jul 04.
    Secretory autophagy during lysosome inhibition (SALI).
    Jayanta Debnath, Andrew M Leidal.
      Both macroautophagy/autophagy and extracellular vesicle (EV) secretion pathways converge upon the endolysosome system. Although lysosome impairment leads to defects in autophagic degradation, the impact of such dysfunction on EV secretion remains poorly understood. Recently, we uncovered a novel secretory autophagy pathway that employs EVs and nanoparticles (EVPs) for the secretion of autophagy cargo receptors outside the cell when either autophagosome maturation or lysosomal function is blocked. We term this process secretory autophagy during lysosome inhibition (SALI). SALI functionally requires multiple steps in classical autophagosome formation and the small GTPase RAB27A. Because the intracellular accumulation of autophagy cargo receptors perturbs cell signaling and quality control pathways, we propose that SALI functions as a failsafe mechanism to preserve protein and cellular homeostasis when autophagic or lysosomal degradation is impaired.
    Keywords:  Autophagy cargo receptors; extracellular vesicles; lysosome; proteostasis; secretory autophagy; vesicular trafficking
    DOI:  https://doi.org/10.1080/15548627.2022.2095788
  2. Autophagy. 2022 Jul 05.
    CHAPERONE-MEDIATED AUTOPHAGY PROTECTS AGAINST ATHEROSCLEROSIS.
    Julio Madrigal-Matute, Ana Maria Cuervo, Judith C Sluimer.
      Atherosclerosis, the leading cause of cardiovascular death, is driven by hyperlipidemia, inflammation and aggravated by aging. As chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation for intracellular proteins, diminishes with age and is inhibited by lipid excess, we studied if the decline in CMA could contribute to atherosclerosis pathogenesis. We found that CMA declines in human and murine vasculature with disease progression. Inhibition and reactivation of CMA using transgenic mouse models establishes a protective effect of CMA against atherogenesis. CMA upregulation ameliorates both systemic metabolic parameters, and vascular cell function. Our work suggests CMA reactivation could be a viable therapeutic strategy to prevent and reduce cardiovascular disease.
    Keywords:  Cardiovascular disease; cholesterol; inflammation; insulin; lysosomes; macrophages; smooth muscle cells
    DOI:  https://doi.org/10.1080/15548627.2022.2096397
  3. Autophagy. 2022 Jul 07. 1-4
    SQSTM1, lipid droplets and current state of their lipophagy affairs.
    Ankit Shroff, Taras Y Nazarko.
      SQSTM1/p62 (sequestosome 1) is a well-established indicator of macroautophagic/autophagic flux. It was initially characterized as the ubiquitin-binding autophagic receptor in aggrephagy, the selective autophagy of ubiquitinated protein aggregates. Recently, several studies correlated its levels with the abundance of intracellular lipid droplets (LDs). In the absence of a bona fide receptor for the selective autophagy of LDs (lipophagy), a few studies demonstrated the role of SQSTM1 in lipophagy. Our analysis of these studies shows that SQSTM1 colocalizes with LDs, bridges them with phagophores, is co-degraded with them in the lysosomes, and affects LD abundance in a variety of cells and under diverse experimental conditions. Although only one study reported all these functions together, the overwhelming and complementary evidence from other studies suggests that the role of SQSTM1 in lipophagy via tagging, movement, aggregation/clustering and sequestration of LDs is rather a common phenomenon in mammalian cells. As ubiquitination of the LD-associated proteins under stress conditions is increasingly recognized as another common phenomenon, some other ubiquitin-binding autophagic receptors, such as NBR1 and OPTN, might soon join SQSTM1 on a list of the non-exclusive lipophagy receptors.Abbreviations: LD: lipid droplet; LIR: LC3-interacting region; PAT: Perilipin, ADRP and TIP47 domain; SAR: selective autophagy receptor.
    Keywords:  Lipid droplet; SAR; SQSTM1; lipophagy; lipophagy receptor; p62; phagophore; selective autophagy; selective autophagy receptor; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2022.2094606
  4. Autophagy. 2022 Jul 04.
    Mitochondrial Quality Control Links Two Seemingly Unrelated Neurodegenerative Diseases.
    Yinglu Tang, Yunpeng Huang, Zhihui Wan, Bing Zhou, Zhihao Wu.
      
    Keywords:  Acetylation; CoA; Parkinson disease; Pink1/PINK1; autophagy receptor; fbl/PANK2; mitophagy; pantothenate kinase-associated neurodegeneration; park/PRKN
    DOI:  https://doi.org/10.1080/15548627.2022.2094605
  5. Cells. 2022 Jul 02. pii: 2097. [Epub ahead of print]11(13):
    Hallmarks and Molecular Tools for the Study of Mitophagy in Parkinson's Disease.
    Thomas Goiran, Mohamed A Eldeeb, Cornelia E Zorca, Edward A Fon.
      The best-known hallmarks of Parkinson's disease (PD) are the motor deficits that result from the degeneration of dopaminergic neurons in the substantia nigra. Dopaminergic neurons are thought to be particularly susceptible to mitochondrial dysfunction. As such, for their survival, they rely on the elaborate quality control mechanisms that have evolved in mammalian cells to monitor mitochondrial function and eliminate dysfunctional mitochondria. Mitophagy is a specialized type of autophagy that mediates the selective removal of damaged mitochondria from cells, with the net effect of dampening the toxicity arising from these dysfunctional organelles. Despite an increasing understanding of the molecular mechanisms that regulate the removal of damaged mitochondria, the detailed molecular link to PD pathophysiology is still not entirely clear. Herein, we review the fundamental molecular pathways involved in PINK1/Parkin-mediated and receptor-mediated mitophagy, the evidence for the dysfunction of these pathways in PD, and recently-developed state-of-the art assays for measuring mitophagy in vitro and in vivo.
    Keywords:  PINK1; Parkin; Parkinson’s disease; alpha-syn; mito-Keima; mito-QC; mito-SRAI; mitochondrial quality control; mitophagy; protein quality control; ubiquitin
    DOI:  https://doi.org/10.3390/cells11132097
  6. J Cell Physiol. 2022 Jul 05.
    Expanding the view of the molecular mechanisms of autophagy pathway.
    Sheikh Tahir Majeed, Rabiya Majeed, Khurshid I Andrabi.
      Autophagy is an evolutionarily conserved multistep degradation mechanism in eukaryotes, that maintains cellular homoeostasis by replenishing cells with nutrients through catabolic lysis of the cytoplasmic components. This critically coordinated pathway involves sequential processing events that begin with initiation, nucleation, and elongation of phagophores, followed by the formation of  double-membrane vesicles known as autophagosomes. Finally, autophagosomes migrate towards and fuse with lysosomes in mammals and vacuoles in yeast and plants, for the eventual degradation of the intravesicular cargo. Here, we review the recent advances in our understanding of the molecular events that define the process of autophagy.
    Keywords:  ATG proteins; ULK1 complex; autophagosome; autophagy; lysosomes; phagophore
    DOI:  https://doi.org/10.1002/jcp.30819
  7. Nat Commun. 2022 Jul 02. 13(1): 3812
    Endosomal LC3C-pathway selectively targets plasma membrane cargo for autophagic degradation.
    Paula P Coelho, Geoffrey G Hesketh, Annika Pedersen, Elena Kuzmin, Anne-Marie N Fortier, Emily S Bell, Colin D H Ratcliffe, Anne-Claude Gingras, Morag Park.
      Autophagy selectively targets cargo for degradation, yet mechanistic understanding remains incomplete. The ATG8-family plays key roles in autophagic cargo recruitment. Here by mapping the proximal interactome of ATG8-paralogs, LC3B and LC3C, we uncover a LC3C-Endocytic-Associated-Pathway (LEAP) that selectively recruits plasma-membrane (PM) cargo to autophagosomes. We show that LC3C localizes to peripheral endosomes and engages proteins that traffic between PM, endosomes and autophagosomes, including the SNARE-VAMP3 and ATG9, a transmembrane protein essential for autophagy. We establish that endocytic LC3C binds cargo internalized from the PM, including the Met receptor tyrosine kinase and transferrin receptor, and is necessary for their recruitment into ATG9 vesicles targeted to sites of autophagosome initiation. Structure-function analysis identified that LC3C-endocytic localization and engagement with PM-cargo requires the extended carboxy-tail unique to LC3C, the TBK1 kinase, and TBK1-phosphosites on LC3C. These findings identify LEAP as an unexpected LC3C-dependent pathway, providing new understanding of selective coupling of PM signalling with autophagic degradation.
    DOI:  https://doi.org/10.1038/s41467-022-31465-3
  8. Cells. 2022 Jul 02. pii: 2103. [Epub ahead of print]11(13):
    mTOR-Dependent Autophagy Regulates Slit Diaphragm Density in Podocyte-like Drosophila Nephrocytes.
    Dominik Spitz, Maria Comas, Lea Gerstner, Séverine Kayser, Martin Helmstädter, Gerd Walz, Tobias Hermle.
      Both mTOR signaling and autophagy are important modulators of podocyte homeostasis, regeneration, and aging and have been implicated in glomerular diseases. However, the mechanistic role of these pathways for the glomerular filtration barrier remains poorly understood. We used Drosophila nephrocytes as an established podocyte model and found that inhibition of mTOR signaling resulted in increased spacing between slit diaphragms. Gain-of-function of mTOR signaling did not affect spacing, suggesting that additional cues limit the maximal slit diaphragm density. Interestingly, both activation and inhibition of mTOR signaling led to decreased nephrocyte function, indicating that a fine balance of signaling activity is needed for proper function. Furthermore, mTOR positively controlled cell size, survival, and the extent of the subcortical actin network. We also showed that basal autophagy in nephrocytes is required for survival and limits the expression of the sns (nephrin) but does not directly affect slit diaphragm formation or endocytic activity. However, using a genetic rescue approach, we demonstrated that excessive, mTOR-dependent autophagy is primarily responsible for slit diaphragm misspacing. In conclusion, we established this invertebrate podocyte model for mechanistic studies on the role of mTOR signaling and autophagy, and we discovered a direct mTOR/autophagy-dependent regulation of the slit diaphragm architecture.
    Keywords:  Drosophila; autophagy; mTOR; nephrin; nephrocyte; podocyte; slit diaphragm
    DOI:  https://doi.org/10.3390/cells11132103
  9. J Biol Chem. 2022 Jun 30. pii: S0021-9258(22)00661-5. [Epub ahead of print] 102219
    GRASP55 regulates the unconventional secretion and aggregation of mutant huntingtin.
    Erpan Ahat, Sarah Bui, Jianchao Zhang, Felipe da Veiga Leprevost, Lisa Sharkey, Whitney Reid, Alexey I Nesvizhskii, Henry L Paulson, Yanzhuang Wang.
      Recent studies demonstrated that the Golgi re-assembly stacking proteins (GRASPs), especially GRASP55, regulate Golgi-independent unconventional secretion of certain cytosolic and transmembrane cargoes; however, the underlying mechanism remains unknown. Here, we surveyed several neurodegenerative disease related proteins, including mutant huntingtin (Htt-Q74), SOD1, tau, and TDP43, for unconventional secretion; our results show that Htt-Q74 is most robustly secreted in a GRASP55-dependent manner. Using Htt-Q74 as a model system, we demonstrate that unconventional secretion of Htt is GRASP55- and autophagy-dependent, and is enhanced under stress conditions such as starvation and endoplasmic reticulum (ER) stress. Mechanistically, we show that GRASP55 facilitates Htt secretion by tethering autophagosomes to lysosomes to promote autophagosome maturation and subsequent lysosome secretion, and by stabilizing p23/TMED10, a channel for translocation of cytoplasmic proteins into the lumen of the ER-Golgi intermediate compartment (ERGIC). Moreover, we found that GRASP55 levels are upregulated by various stresses to facilitate unconventional secretion, while inhibition of Htt-Q74 secretion by GRASP55 knockout enhances Htt aggregation and toxicity. Lastly, comprehensive secretomic analysis identified novel cytosolic cargoes secreted by the same unconventional pathway, including TAGLN, PAICS and PRDX1. In conclusion, this study defines the pathway of GRASP55-mediated unconventional protein secretion and provides important insights into the progression of Huntington's disease.
    Keywords:  GRASP55; Golgi; aggregation; huntingtin; neurodegeneration; secretory autophagy; unconventional secretion
    DOI:  https://doi.org/10.1016/j.jbc.2022.102219
  10. Mil Med Res. 2022 Jul 07. 9(1): 38
    Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling.
    Meng-Zhu Li, En-Jie Liu, Qiu-Zhi Zhou, Shi-Hong Li, Shi-Jie Liu, Hai-Tao Yu, Qi-Hang Pan, Fei Sun, Ting He, Wei-Jin Wang, Dan Ke, Yu-Qi Feng, Jun Li, Jian-Zhi Wang.
      BACKGROUND: Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer's disease (AD). This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy.METHODS: The primary hippocampal neurons, N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy, which was analysed by Student's two-tailed t-test. The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1 (mTORC1) activity and the vacuolar H+-ATPase (v-ATPase) activity, respectively, which were analysed by One-way ANOVA with post hoc tests. The Western blotting, co-immunoprecipitation and immunofluorescence staining were conducted to gain insight into the mechanisms underlying the tau effects of mTORC1 signaling alterations, as analysed by Student's two-tailed t-test or One-way ANOVA with post hoc tests. The autophagosome formation was detected by immunofluorescence staining and transmission electron microscopy. The amino acids (AA) levels were detected by high performance liquid chromatography (HPLC).
    RESULTS: We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits. Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1 (PRD-TIA1) and this association significantly increased the intercellular level of amino acids (Leucine, P = 0.0038; Glutamic acid, P = 0.0348; Alanine, P = 0.0037; Glycine, P = 0.0104), with concordant upregulation of mTORC1 activity [phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4EBP1), P < 0.0001; phosphorylated 70 kDa ribosomal protein S6 kinase 1 (p-p70S6K1), P = 0.0001, phosphorylated unc-51-like autophagy-activating kinase 1 (p-ULK1), P = 0.0015] and inhibition of autophagosome formation [microtubule-associated protein light chain 3 II (LC3 II), P = 0.0073; LC3 puncta, P < 0.0001]. As expected, this tau-induced deficit of autophagosome formation in turn aggravated tau accumulation. Importantly, we also found that blocking TIA1 and tau interaction by overexpressing PRD-TIA1, downregulating the endogenous TIA1 expression by shRNA, or downregulating tau protein level by a small proteolysis targeting chimera (PROTAC) could remarkably attenuate tau-induced autophagy impairment.
    CONCLUSIONS: Our findings reveal that AD-like tau accumulation inhibits autophagosome formation and induces autophagy deficits by activating the TIA1/amino acid/mTORC1 pathway, and thus this work reveals new insight into tau-associated neurodegeneration and provides evidence supporting the use of new therapeutic targets for AD treatment and that of related tauopathies.
    Keywords:  Amino acid pathway; Autophagy; Mammalian target of rapamycin kinase complex 1 (mTORC1); T cell intracellular antigen 1 (TIA1); Tau
    DOI:  https://doi.org/10.1186/s40779-022-00396-x
  11. Autophagy. 2022 Jul 04.
    Autophagy and its mediated mitochondrial quality control maintain pollen tube growth and male fertility in Arabidopsis.
    He Yan, Menglong Zhuang, Xiaoyu Xu, Shanshan Li, Mingkang Yang, Nianle Li, Xiaojuan Du, Kangwei Hu, Xiaomin Peng, Wei Huang, Hong Wu, Yu Chung Tse, Lifeng Zhao, Hao Wang.
      Macroautophagy/autophagy, a major catabolic pathway in eukaryotes, participates in plant sexual reproduction including the processes of male gametogenesis and the self-incompatibility response. Rapid pollen tube growth is another essential reproductive process that is metabolically highly demanding to drive the vigorous cell growth for delivery of male gametes for fertilization in angiosperms. Whether and how autophagy operates to maintain the homeostasis of pollen tubes remains unknown. Here, we provide evidence that autophagy is elevated in growing pollen tubes and critically required during pollen tube growth and male fertility in Arabidopsis. We demonstrate that SH3P2, a critical non-ATG regulator of plant autophagy, colocalizes with representative ATG proteins during autophagosome biogenesis in growing pollen tubes. Downregulation of SH3P2 expression significantly disrupts Arabidopsis pollen germination and pollen tube growth. Further analysis of organelle dynamics reveals crosstalk between autophagosomes and prevacuolar compartments following the inhibition of phosphatidylinositol 3-kinase. In addition, time-lapse imaging and tracking of ATG8e-labeled autophagosomes and depolarized mitochondria demonstrate that they interact specifically via the ATG8-family interacting motif (AIM)-docking site to mediate mitophagy. Ultrastructural identification of mitophagosomes and two additional forms of autophagosomes imply that multiple types of autophagy are likely to function simultaneously within pollen tubes. Altogether, our results suggest that autophagy is functionally crucial for mediating mitochondrial quality control and canonical cytoplasm recycling during pollen tube growth.
    Keywords:  ATG8e; Arabidopsis; SH3P2; autophagy; male fertility; mitophagy; pollen tube growth
    DOI:  https://doi.org/10.1080/15548627.2022.2095838
  12. Mol Biol Rep. 2022 Jul 06.
    Role of Mitophagy in neurodegenerative Diseases and potential tagarts for Therapy.
    Lingling Jiao, Xixun Du, Yong Li, Qian Jiao, Hong Jiang.
      Mitochondria dysfunction has been defined as one of the hallmarks of aging-related diseases as is characterized by the destroyed integrity, abnormal distribution and size, insufficient ATP supply, increased ROS production, and subsequently damage and oxidize the proteins, lipids and nucleic acid. Mitophagy, an efficient way of removing damaged or defective mitochondria by autophagy, plays a pivotal role in maintaining the mitochondrial quantity and quality control enabling the degradation of unwanted mitochondria, and thus rescues cellular homeostasis in response to stress. Accumulating evidence demonstrates that impaired mitophagy has been associated with many neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) in a variety of patients and disease models with neural death, oxidative stress and disturbed metabolism, either as the cause or consequence. These findings suggest that modulation of mitophagy may be considered as a valid therapeutic strategy in neurodegenerative diseases. In this review, we summarize recent findings on the mechanisms of mitophagy and its role in neurodegenerative diseases, with a particular focus on mitochondrial proteins acting as receptors that mediate mitophagy in these diseases.
    Keywords:  FUNDC1; Mitophagy; NIX/BNIP3L; Neurodegenerative diseases; PINK1/Parkin
    DOI:  https://doi.org/10.1007/s11033-022-07738-x
  13. J Physiol. 2022 Jul 04.
    Is denervation-induced TFEB translocation hitting an mTOR nerve?
    Cassidy T Tinline-Goodfellow, Hugo J W Fung, Stephanie Estafanos, Celine Bailleul, Matthew J Lees.
      
    Keywords:  autophagy; mTOR; mitochondria; mitophagy; protein synthesis
    DOI:  https://doi.org/10.1113/JP283409
  14. Cells. 2022 Jun 30. pii: 2085. [Epub ahead of print]11(13):
    The Function of Autophagy as a Regulator of Melanin Homeostasis.
    Ki Won Lee, Minju Kim, Si Hyeon Lee, Kwang Dong Kim.
      Melanosomes are melanocyte-specific organelles that protect cells from ultraviolet (UV)-induced deoxyribonucleic acid damage through the production and accumulation of melanin and are transferred from melanocytes to keratinocytes. The relatively well-known process by which melanin is synthesized from melanocytes is known as melanogenesis. The relationship between melanogenesis and autophagy is attracting the attention of researchers because proteins associated with autophagy, such as WD repeat domain phosphoinositide-interacting protein 1, microtubule-associated protein 1 light chain 3, autophagy-related (ATG)7, ATG4, beclin-1, and UV-radiation resistance-associated gene, contribute to the melanogenesis signaling pathway. Additionally, there are reports that some compounds used as whitening cosmetics materials induce skin depigmentation through autophagy. Thus, the possibility that autophagy is involved in the removal of melanin has been suggested. To date, however, there is a lack of data on melanosome autophagy and its underlying mechanism. This review highlights the importance of autophagy in melanin homeostasis by providing an overview of melanogenesis, autophagy, the autophagy machinery involved in melanogenesis, and natural compounds that induce autophagy-mediated depigmentation.
    Keywords:  autophagy; melanin; melanogenesis
    DOI:  https://doi.org/10.3390/cells11132085
  15. Cell Rep. 2022 Jul 05. pii: S2211-1247(22)00826-9. [Epub ahead of print]40(1): 111032
    mTORC1 signaling in antigen-presenting cells of the skin restrains CD8+ T cell priming.
    Leonard R Pelgrom, Thiago A Patente, Frank Otto, Lonneke V Nouwen, Arifa Ozir-Fazalalikhan, Alwin J van der Ham, Hendrik J P van der Zande, Graham A Heieis, Ramon Arens, Bart Everts.
      How mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of cellular metabolism, affects dendritic cell (DC) metabolism and T cell-priming capacity has primarily been investigated in vitro, but how mTORC1 regulates this in vivo remains poorly defined. Here, using mice deficient for mTORC1 component raptor in DCs, we find that loss of mTORC1 negatively affects glycolytic and fatty acid metabolism and maturation of conventional DCs, particularly cDC1s. Nonetheless, antigen-specific CD8+ T cell responses to infection are not compromised and are even enhanced following skin immunization. This is associated with increased activation of Langerhans cells and a subpopulation of EpCAM-expressing cDC1s, of which the latter show an increased physical interaction with CD8+ T cells in situ. Together, this work reveals that mTORC1 limits CD8+ T cell priming in vivo by differentially orchestrating the metabolism and immunogenicity of distinct antigen-presenting cell subsets, which may have implications for clinical use of mTOR inhibitors.
    Keywords:  CD8(+) T cells; CP: Immunology; IL-12; Langerhans cells; MHCI; immunization; mTORC1; metabolism; type 1 conventional dendritic cells
    DOI:  https://doi.org/10.1016/j.celrep.2022.111032
  16. Mediators Inflamm. 2022 ;2022 2396487
    Enriched Environment-Induced Neuroprotection against Cerebral Ischemia-Reperfusion Injury Might Be Mediated via Enhancing Autophagy Flux and Mitophagy Flux.
    Qi-Qi Zhang, Lu Luo, Mei-Xi Liu, Chuan-Jie Wang, Yi Wu, Ke-Wei Yu.
      Background: Enriched environment (EE) can protect the brain against damages caused by an ischemic stroke; however, the underlying mechanism remains elusive. Autophagy and mitochondria quality control are instrumental in the pathogenesis of ischemic stroke. In this study, we investigated whether and how autophagy and mitochondria quality control contribute to the protective effect of EE in the acute phase of cerebral ischemia-reperfusion injury.Methods: We exposed transient middle cerebral artery occlusion (tMCAO) mice to EE or standard condition (SC) for 7 days and then studied them for neurological deficits, autophagy and inflammation-related proteins, and mitochondrial morphology and function.
    Results: Compared to tMCAO mice in the SC group, those in the EE group showed fewer neurological deficits, relatively downregulated inflammation, higher LC3 expression, higher mitochondrial Parkin levels, higher mitochondrial fission factor dynamin-related protein-1 (Drp1) levels, lower p62 expression, and lower autophagy inhibitor mTOR expression. Furthermore, we found that the EE group showed a higher number of mitophagosomes and normal mitochondria, fewer mitolysosomes, and relatively increased mitochondrial membrane potential.
    Conclusion: These results suggested that EE enhances autophagy flux by inhibiting mTOR and enhances mitophagy flux via recruiting Drp1 and Parkin to eliminate dysfunctional mitochondria, which in turn inhibits inflammation and alleviates neurological deficits. Limitations. The specific mechanisms through which EE promotes autophagy and mitophagy and the signaling pathways that link them with inflammation need further study.
    DOI:  https://doi.org/10.1155/2022/2396487
  17. J Exp Bot. 2022 Jul 04. pii: erac278. [Epub ahead of print]
    The Social Network of TORC1 in plants.
    K Muhammed Jamsheer, Prakhar Awasthi, Ashverya Laxmi.
      The Target Of Rapamycin Complex 1 (TORC1) is a highly conserved serine-threonine protein kinase crucial for coordinating growth according to nutrient availability in eukaryotes. TORC1 works as a central integrator of multiple nutrient inputs such as sugar, nitrogen, and phosphate and promotes growth and biomass accumulation in response to nutrient sufficiency. Studies especially in the past decade identified the central role of TORC1 in regulating growth through interaction with hormones, photoreceptors, and stress signaling machinery in plants. In this review, we comprehensively analyzed the interactome and phosphoproteome of the Arabidopsis TORC1 signaling network. Our analysis highlights the role of TORC1 as a central hub kinase communicating with transcriptional and translational apparatus, ribosomes, chaperones, protein kinases, metabolic enzymes, and autophagy and stress response machinery to orchestrate growth in response to the nutrient signals. This analysis also suggests that along with the conserved downstream components shared with other eukaryotic lineages, the plant TORC1 signaling underwent several evolutionary innovations and coopted many lineage-specific components during the plant evolution. Based on the protein-protein interaction and phosphoproteome data, we also discuss several uncharacterized and unexplored components of the TORC1 signaling network highlighting potential links for future studies.
    Keywords:  Nutrient Sensing; Plant development; Protein Kinase; Protein phosphorylation; Sugar Signaling; TORC1
    DOI:  https://doi.org/10.1093/jxb/erac278
  18. Nucleic Acids Res. 2022 Jul 08. pii: gkac593. [Epub ahead of print]
    Systemic approaches using single cell transcriptome reveal that C/EBPγ regulates autophagy under amino acid starved condition.
    Dongha Kim, Junil Kim, Young Suk Yu, Yong Ryoul Kim, Sung Hee Baek, Kyoung-Jae Won.
      Autophagy, a catabolic process to remove unnecessary or dysfunctional organelles, is triggered by various signals including nutrient starvation. Depending on the types of the nutrient deficiency, diverse sensing mechanisms and signaling pathways orchestrate for transcriptional and epigenetic regulation of autophagy. However, our knowledge about nutrient type-specific transcriptional regulation during autophagy is limited. To understand nutrient type-dependent transcriptional mechanisms during autophagy, we performed single cell RNA sequencing (scRNAseq) in the mouse embryonic fibroblasts (MEFs) with or without glucose starvation (GS) as well as amino acid starvation (AAS). Trajectory analysis using scRNAseq identified sequential induction of potential transcriptional regulators for each condition. Gene regulatory rules inferred using TENET newly identified CCAAT/enhancer binding protein γ (C/EBPγ) as a regulator of autophagy in AAS, but not GS, condition, and knockdown experiment confirmed the TENET result. Cell biological and biochemical studies validated that activating transcription factor 4 (ATF4) is responsible for conferring specificity to C/EBPγ for the activation of autophagy genes under AAS, but not under GS condition. Together, our data identified C/EBPγ as a previously unidentified key regulator under AAS-induced autophagy.
    DOI:  https://doi.org/10.1093/nar/gkac593
  19. Autophagy. 2022 Jul 04.
    Multiparameter phenotypic screening for endogenous TFEB and TFE3 translocation identifies novel chemical series modulating lysosome function.
    Phillippa J Carling, Brent J Ryan, William McGuinness, Shikha Kataria, Stewart W Humble, Stefan Milde, James A Duce, Nirav Kapadia, William J Zuercher, John B Davis, Elena Di Daniel, Richard Wade-Martins.
      The accumulation of toxic protein aggregates in multiple neurodegenerative diseases is associated with defects in the macroautophagy/autophagy-lysosome pathway. The amelioration of disease phenotypes across multiple models of neurodegeneration can be achieved through modulating the master regulator of lysosome function, TFEB (transcription factor EB). Using a novel multi-parameter high-throughput screen for cytoplasmic:nuclear translocation of endogenous TFEB and the related transcription factor TFE3, we screened the Published Kinase Inhibitor Set 2 (PKIS2) library as proof of principle and to identify kinase regulators of TFEB and TFE3. Given that TFEB and TFE3 are responsive to cellular stress we have established assays for cellular toxicity and lysosomal function, critical to ensuring the identification of hit compounds with only positive effects on lysosome activity. In addition to AKT inhibitors which regulate TFEB localization, we identified a series of quinazoline-derivative compounds that induced TFEB and TFE3 translocation. A novel series of structurally-related analogs was developed, and several compounds induced TFEB and TFE3 translocation at higher potency than previously screened compounds. KINOMEscan and cell-based KiNativ kinase profiling revealed high binding for the PRKD (protein kinase D) family of kinases, suggesting good selectivity for these compounds. We describe and utilize a cellular target-validation platform using CRISPRi knockdown and orthogonal PRKD inhibitors to demonstrate that the activity of these compounds is independent of PRKD inhibition. The more potent analogs induced subsequent upregulation of the CLEAR gene network and cleared pathological HTT protein in a cellular model of proteinopathy, demonstrating their potential to alleviate neurodegeneration-relevant phenotypes.
    Keywords:  High-content screening; PKIS2; TFEB; lysosome activity; lysosome biogenesis; protein aggregation
    DOI:  https://doi.org/10.1080/15548627.2022.2095834
  20. Mol Cell. 2022 Jun 28. pii: S1097-2765(22)00577-9. [Epub ahead of print]
    Ubiquitin profiling of lysophagy identifies actin stabilizer CNN2 as a target of VCP/p97 and uncovers a link to HSPB1.
    Bojana Kravić, Tihana Bionda, Alexander Siebert, Pinki Gahlot, Sophie Levantovsky, Christian Behrends, Hemmo Meyer.
      Lysosomal membrane permeabilization (LMP) is an underlying feature of diverse conditions including neurodegeneration. Cells respond by extensive ubiquitylation of membrane-associated proteins for clearance of the organelle through lysophagy that is facilitated by the ubiquitin-directed AAA-ATPase VCP/p97. Here, we assessed the ubiquitylated proteome upon acute LMP and uncovered a large diversity of targets and lysophagy regulators. They include calponin-2 (CNN2) that, along with the Arp2/3 complex, translocates to damaged lysosomes and regulates actin filaments to drive phagophore formation. Importantly, CNN2 needs to be ubiquitylated during the process and removed by VCP/p97 for efficient lysophagy. Moreover, we identified the small heat shock protein HSPB1 that assists VCP/p97 in the extraction of CNN2 and show that other membrane regulators including SNAREs, PICALM, AGFG1, and ARL8B are ubiquitylated during lysophagy. Our data reveal a framework of how ubiquitylation and two effectors, VCP/p97 and HSPB1, cooperate to protect cells from the deleterious effects of LMP.
    Keywords:  AAA+ protein; HSPB1; VCP/p97; actin; autophagy; calponin; lysophagy; lysosome; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2022.06.012
  21. Front Mol Neurosci. 2022 ;15 877609
    mTOR-Dependent Spine Dynamics in Autism.
    Shabani Chaudry, Nandini Vasudevan.
      Autism Spectrum Conditions (ASC) are a group of neurodevelopmental disorders characterized by deficits in social communication and interaction as well as repetitive behaviors and restricted range of interests. ASC are complex genetic disorders with moderate to high heritability, and associated with atypical patterns of neural connectivity. Many of the genes implicated in ASC are involved in dendritic spine pruning and spine development, both of which can be mediated by the mammalian target of rapamycin (mTOR) signaling pathway. Consistent with this idea, human postmortem studies have shown increased spine density in ASC compared to controls suggesting that the balance between autophagy and spinogenesis is altered in ASC. However, murine models of ASC have shown inconsistent results for spine morphology, which may underlie functional connectivity. This review seeks to establish the relevance of changes in dendritic spines in ASC using data gathered from rodent models. Using a literature survey, we identify 20 genes that are linked to dendritic spine pruning or development in rodents that are also strongly implicated in ASC in humans. Furthermore, we show that all 20 genes are linked to the mTOR pathway and propose that the mTOR pathway regulating spine dynamics is a potential mechanism underlying the ASC signaling pathway in ASC. We show here that the direction of change in spine density was mostly correlated to the upstream positive or negative regulation of the mTOR pathway and most rodent models of mutant mTOR regulators show increases in immature spines, based on morphological analyses. We further explore the idea that these mutations in these genes result in aberrant social behavior in rodent models that is due to these altered spine dynamics. This review should therefore pave the way for further research on the specific genes outlined, their effect on spine morphology or density with an emphasis on understanding the functional role of these changes in ASC.
    Keywords:  autism spectrum conditions; autophagy; mTORC1; neurocircuitry; rodent models; social behaviors; spine density; synaptic transmission
    DOI:  https://doi.org/10.3389/fnmol.2022.877609
  22. Autophagy. 2022 Jul 04.
    Autophagy Loss Impedes Cancer-Associated Fibroblast Activation via Downregulating Proline Biosynthesis.
    Jingru Bai, Tong Liu, Bo Tu, Meng Yuan, Zhaoqi Shu, Minghe Fan, Sihan Huo, Yuyao Guo, Lina Wang, Hua Wang, Ying Zhao.
      Cancer-associated fibroblasts (CAFs) are considered one of the most critical stromal cells that interact with pancreatic ductal adenocarcinoma (PDAC) and promote tumor growth, metastasis, and treatment resistance. Previous studies illustrated macroautophagy/autophagy contributes to CAF activation during tumor progression. Here in our study, we found that autophagy deficiency in CAFs impedes CAF activation by inhibiting proline biosynthesis and collagen production. Furthermore, we uncovered that autophagy promotes proline biosynthesis through mitophagy-mediated regulation of NADK2 (NAD kinase 2, mitochondrial), an enzyme responsible for production of mitochondrial NADP(H). Using an orthotopic mouse model of PDAC, we found that inhibiting mitophagy by targeting PRKN (parkin RBR E3 ubiquitin protein ligase) in the stroma reduced tumor weight. Thus, inhibition of CAFs mitophagy might be an attractive strategy for stroma-focused anti-cancer intervention.
    Keywords:  NADK2; autophagy; cancer-associated fibroblasts (CAFs); mitophagy; proline biosynthesis
    DOI:  https://doi.org/10.1080/15548627.2022.2093026
  23. Cells. 2022 Jun 29. pii: 2061. [Epub ahead of print]11(13):
    Salmonella Promotes Its Own Survival in B Cells by Inhibiting Autophagy.
    Lopez-Bailon Luis, Gonzalez-Telona Ana, Galán-Enríquez Carlos, García-Gil Abraham, Estrada-García Iris, Moreno-Lafont Martha, Ortiz-Navarrete Vianney.
      Salmonella is a Gram-negative bacterium known to be the major cause of gastrointestinal diseases and systemic infections. During infection of murine B cells, Salmonella activates the PI3K/Akt pathway through its effector, SopB. This signaling pathway induces the downregulation of NLRC4 transcription, resulting in reduced secretion of IL-1β. Thus, Salmonella-infected B cells do not progress to pyroptosis; consequently, the bacteria can survive inside these cells. However, the mechanism by which Salmonella evades the control of B cells has not yet been elucidated. In this study, we found that SopB activates mTORC1, which is necessary for bacterial survival, since B cells cultured with the mTORC1 inhibitor rapamycin and B cells lacking raptor can control Salmonella infection. A similar result was observed in B cells when they were infected with the Salmonella SopB mutant (Δsopb). Salmonella also promoted the phosphorylation of the ULK1 complex at serine 757 (Ser757) by mTORC1, resulting in decreased levels of LC3-II in infected B cells. In this study, we did not observe these results when B cells were infected with Δsopb Salmonella. Our results demonstrated that Salmonella survival within B cells depends on the inhibition of autophagy by mTORC1 activation.
    Keywords:  B cells; Salmonella; SopB; ULK1; autophagy; mTORC1
    DOI:  https://doi.org/10.3390/cells11132061
  24. Autophagy. 2022 Jul 04.
    Autophagy regulates organelle reorganization during spermiogenesis in the liverwort Marchantia polymorpha.
    Takuya Norizuki, Takashi Ueda.
      Sperm mitochondria generally exhibit distinctive and diverse morphologies in animals and plants. Bryophytes, a plant group consisting of liverworts, mosses, and hornworts, produce motile male gametes, called spermatozoids, that possess a fixed number of two mitochondria in their cell bodies. Electron microscopy observations have revealed the detailed morphological aspects of plant spermatozoids, including mitochondrial morphology; however, the mechanism by which mitochondria are reorganized during spermiogenesis in bryophytes remains largely unknown. Our recent study using the liverwort, Marchantia polymorpha, revealed that the mitochondrial number is reduced to one via mitochondrial fission and macroautophagic/autophagic degradation, which subsequently becomes two via asymmetric division to form large anterior and small posterior mitochondria. Other cytoplasmic components, such as peroxisomes, are also degraded via autophagy; however, mitochondria are degraded at a time distinct from other cytoplasmic components. We also found that some cytoplasmic components were degraded in the vacuole independent of autophagy. Our study highlights the dynamic reorganization of organelles via multiple degradation pathways during spermiogenesis in M. polymorpha.
    Keywords:  Autophagy; Marchantia polymorpha; mitochondria; mitochondrial fission; mitophagy; organelle reorganization; spermatozoid; spermiogenesis
    DOI:  https://doi.org/10.1080/15548627.2022.2096396
  25. Plant J. 2022 Jul 03.
    The Ubiquitin-26S Proteasome System and Autophagy Relay Proteome Homeostasis Regulation During Silique Development.
    Peifeng Yu, Zhihua Hua.
      Functional studies of the ubiquitin-26S proteasome system (UPS) have demonstrated that virtually all aspects of the plant's life involve UPS-mediated turnover of abnormal or short-lived proteins. However, developmental characterization of the UPS, including in seeds and fruits, remains scarce although mutants of its several core elements are embryonically lethal. Unfortunately, early termination of embryogenesis limits the scope for characterizing the UPS activities in reproductive organs. Given both economic and societal impact of reproductive production, such studies are indispensable. Here, we systematically compared expression changes of multiple 26S proteasome subunits along with the dynamics of proteasome activity and total protein ubiquitylation in seedlings, developing siliques or embryos of Arabidopsis thaliana. Since autophagy plays the second largest role in maintaining proteome stability, we parallelly studied three rate-limiting enzymes that are involved in autophagy flux. Our experiments unexpectedly discovered that, in opposite to the activities in seedlings, both protein and transcript levels of six selected 26S proteasome subunits gradually decline in immature siliques or embryos toward maturation while the autophagy flux rises albeit in a nutrient-rich condition. We also discovered a reciprocal turnover pathway between the proteasome and autophagy. While the autophagy flux is suppressed in seedlings by UPS-mediated degradation of its three key enzymes, transcriptional reprogramming dampens this process in siliques that in turn stimulates a bulk autophagic degradation of proteasomes. Collectively, our discovery about the developmental changes of the UPS and autophagy activities suggests that they relay the proteome homeostasis regulation in early silique and/or seed development highlighting their developmental interactions.
    Keywords:  26S proteasome; Development; autophagy; cellular homeostasis; protein degradation; ubiquitylation
    DOI:  https://doi.org/10.1111/tpj.15891
  26. Int J Mol Sci. 2022 Jun 30. pii: 7301. [Epub ahead of print]23(13):
    Degradation Mechanism of Autophagy-Related Proteins and Research Progress.
    Yanhui Zhou, Hakim Manghwar, Weiming Hu, Fen Liu.
      In all eukaryotes, autophagy is the main pathway for nutrient recycling, which encapsulates parts of the cytoplasm and organelles in double-membrane vesicles, and then fuses with lysosomes/vacuoles to degrade them. Autophagy is a highly dynamic and relatively complex process influenced by multiple factors. Under normal growth conditions, it is maintained at basal levels. However, when plants are subjected to biotic and abiotic stresses, such as pathogens, drought, waterlogging, nutrient deficiencies, etc., autophagy is activated to help cells to survive under stress conditions. At present, the regulation of autophagy is mainly reflected in hormones, second messengers, post-transcriptional regulation, and protein post-translational modification. In recent years, the degradation mechanism of autophagy-related proteins has attracted much attention. In this review, we have summarized how autophagy-related proteins are degraded in yeast, animals, and plants, which will help us to have a more comprehensive and systematic understanding of the regulation mechanisms of autophagy. Moreover, research progress on the degradation of autophagy-related proteins in plants has been discussed.
    Keywords:  autophagy; autophagy-related protein; degradation; proteasome; ubiquitin
    DOI:  https://doi.org/10.3390/ijms23137301
  27. Plant Cell. 2022 Jul 06. pii: koac201. [Epub ahead of print]
    The plant TOR kinase tunes autophagy and meristem activity for nutrient stress-induced developmental plasticity.
    Yihan Dong, Rasha Aref, Ilaria Forieri, David Schiel, Wiebke Leemhuis, Christian Meyer, Ruediger Hell, Markus Wirtz.
      Plants, unlike animals, respond to environmental challenges with comprehensive developmental transitions that allow them to cope with these stresses. Here we discovered that antagonistic activation of the Target of Rapamycin (TOR) kinase in Arabidopsis thaliana roots and shoots is essential for the nutrient deprivation-induced increase in the root-to-shoot ratio to improve foraging for mineral ions. We demonstrate that sulfate limitation-induced downregulation of TOR in shoots activates autophagy, resulting in enhanced carbon allocation to the root. The allocation of carbon to the roots is facilitated by the specific upregulation of the sucrose-transporter genes SWEET11/12 in shoots. SWEET11/12 activation is indispensable for enabling sucrose to act as a carbon source for growth and as a signal for tuning root apical meristem activity via glucose-TOR signaling. The sugar-stimulated TOR activity in the root suppresses autophagy and maintains root apical meristem activity to support root growth to enhance mining for new sulfate resources in the soil. We provide direct evidence that the organ-specific regulation of autophagy is essential for the increased root-to-shoot ratio in response to sulfur limitation. These findings uncover how sulfur limitation controls the central sensor kinase TOR to enable nutrient recycling for stress-induced morphological adaptation of the plant body.
    DOI:  https://doi.org/10.1093/plcell/koac201
  28. Front Cell Dev Biol. 2022 ;10 918511
    Editorial: Molecular Mechanisms of Autophagy in Cancer.
    Magali Humbert, Silvia Vega-Rubin-de-Celis, Guillermo Velasco, Yongjie Wei.
      
    Keywords:  CMA; autophagy; biomarkers; cancer; therapy
    DOI:  https://doi.org/10.3389/fcell.2022.918511
  29. Int J Mol Sci. 2022 Jun 22. pii: 6932. [Epub ahead of print]23(13):
    eIF4A1 Inhibitor Suppresses Hyperactive mTOR-Associated Tumors by Inducing Necroptosis and G2/M Arrest.
    Luyang Han, Yuting Wu, Fangming Liu, Hongbing Zhang.
      Aberrantly activated mechanistic target of rapamycin (mTOR) signaling pathway stimulates translation initiation/protein synthesis and eventually causes tumors. Targeting these processes thus holds potential for treating mTOR-associated diseases. We tested the potential of eFT226, a sequence-selective inhibitor of eIF4A-mediated translation, in the treatment of mTOR hyperactive cells caused by the deletion of tuberous sclerosis complex 1/2 (TSC1/2) or phosphatase and TENsin homology (PTEN). eFT226 preferentially inhibited the proliferation of Tsc2- and Pten-deficient cells by inducing necroptosis and G2/M phase arrest. In addition, eFT226 blocked the development of TSC2-deficient tumors. The translation initiation inhibitor is thus a promising regimen for the treatment of hyperactive mTOR-mediated tumors.
    Keywords:  Pten; Tsc2; eFT226; mTOR; necroptosis; tumor
    DOI:  https://doi.org/10.3390/ijms23136932
  30. Anal Cell Pathol (Amst). 2022 ;2022 8213683
    Numb Promotes Autophagy through p53 Pathway in Acute Kidney Injury Induced by Cisplatin.
    Ze Liu, Yong Li, Yongmei He, Junjie Wang.
      Acute kidney injury (AKI) is an important public health concern and characterized as tubular death involved in apoptosis and necrosis. Autophagy is rapidly induced in tubules and associates with renal tubular cells homeostasis to have a complex link with tubular death in AKI. Numb is a multifunctional protein and exerts protective role in tubular death in AKI induced by Cisplatin. However, the effect of Numb on tubular autophagy remains to be investigated. In the present study, the protein expression of LC3 and Beclin-1 related to autophagy was analyzed in Cisplatin-induced AKI mice with knocking down Numb. In model of tubular injury induced by Cisplatin in vitro, downregulation of Numb in NRK-52E cells also inhibited the activation of autophagy accompanied with the decreased protein level of p53. Overexpression of Numb in NRK-52E cells activated autophagy with increased LC3 and Beclin-1 expression accompanied with increased protein level of p53. Moreover, autophagy activation following Numb overexpression was suppressed by p53 inhibitor pifithrin-α. These data indicate that Numb promotes p53-mediated activation of tubular autophagy in AKI induced by Cisplatin and therefore may provide important targets for the treatment of AKI.
    DOI:  https://doi.org/10.1155/2022/8213683
  31. J Biol Chem. 2022 Jul 01. pii: S0021-9258(22)00670-6. [Epub ahead of print] 102228
    A quantitative high throughput screen identifies compounds that lower expression of the SCA2- and ALS-associated gene ATXN2.
    Daniel R Scoles, Mandi Gandelman, Sharan Paul, Thomas Dexheimer, Warunee Dansithong, Karla P Figueroa, Lance T Pflieger, Scott Redlin, Stephen C Kales, Hongmao Sun, David Maloney, Robert Damoiseaux, Mark J Henderson, Anton Simeonov, Ajit Jadhav, Stefan M Pulst.
      CAG repeat expansions in the ATXN2 gene can cause the autosomal dominant disorder spinocerebellar ataxia type 2 (SCA2), as well as increase the risk of amyotrophic lateral sclerosis (ALS). Abnormal molecular, motor, and neurophysiological phenotypes in SCA2 mouse models are normalized by lowering ATXN2 transcription, and reduction of non-mutant Atxn2 expression has been shown to increase the lifespan of mice overexpressing the TDP-43 ALS protein, demonstrating the potential benefits of targeting ATXN2 transcription in humans. Here we describe a quantitative high throughput screen (qHTS) to identify compounds that lower ATXN2 transcription. We screened 428,759 compounds in a multiplexed assay using an ATXN2-luciferase reporter in HEK-293 cells and identified a diverse set of compounds capable of lowering ATXN2 transcription. We observed dose-dependent reductions of endogenous ATXN2 in HEK-293 cells treated with procillaridin A, 17-DMAG, and HSP990, known inhibitors of HSP90 and Na+/K+-ATPases. Furthermore, HEK-293 cells expressing polyglutamine-expanded ATXN2-Q58 treated with 17-DMAG had minimally detectable ATXN2, as well as normalized markers of autophagy and endoplasmic reticulum (ER) stress, including STAU1, mTOR, p62, LC3-II, CHOP, and phospho-eIF2α. Finally, BAC ATXN2-Q22 mice treated with 17-DMAG or HSP990 exhibited highly reduced ATXN2 protein abundance in the cerebellum. Taken together, our study demonstrates inhibition of HSP90 or Na+/K+-ATPases as potentially effective therapeutic strategies for treating SCA2 and ALS.
    Keywords:  17-DMAG; HSP90; HSP990; NaK-ATPases; Spinocerebellar ataxia type 2 (SCA2); ataxin-2 (ATXN2); cardiac glycoside; proscillaridin A; quantitative high throughput screening (qHTS)
    DOI:  https://doi.org/10.1016/j.jbc.2022.102228
  32. Aging Cell. 2022 Jul 07. e13663
    A partial reduction of VDAC1 enhances mitophagy, autophagy, synaptic activities in a transgenic Tau mouse model.
    Murali Vijayan, Rainier Vladlen Alvir, Razelle Vladlen Alvir, Lloyd E Bunquin, Jangampalli Adi Pradeepkiran, P Hemachandra Reddy.
      Alzheimer's disease (AD) is the most common cause of mental dementia in the aged population. AD is characterized by the progressive decline of memory and multiple cognitive functions, and changes in behavior and personality. Recent research has revealed age-dependent increased levels of VDAC1 in postmortem AD brains and cerebral cortices of APP, APPxPS1, and 3xAD.Tg mice. Further, we found abnormal interaction between VDAC1 and P-Tau in the AD brains, leading to mitochondrial structural and functional defects. Our current study aimed to understand the impact of a partial reduction of voltage-dependent anion channel 1 (VDAC1) protein on mitophagy/autophagy, mitochondrial and synaptic activities, and behavior changes in transgenic TAU mice in Alzheimer's disease. To determine if a partial reduction of VDAC1 reduces mitochondrial and synaptic toxicities in transgenic Tau (P301L) mice, we crossed heterozygote VDAC1 knockout (VDAC1+/- ) mice with TAU mice and generated double mutant (VDAC1+/- /TAU) mice. We assessed phenotypic behavior, protein levels of mitophagy, autophagy, synaptic, other key proteins, mitochondrial morphology, and dendritic spines in TAU mice relative to double mutant mice. Partial reduction of VDAC1 rescued the TAU-induced behavioral impairments such as motor coordination and exploratory behavioral changes, and learning and spatial memory impairments in VDAC1+/- /TAU mice. Protein levels of mitophagy, autophagy, and synaptic proteins were significantly increased in double mutant mice compared with TAU mice. In addition, dendritic spines were significantly increased; the mitochondrial number was significantly reduced, and mitochondrial length was increased in double mutant mice. Based on these observations, we conclude that reduced VDAC1 is beneficial in symptomatic-transgenic TAU mice.
    Keywords:  Alzheimer's disease; autophagy; hexokinases; mitochondria; mitochondrial biogenesis; mitophagy; oxidative stress; voltage-dependent anion channel 1
    DOI:  https://doi.org/10.1111/acel.13663
  33. J Diabetes Res. 2022 ;2022 1610416
    Tangshenning Attenuates High Glucose-Induced Podocyte Injury via Restoring Autophagy Activity through Inhibiting mTORC1 Activation.
    Jiayi Xu, Xiaomeng Shan, Chunwei Chen, Yanbin Gao, Dawei Zou, Xiaolei Wang, Tao Wang, Yimin Shi.
      Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus (DM) and the most common cause of death in diabetic patients. DN progression is associated with podocyte damage due to reduced autophagy caused by mTORC1 activation. Tangshenning (TSN) has been shown to reduce proteinuria, protect renal function, and reduce podocyte damage. Still, the effect of TSN on the autophagic activity of podocytes remains unclear. Herein, in vitro experiments using a high glucose-induced podocyte injury model were performed. Results showed that TSN treatment enhanced the weakened nephrin expression and autophagic activity of podocytes and inhibited the mTORC1 pathway (p-mTOR, mTOR, p-p70S6K, p70S6K, ULK1, and 4EBP1) under high glucose conditions. Furthermore, the mTORC1 activator (siRNA-TSC2) partially inhibited the above beneficial effects of TSN, suggesting that mTORC1 was the target of TSN to regulate autophagy. In summary, TSN reduces podocyte damage induced by high glucose via inhibiting mTORC1 pathway and downstream targets and restoring podocyte autophagy.
    DOI:  https://doi.org/10.1155/2022/1610416
  34. Behav Brain Res. 2022 Jul 01. pii: S0166-4328(22)00255-8. [Epub ahead of print]432 113987
    Lysosomal dysfunction is associated with NLRP3 inflammasome activation in chronic unpredictable mild stress-induced depressive mice.
    Meng-Meng Li, Xi Wang, Xiao-Dong Chen, Hai-Long Yang, Huai-Sha Xu, Ping Zhou, Rong Gao, Ning Zhang, Jun Wang, Lei Jiang, Na Liu.
      NLRP3 inflammasome pathway-mediated inflammatory response is closely associated with depression. Increasing attention has been recently paid to the links between autophagy and depression, however, the relationship between autophagy and NLRP3 inflammasome in depressive behavior remain poorly understood. In the present study, the potential roles of autophagy-lysosome pathway in NLRP3 inflammasome regulation were investigated both in vivo (chronic unpredictable mild stress (CUMS)-induced depressive mouse model) and in vitro (LPS-induced cellular model) model. It demonstrated that CUMS induces depressive-like behaviors in mice, accompanied by increased expression of NLRP3 inflammasome and inflammatory responses. Meanwhile, it promoted the autophagosome marker LC3 and autophagic adapter protein p62 accumulation, accompanied by the decrease of lysosomal cathepsins B and D expression in the prefrontal cortex of mice. Notably, a significant colocalization of NLRP3 and LC3 in CUMS mice by immunofluorescence co-staining were observed. For the in vitro study, disrupting the lysosomal function with Baf A1 significantly increased the LPS-induced NLRP3 inflammasome accumulation and pro-inflammatory factors (IL-1β and IL-18) production in BV2 cells. Collectively, our results suggested that the autophagic process is related to NLRP3 inflammasome activation, and dysfunctional lysosome in autophagy-lysosomal pathway may retard NLRP3 inflammasome degradation, facilitating the production of pro-inflammatory factors, thereby contributing to depressive behavior in CUMS mice.
    Keywords:  Autophagy; Depression; Inflammation; Lysosome; NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.bbr.2022.113987
  35. Autophagy. 2022 Jul 05.
    Current opinions on mitophagy in fungi.
    Zi-Fang Shen, Lin Li, Xue-Ming Zhu, Xiao-Hong Liu, Daniel J Klionsky, Fu-Cheng Lin.
      Mitophagy, as one of the most important cellular processes to ensure quality control of mitochondria, aims at transporting damaged, aging, dysfunctional or excess mitochondria to vacuoles (plants and fungi) or lysosomes (mammals) for degradation and recycling. The normal functioning of mitophagy is critical for cellular homeostasis from yeasts to humans. Although the role of mitophagy has been well studied in mammalian cells and in certain model organisms, especially the budding yeast Saccharomyces cerevisiae, our understanding of its significance in other fungi, particularly in pathogenic filamentous fungi, is still at the preliminary stage. Recent studies have shown that mitophagy plays a vital role in spore production, vegetative growth and virulence of pathogenic fungi, which are very different from its roles in mammal and yeast. In this review, we summarize the functions of mitophagy for mitochondrial quality and quantity control, fungal growth and pathogenesis that have been reported in the field of molecular biology over the past two decades. These findings may help researchers and readers to better understand the multiple functions of mitophagy and provide new perspectives for the study of mitophagy in fungal pathogenesis.
    Keywords:  Fission; fungi; mitochondria; mitophagy; pathogenesis; quantity and quality control
    DOI:  https://doi.org/10.1080/15548627.2022.2098452
  36. Int J Mol Sci. 2022 Jun 22. pii: 6935. [Epub ahead of print]23(13):
    Seventy-Two-Hour LRRK2 Kinase Activity Inhibition Increases Lysosomal GBA Expression in H4, a Human Neuroglioma Cell Line.
    Clara Ruz, José Luis Alcantud, Francisco Vives, Francisco Arrebola, John Hardy, Patrick A Lewis, Claudia Manzoni, Raquel Duran.
      Mutations in LRRK2 and GBA1 are key contributors to genetic risk of developing Parkinson's disease (PD). To investigate how LRRK2 kinase activity interacts with GBA and contributes to lysosomal dysfunctions associated with the pathology of PD. The activity of the lysosomal enzyme β-Glucocerebrosidase (GCase) was assessed in a human neuroglioma cell model treated with two selective inhibitors of LRKK2 kinase activity (LRRK2-in-1 and MLi-2) and a GCase irreversible inhibitor, condutirol-beta-epoxide (CBE), under 24 and 72 h experimental conditions. We observed levels of GCase activity comparable to controls in response to 24 and 72 h treatments with LRRK2-in-1 and MLi-2. However, GBA protein levels increased upon 72 h treatment with LRRK2-in-1. Moreover, LC3-II protein levels were increased after both 24 and 72 h treatments with LRRK2-in-1, suggesting an activation of the autophagic pathway. These results highlight a possible regulation of lysosomal function through the LRRK2 kinase domain and suggest an interplay between LRRK2 kinase activity and GBA. Although further investigations are needed, the enhancement of GCase activity might restore the defective protein metabolism seen in PD.
    Keywords:  LRRK2; Parkinson’s disease; autophagy; glucocerebrosidase; lysosomal dysfunction
    DOI:  https://doi.org/10.3390/ijms23136935
  37. Angew Chem Int Ed Engl. 2022 Jul 06.
    A pH-Driven Small-Molecule Nanotransformer Hijacks Lysosomes and Overcomes Autophagy-Induced Resistance in Cancer.
    Zhao Ma, Kai Lin, Menghuan Tang, Mythili Ramachandran, Reng Qiu, Jin Li, Lucas N Solano, Yanyu Huang, Cristabelle De Souza, Sara Abou-Adas, Bai Xiang, Lanwei Zhang, Minyong Li, Yuanpei Li.
      Smart conversion of supramolecular structures in vivo is an attractive strategy in cancer nanomedicine, which is usually achieved via specific peptide sequences. Here we developed a lysosomal targeting small-molecule conjugate, PBC, which self-assembles into nanoparticles at physiological pH and smartly converts to nanofibrils in lysosomes of tumor cells. Such transformation mechanically leads to lysosomal dysfunction, autophagy inhibition, and unusual cytoplasmic vacuolation, thus granting PBC a unique anticancer activity as a monotherapy. Importantly, the photo-activated PBC elicits significant phototoxicity to lysosomes and shows enormous advantages in overcoming autophagy-caused treatment resistance frequently occurring in conventional phototherapy. This improved phototherapy achieves a complete cure of oral cancer xenografts upon limited administration. Our work provides a new paradigm for the construction of nonpeptide nanotransformers with biomedical activities.
    Keywords:  transformable nanoparticles, nanofibrils, lysosomes, autophagy, photodynamic therapy
    DOI:  https://doi.org/10.1002/anie.202204567
  38. Cells. 2022 Jul 03. pii: 2104. [Epub ahead of print]11(13):
    Extracellular Vesicles from BMSCs Prevent Glucocorticoid-Induced BMECs Injury by Regulating Autophagy via the PI3K/Akt/mTOR Pathway.
    Jinhui Ma, Mengran Shen, Debo Yue, Weiguo Wang, Fuqiang Gao, Bailiang Wang.
      Osteonecrosis of the femoral head (ONFH) is a common clinical disease with a high disability rate. Injury of bone microvascular endothelial cells (BMECs) caused by glucocorticoid administration is one of the important causes of ONFH, and there is currently a lack of effective clinical treatments. Extracellular vesicles derived from bone stem cells (BMSC-EVs) can prevent ONFH by promoting angiogenesis and can inhibit cell apoptosis by regulating autophagy via the PI3K/Akt/mTOR signaling pathway. The present study aimed to investigate the effect of extracellular vesicles derived from bone marrow stem cells (BMSC) on a glucocorticoid-induced injury of BMECs and possible mechanisms. We found that BMSC-EVs attenuated glucocorticoid-induced viability, angiogenesis capacity injury, and the apoptosis of BMECs. BMSC-EVs increased the LC3 level, but decreased p62 (an autophagy protein receptor) expression, suggesting that BMSC-Exos activated autophagy in glucocorticoid-treated BMECs. The protective effects of BMSC-EVs on the glucocorticoid-induced injury of BMECs was mimicked by a known stimulator of autophagy (rapamycin) and could be enhanced by co-treatment with an autophagy inhibitor (LY294002). BMSC-EVs also suppressed the PI3K/Akt/mTOR signaling pathway, which regulates cell autophagy, in glucocorticoid-treated BMECs. In conclusion, the results indicate that BMSC-EVs prevent the glucocorticoid-induced injury of BMECs by regulating autophagy via the PI3K/Akt/mTOR pathway.
    Keywords:  PI3K/Akt/mTOR pathway; autophagy; bone marrow mesenchymal stem cells; bone microvascular endothelial cells; extracellular vesicles
    DOI:  https://doi.org/10.3390/cells11132104
  39. Front Immunol. 2022 ;13 842077
    MiR-142-5p/FAM134B Axis Manipulates ER-Phagy to Control PRRSV Replication.
    Kaifeng Guan, Qiuju Su, Kailin Kuang, Xiangge Meng, Xiang Zhou, Bang Liu.
      Porcine reproductive and respiratory syndrome virus (PRRSV) can replicate its RNA genome in endoplasmic reticulum (ER) and utilize ER to facilitate its assembly and maturation. To maintain ER homeostasis, host cells initiate reticulophagy (known as ER-phagy) to effectively digest the stressed ER. In this study, we found that PRRSV infection subverted ER-phagy by downregulating ER-phagy receptor FAM134B. PRRSV-induced miR-142-5p directly targeted FAM134B and significantly promoted PRRSV replication. Meanwhile, siRNA-mediated depletion of FAM134B protein and overexpression of FAM134B mutant protein significantly disrupted ER-phagy and facilitated PRRSV replication. Furthermore, our results showed that FAM134B-mediated ER-phagy activated type I interferon signaling to inhibit PRRSV replication. Overall, this study reveals the important role of ER-phagy in PRRSV replication in a FAM134B-dependent manner. Our findings provide an insight into the pathogenesis of PRRSV and offer a theoretical basis for further development of antiviral therapeutic targets.
    Keywords:  ER-phagy; FAM134B; PRRSV; Type I interferon; miR-142-5p
    DOI:  https://doi.org/10.3389/fimmu.2022.842077
  40. Am J Chin Med. 2022 Jul 02. 1-17
    Cornel Iridoid Glycoside and Its Effective Component Regulate ATPase Vps4A/JNK to Alleviate Autophagy Deficit with Autophagosome Accumulation.
    Cui-Cui Yang, Ceng-Ceng Zheng, Yi Luo, Kai-Wen Guo, Dan Gao, Li Zhang, Lin Li, Lan Zhang.
      Improving autophagy-lysosome fusion has been considered a key method in the treatment of Alzheimer's disease (AD). Cornel iridoid glycoside (CIG) is extracted from Cornus officinalis and has been shown to promote the clearance of tau oligomers via the autophagy pathway. However, the mechanisms of CIG on autophagy deficits are not understood. Here, we found autophagy deficit and tau aggregation in the brains of P301S tau transgenic mice and MAPT cells edited using CRISPR-Cas9 technology. CIG decreased tau aggregation and alleviated autophagic markers involving the JNK/Beclin-1 signaling pathway which demonstrated CIG that might enhance lysosome formation by upregulating ATPase Vps4A expression. Knocking down VPS4A increased autophagosome accumulation and attenuated the effect of CIG on p62. In addition, CIG had no effect on tau oligomers but still inhibited the level of tau monomer in VPS4A knockout cells. The effective component (Sweroside, SWE) of CIG attenuated tau oligomers accumulation and increased Vps4A level but not CHMP2B. SWE could not change the level of tau oligomers in VPS4A knockout cells. In conclusion, CIG suppressed autophagosome accumulation by regulating the ATPase Vps4A/JNK. SWE is a core of active factors of CIG in Vps4A regulation. These findings suggest CIG may be a potential drug in AD treatment.
    Keywords:  ATPase Vps4A; Autophagy–Lysosomal; Beclin-1; JNK; Tau Accumulation
    DOI:  https://doi.org/10.1142/S0192415X22500677
  41. Cells. 2022 Jul 04. pii: 2111. [Epub ahead of print]11(13):
    Activation of Autophagic Flux Maintains Mitochondrial Homeostasis during Cardiac Ischemia/Reperfusion Injury.
    Lihao He, Yuxin Chu, Jing Yang, Jin He, Yutao Hua, Yunxi Chen, Gloria Benavides, Glenn C Rowe, Lufang Zhou, Scott Ballinger, Victor Darley-Usmar, Martin E Young, Sumanth D Prabhu, Palaniappan Sethu, Yingling Zhou, Cheng Zhang, Min Xie.
      Reperfusion injury after extended ischemia accounts for approximately 50% of myocardial infarct size, and there is no standard therapy. HDAC inhibition reduces infarct size and enhances cardiomyocyte autophagy and PGC1α-mediated mitochondrial biogenesis when administered at the time of reperfusion. Furthermore, a specific autophagy-inducing peptide, Tat-Beclin 1 (TB), reduces infarct size when administered at the time of reperfusion. However, since SAHA affects multiple pathways in addition to inducing autophagy, whether autophagic flux induced by TB maintains mitochondrial homeostasis during ischemia/reperfusion (I/R) injury is unknown. We tested whether the augmentation of autophagic flux by TB has cardioprotection by preserving mitochondrial homeostasis both in vitro and in vivo. Wild-type mice were randomized into two groups: Tat-Scrambled (TS) peptide as the control and TB as the experimental group. Mice were subjected to I/R surgery (45 min coronary ligation, 24 h reperfusion). Autophagic flux, mitochondrial DNA (mtDNA), mitochondrial morphology, and mitochondrial dynamic genes were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were treated with a simulated I/R injury to verify cardiomyocyte specificity. The essential autophagy gene, ATG7, conditional cardiomyocyte-specific knockout (ATG7 cKO) mice, and isolated adult mouse ventricular myocytes (AMVMs) were used to evaluate the dependency of autophagy in adult cardiomyocytes. In NRVMs subjected to I/R, TB increased autophagic flux, mtDNA content, mitochondrial function, reduced reactive oxygen species (ROS), and mtDNA damage. Similarly, in the infarct border zone of the mouse heart, TB induced autophagy, increased mitochondrial size and mtDNA content, and promoted the expression of PGC1α and mitochondrial dynamic genes. Conversely, loss of ATG7 in AMVMs and in the myocardium of ATG7 cKO mice abolished the beneficial effects of TB on mitochondrial homeostasis. Thus, autophagic flux is a sufficient and essential process to mitigate myocardial reperfusion injury by maintaining mitochondrial homeostasis and partly by inducing PGC1α-mediated mitochondrial biogenesis.
    Keywords:  ROS; autophagy; mitochondrial biogenesis; mitochondrial dynamics; myocardial ischemia/reperfusion injury
    DOI:  https://doi.org/10.3390/cells11132111
  42. Autophagy. 2022 Jul 04.
    Spermidine overrides INSR (insulin receptor)-IGF1R (insulin-like growth factor 1 receptor)-mediated inhibition of autophagy in the aging heart.
    Mahmoud Abdellatif, Frank Madeo, Guido Kroemer, Simon Sedej.
      Although attenuated IGF1R (insulin-like growth factor 1 receptor) signaling has long been viewed to promote longevity in model organisms, adverse effects on the heart have been the subject of major concern. We observed that IGF1R is overexpressed in cardiac tissues from patients with end-stage non-ischemic heart failure, coupled to the activation of the IGF1R downstream effector AKT/protein kinase B and inhibition of ULK1 (unc-51 like autophagy activating kinase 1). Transgenic overexpression of human IGF1R in cardiomyocytes from mice initially induces physiological cardiac hypertrophy and superior function, but later in life confers a negative impact on cardiac health, causing macroautophagy/autophagy inhibition as well as impaired oxidative phosphorylation, thus reducing life expectancy. Treatment with the autophagy inducer and caloric restriction mimetic spermidine ameliorates most of these IGF1R-induced cardiotoxic effects in vivo. Moreover, inhibition of IGF1R signaling by means of a dominant-negative phosphoinositide 3-kinase (PI3K) mutant induces cardioprotective autophagy, restores myocardial bioenergetics and improves late-life survival. Hence, our results demonstrate that IGF1R exerts a dual biphasic impact on cardiac health, and that autophagy mediates the late-life geroprotective effects of IGF1R inhibition in the heart.
    Keywords:  Heart failure; IGF1R; PI3K; human; insulin signaling; longevity; mitochondrial dysfunction; mouse
    DOI:  https://doi.org/10.1080/15548627.2022.2095835
  43. Sci Rep. 2022 Jul 08. 12(1): 11662
    Lack of Cathepsin D in the central nervous system results in microglia and astrocyte activation and the accumulation of proteinopathy-related proteins.
    Chigure Suzuki, Junji Yamaguchi, Takahito Sanada, Juan Alejandro Oliva Trejo, Souichirou Kakuta, Masahiro Shibata, Isei Tanida, Yasuo Uchiyama.
      Neuronal ceroid lipofuscinosis is one of many neurodegenerative storage diseases characterized by excessive accumulation of lipofuscins. CLN10 disease, an early infantile neuronal ceroid lipofuscinosis, is associated with a gene that encodes cathepsin D (CtsD), one of the major lysosomal proteases. Whole body CtsD-knockout mice show neurodegenerative phenotypes with the accumulation of lipofuscins in the brain and also show defects in other tissues including intestinal necrosis. To clarify the precise role of CtsD in the central nervous system (CNS), we generated a CNS-specific CtsD-knockout mouse (CtsD-CKO). CtsD-CKO mice were born normally but developed seizures and their growth stunted at around postnatal day 23 ± 1. CtsD-CKO did not exhibit apparent intestinal symptoms as those observed in whole body knockout. Histologically, autofluorescent materials were detected in several areas of the CtsD-CKO mouse's brain, including: thalamus, cerebral cortex, hippocampus, and cerebellum. Expression of ubiquitin and autophagy-associated proteins was also increased, suggesting that the autophagy-lysosome system was impaired. Microglia and astrocytes were activated in the CtsD-CKO thalamus, and inducible nitric oxide synthase (iNOS), an inflammation marker, was increased in the microglia. Interestingly, deposits of proteinopathy-related proteins, phosphorylated α-synuclein, and Tau protein were also increased in the thalamus of CtsD-CKO infant mice. Considering these results, we propose thatt the CtsD-CKO mouse is a useful mouse model to investigate the contribution of cathepsin D to the early phases of neurodegenerative diseases in relation to lipofuscins, proteinopathy-related proteins and activation of microglia and astrocytes.
    DOI:  https://doi.org/10.1038/s41598-022-15805-3
  44. EMBO J. 2022 Jul 06. e110501
    Neuron-specific translational control shift ensures proteostatic resilience during ER stress.
    Kimberly Wolzak, Anna Nölle, Margherita Farina, Truus Em Abbink, Marjo S van der Knaap, Matthijs Verhage, Wiep Scheper.
      Proteostasis is essential for cellular survival and particularly important for highly specialised post-mitotic cells such as neurons. Transient reduction in protein synthesis by protein kinase R-like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type-specific mechanisms that secure proteostatic stress resilience. Here, we demonstrate that PERK-deficient neurons, unlike other cell types, fully retain the capacity to control translation during ER stress. We observe rescaling of the ATF4 response, while the reduction in protein synthesis is fully retained. We identify two molecular pathways that jointly drive translational control in PERK-deficient neurons. Haem-regulated inhibitor (HRI) mediates p-eIF2α and the ATF4 response and is complemented by the tRNA cleaving RNase angiogenin (ANG) to reduce protein synthesis. Overall, our study elucidates an intricate back-up mechanism to ascertain translational control during ER stress in neurons that provides a mechanistic explanation for the thus far unresolved observation of neuronal resilience to proteostatic stress.
    Keywords:  ANG; HRI; PERK; neuron-specific; translational control
    DOI:  https://doi.org/10.15252/embj.2021110501
  45. Front Cell Dev Biol. 2022 ;10 884020
    Role of SNAREs in Unconventional Secretion-Focus on the VAMP7-Dependent Secretion.
    Somya Vats, Thierry Galli.
      Intracellular membrane protein trafficking is crucial for both normal cellular physiology and cell-cell communication. The conventional secretory route follows transport from the Endoplasmic reticulum (ER) to the plasma membrane via the Golgi apparatus. Alternative modes of secretion which can bypass the need for passage through the Golgi apparatus have been collectively termed as Unconventional protein secretion (UPS). UPS can comprise of cargo without a signal peptide or proteins which escape the Golgi in spite of entering the ER. UPS has been classified further depending on the mode of transport. Type I and Type II unconventional secretion are non-vesicular and non-SNARE protein dependent whereas Type III and Type IV dependent on vesicles and on SNARE proteins. In this review, we focus on the Type III UPS which involves the import of cytoplasmic proteins in membrane carriers of autophagosomal/endosomal origin and release in the extracellular space following SNARE-dependent intracellular membrane fusion. We discuss the role of vesicular SNAREs with a strong focus on VAMP7, a vesicular SNARE involved in exosome, lysosome and autophagy mediated secretion. We further extend our discussion to the role of unconventional secretion in health and disease with emphasis on cancer and neurodegeneration.
    Keywords:  SNARE; VAMP7; cancer; neurodegeneration; unconventional protein secretion
    DOI:  https://doi.org/10.3389/fcell.2022.884020
  46. Oncogene. 2022 Jul 02.
    Alkalization of cellular pH leads to cancer cell death by disrupting autophagy and mitochondrial function.
    Chang Ying, Chengmeng Jin, Siying Zeng, Ming Chao, Xun Hu.
      We previously found that lactic acidosis in the tumor environment was permissive to cancer cell surviving under glucose deprivation and demonstrated that neutralizing lactic acidosis restored cancer cell susceptibility to glucose deprivation. We then reported that alternate infusion of bicarbonate and anticancer agent into tumors via tumor feeding artery markedly enhanced the efficacy of transarterial chemoembolization (TACE) in the local control of hepatocellular carcinoma (HCC). Here we sought to further investigate the mechanism by which bicarbonate enhances the anticancer activity of TACE. We propose that interfering cellular pH by bicarbonate could induce a cascade of molecular events leading to cancer cell death. Alkalizing cellular pH by bicarbonate decreased pH gradient (ΔpH), membrane potential (ΔΨm), and proton motive force (Δp) across the inner membrane of mitochondria; disruption of oxidative phosphorylation (OXPHOS) due to collapsed Δp led to a significant increase in adenosine monophosphate (AMP), which activated the classical AMPK-mediated autophagy. Meanwhile, the autophagic flux was ultimately blocked by increased cellular pH, reduced OXPHOS, and inhibition of lysosomal proton pump in alkalized lysosome. Bicarbonate also induced persistent mitochondrial permeability (MPT) and damaged mitochondria. Collectively, this study reveals that interfering cellular pH may provide a valuable approach to treat cancer.
    DOI:  https://doi.org/10.1038/s41388-022-02396-6
  47. Clin Transl Oncol. 2022 Jul 04.
    AMPK's double-faced role in advanced stages of prostate cancer.
    Faeze Gharibpoor, Sara Kamali Zonouzi, Sepideh Razi, Nima Rezaei.
      Prostate cancer (PCa) is the second leading cause of cancer deaths in men. Unfortunately, a very limited number of drugs are available for the relapsed and advanced stages of PCa, adding only a few months to survival; therefore, it is vital to develop new drugs. 5´ AMP-activated protein kinase (AMPK) is a master regulator of cell metabolism. It plays a significant role in the metabolism of PCa; hence, it can serve well as a treatment option for the advanced stages of PCa. However, whether this pathway contributes to cancer cell survival or death remains unknown. The present study reviews the possible pathways by which AMPK plays role in the advanced stages of PCa, drug resistance, and metastasis: (1) AMPK has a contradictory role in promoting glycolysis and the Warburg effect which are correlated with cancer stem cells (CSCs) survival and advanced PCa. It exerts its effect by interacting with hypoxia-induced factor 1 (HIF1) α, pyruvate kinase 2 (PKM2), glucose transporter (GLUT) 1 and pyruvate dehydrogenase complex (PDHC), which are key regulators of glycolysis; however, whether it promotes or discourage glycolysis is not conclusive. It can also exert an anti-CSC effect by negative regulation of NANOG and epithelial-mesenchymal transition (EMT) transcription factors, which are the major drivers of CSC maintenance; (2) the regulatory effect of AMPK on autophagy is also noticeable. Androgen receptors' expression increases AMPK activation through Calcium/calmodulin-dependent protein kinase 2 (CaMKK2) and induces autophagy. In addition, AMPK itself increases autophagy by downregulating the mammalian target of rapamycin complex (mTORC). However, whether increased autophagy inhibits or promotes cell death and drug resistance is contradictory. This study reveals that there are numerous pathways other than cell metabolism by which AMPK exerts its effects in the advanced stages of PCa, making it a priceless treatment target. Finally, we mention some drugs developed to treat the advanced stages of PCa by acting on AMPK.
    Keywords:  AMPK; Autophagy; Cancer stem cell; Prostate cancer; Warburg
    DOI:  https://doi.org/10.1007/s12094-022-02874-z
  48. Cells. 2022 Jun 28. pii: 2048. [Epub ahead of print]11(13):
    The Interaction of mTOR and Nrf2 in Neurogenesis and Its Implication in Neurodegenerative Diseases.
    Linda Ines Zoungrana, Meredith Krause-Hauch, Hao Wang, Mohammad Kasim Fatmi, Lauryn Bates, Zehui Li, Parth Kulkarni, Di Ren, Ji Li.
      Neurogenesis occurs in the brain during embryonic development and throughout adulthood. Neurogenesis occurs in the hippocampus and under normal conditions and persists in two regions of the brain-the subgranular zone (SGZ) in the dentate gyrus of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles. As the critical role in neurogenesis, the neural stem cells have the capacity to differentiate into various cells and to self-renew. This process is controlled through different methods. The mammalian target of rapamycin (mTOR) controls cellular growth, cell proliferation, apoptosis, and autophagy. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a major regulator of metabolism, protein quality control, and antioxidative defense, and is linked to neurogenesis. However, dysregulation in neurogenesis, mTOR, and Nrf2 activity have all been associated with neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's. Understanding the role of these complexes in both neurogenesis and neurodegenerative disease could be necessary to develop future therapies. Here, we review both mTOR and Nrf2 complexes, their crosstalk and role in neurogenesis, and their implication in neurodegenerative diseases.
    Keywords:  Nrf2; mTOR; neurodegenerative diseases; neurogenesis
    DOI:  https://doi.org/10.3390/cells11132048
  49. Neoplasma. 2022 Jun 30. pii: 220428N462. [Epub ahead of print]
    BRAF inhibition promotes ER stress-mediated cell death in uveal melanoma.
    Yinu Zhao, Yue Wang, Li Zhang, Weibin Wang, Thomas J Fahey, Ke Yao.
      Melanoma with a BRAF mutation is more common to develop into a fatal disease. BRAF mutation inhibitor-induced autophagy affects the drug efficacy in many cancer types. The role of autophagy during BRAF inhibition in uveal melanoma (UM) remains unclear. In this study, we examined the autophagic flux and compared the number of autophagic vacuoles during the BRAF inhibition in UM. The PKR-like endoplasmic reticulum (ER) kinase (PERK) arm was studied to test whether the ER stress was involved. The effects of downregulation of ER stress by targeting the PERK arm (pharmacologically and genetically) were also assessed. We found a dose-dependent increase of autophagic flux in OCM1A cells during the BRAF inhibition. This phenomenon was further verified by an enhanced number of GFP-LC3 puncta and was finally confirmed by raised autophagic index examined by transmission electron microscopy. Pathway analysis revealed that the vemurafenib (the BRAF inhibitor)-induced autophagy was independent of the MAPK signaling pathway. Instead, it was possibly regulated via the enhanced ER stress response. We further found that the inhibition of ER stress response rescued cell death. Therefore, our results suggest BRAF inhibition promotes ER stress response-induced autophagy in UM. Targeting ER stress response can partially revert autophagy and rescue cell death, which may impair the anti-tumor effect of BRAF inhibitor in UM.
    DOI:  https://doi.org/10.4149/neo_2022_220428N462
  50. Nat Commun. 2022 Jul 07. 13(1): 3775
    Modulating mitofusins to control mitochondrial function and signaling.
    Emmanouil Zacharioudakis, Bogos Agianian, Vasantha Kumar Mv, Nikolaos Biris, Thomas P Garner, Inna Rabinovich-Nikitin, Amanda T Ouchida, Victoria Margulets, Lars Ulrik Nordstrøm, Joel S Riley, Igor Dolgalev, Yun Chen, Andre J H Wittig, Ryan Pekson, Chris Mathew, Peter Wei, Aristotelis Tsirigos, Stephen W G Tait, Lorrie A Kirshenbaum, Richard N Kitsis, Evripidis Gavathiotis.
      Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins.
    DOI:  https://doi.org/10.1038/s41467-022-31324-1
  51. FEBS Lett. 2022 Jul 04.
    Transcription factor EB controls both motogenic and mitogenic cell activities.
    Elena Astanina, Federico Bussolino, Gabriella Doronzo.
      Transcription factor EB (TFEB) belongs to the microphthalmia family of bHLH-leucine zipper transcription factors and was first identified as an oncogene in a subset of renal cell carcinomas. In addition to exhibiting oncogenic activity, TFEB coordinates genetic programs connected with the cellular response to stress conditions, including roles in lysosome biogenesis, autophagy, modulation of metabolism. As is the case for other transcription factors, the activities of TFEB are not limited to a specific cellular condition such as the response to stress and recent findings indicate that TFEB has more widespread functions. Here, we review the emerging roles of TFEB in regulating cellular proliferation and motility. The well-established and emerging roles of TFEB suggest that this protein serves as a hub of signalling networks involved in many non-communicable diseases, such as cancer, ischaemic diseases and immune disorders, drug resistance mechanisms, and tissue generation.
    Keywords:  TFEB; autophagy; cell motility; cell-cycle
    DOI:  https://doi.org/10.1002/1873-3468.14442
  52. Cells. 2022 Jun 26. pii: 2031. [Epub ahead of print]11(13):
    Cytoplasmic LMO2-LDB1 Complex Activates STAT3 Signaling through Interaction with gp130-JAK in Glioma Stem Cells.
    Cheol Gyu Park, Sang-Hun Choi, Seon Yong Lee, Kiyoung Eun, Min Gi Park, Junseok Jang, Hyeon Ju Jeong, Seong Jin Kim, Sohee Jeong, Kanghun Lee, Hyunggee Kim.
      The oncogenic role of nuclear LIM domain only 2 (LMO2) as a transcriptional regulator is well established, but its function in the cytoplasm is largely unknown. Here, we identified LMO2 as a cytoplasmic activator for signal transducer and activator of transcription 3 (STAT3) signaling in glioma stem cells (GSCs) through biochemical and bioinformatics analyses. LMO2 increases STAT3 phosphorylation by interacting with glycoprotein 130 (gp130) and Janus kinases (JAKs). LMO2-driven activation of STAT3 signaling requires the LDB1 protein and leads to increased expression of an inhibitor of differentiation 1 (ID1), a master regulator of cancer stemness. Our findings indicate that the cytoplasmic LMO2-LDB1 complex plays a crucial role in the activation of the GSC signaling cascade via interaction with gp130 and JAK1/2. Thus, LMO2-LDB1 is a bona fide oncogenic protein complex that activates either the JAK-STAT signaling cascade in the cytoplasm or direct transcriptional regulation in the nucleus.
    Keywords:  LMO2; STAT3; cancer stem cells; glioblastoma; glioma stem cells
    DOI:  https://doi.org/10.3390/cells11132031
  53. Front Cardiovasc Med. 2022 ;9 917135
    Mitochondrial Dynamics and Mitophagy in Cardiometabolic Disease.
    Jianguo Lin, Jinlong Duan, Qingqing Wang, Siyu Xu, Simin Zhou, Kuiwu Yao.
      Mitochondria play a key role in cellular metabolism. Mitochondrial dynamics (fusion and fission) and mitophagy, are critical to mitochondrial function. Fusion allows organelles to share metabolites, proteins, and mitochondrial DNA, promoting complementarity between damaged mitochondria. Fission increases the number of mitochondria to ensure that they are passed on to their offspring during mitosis. Mitophagy is a process of selective removal of excess or damaged mitochondria that helps improve energy metabolism. Cardiometabolic disease is characterized by mitochondrial dysfunction, high production of reactive oxygen species, increased inflammatory response, and low levels of ATP. Cardiometabolic disease is closely related to mitochondrial dynamics and mitophagy. This paper reviewed the mechanisms of mitochondrial dynamics and mitophagy (focus on MFN1, MFN2, OPA1, DRP1, and PINK1 proteins) and their roles in diabetic cardiomyopathy, myocardial infarction, cardiac hypertrophy, heart failure, atherosclerosis, and obesity.
    Keywords:  cardiometabolic disease; diabetic cardiomyopathy; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitophagy; myocardial infarction
    DOI:  https://doi.org/10.3389/fcvm.2022.917135
  54. Biochem Biophys Res Commun. 2022 Jun 25. pii: S0006-291X(22)00929-9. [Epub ahead of print]620 121-128
    Marimastat alleviates oxidative stress induced cellular senescence by activating autophagy.
    Jing Xia, Jun Chen, Manoj Kumar Vashisth, Huijie Jia, Hui Hua, Xiao-Jian Wu, Xiao-Bo Wang.
      Marimastat is one of the potent inhibitors of MMP (MMPIs) with few side effects. The impact of marimastat on cellular senescence remains unexplored. Our study evaluated the marimastate effect on oxidative stress-induced cell senescence using NIH3T3 cells. Marimastate administration was found to suppress senescence-β-galactosidase (SA-β-gal) activity and development linked with aging. Furthermore, we observed that this effect of marimastat was closely linked with the recovery of autophagy dysfunction and mTOR suppression in H2O2-treated cells. Notably, this study demonstrated the marimastat effect on senescence inhibition for the first time.
    Keywords:  Autophagy; Marimastat; Oxidative stress; Senescence; mTOR
    DOI:  https://doi.org/10.1016/j.bbrc.2022.06.075
  55. Nat Cell Biol. 2022 Jul 07.
    A p53-phosphoinositide signalosome regulates nuclear AKT activation.
    Mo Chen, Suyong Choi, Tianmu Wen, Changliang Chen, Narendra Thapa, Jeong Hyo Lee, Vincent L Cryns, Richard A Anderson.
      The tumour suppressor p53 and PI3K-AKT pathways have fundamental roles in the regulation of cell growth and apoptosis, and are frequently mutated in cancer. Here, we show that genotoxic stress induces nuclear AKT activation through a p53-dependent mechanism that is distinct from the canonical membrane-localized PI3K-AKT pathway. Following genotoxic stress, a nuclear PI3K binds p53 in the non-membranous nucleoplasm to generate a complex of p53 and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), which recruits AKT, PDK1 and mTORC2 to activate AKT and phosphorylate FOXO proteins, thereby inhibiting DNA damage-induced apoptosis. Wild-type p53 activates nuclear AKT in an on/off fashion following stress, whereas mutant p53 dose-dependently stimulates high basal AKT activity. The p53-PtdIns(3,4,5)P3 complex is dephosphorylated to p53-phosphatidylinositol 4,5-bisphosphate by PTEN to inhibit AKT activation. The nuclear p53-phosphoinositide signalosome is distinct from the canonical membrane-localized pathway and insensitive to PI3K inhibitors currently in the clinic, which underscores its therapeutic relevance.
    DOI:  https://doi.org/10.1038/s41556-022-00949-1
  56. Pathol Res Pract. 2022 Jun 30. pii: S0344-0338(22)00245-X. [Epub ahead of print]236 154001
    Autophagic factors in Paget disease.
    Georgia Karpathiou, Mousa Mobarki, Alexandra Papoudou-Bai, Vincent Grosjean, Celine Chauleur, Michel Péoc'h.
      BACKGROUND: Despite autophagy being a principal mechanism of tumor progression, its role has been never studied in Paget disease, a difficult to treat intraepithelial neoplasia affecting mainly the breast and the vulvar regions.MATERIAL AND METHODS: Twenty seven cases (17 extramammary and 10 mammary) of Paget disease were immunohistochemically studied for the expression of the two principal autophagic factors, LC3B and p62.
    RESULTS: The majority of Paget diseases showed strong cytoplasmic expression of p62 in contrast to nearby keratinocytes which presented nuclear-only p62 staining. LC3B was negative or only mildly positive in neoplastic cells. No difference was seen between mammary and extramammary cases.
    CONCLUSION: The immunohistochemical autophagic profile of Paget disease suggests a down-regulated autophagic process which, thus, may be implicated in the invasive potential of these cells.
    Keywords:  Adenocarcinoma; Autophagy; In situ; LC3B; Mammary; P62; Vulvar
    DOI:  https://doi.org/10.1016/j.prp.2022.154001
  57. Cells. 2022 Jun 29. pii: 2063. [Epub ahead of print]11(13):
    Regulation of Cellular Ribonucleoprotein Granules: From Assembly to Degradation via Post-translational Modification.
    Pureum Jeon, Hyun-Ji Ham, Semin Park, Jin-A Lee.
      Cells possess membraneless ribonucleoprotein (RNP) granules, including stress granules, processing bodies, Cajal bodies, or paraspeckles, that play physiological or pathological roles. RNP granules contain RNA and numerous RNA-binding proteins, transiently formed through the liquid-liquid phase separation. The assembly or disassembly of numerous RNP granules is strongly controlled to maintain their homeostasis and perform their cellular functions properly. Normal RNA granules are reversibly assembled, whereas abnormal RNP granules accumulate and associate with various neurodegenerative diseases. This review summarizes current studies on the physiological or pathological roles of post-translational modifications of various cellular RNP granules and discusses the therapeutic methods in curing diseases related to abnormal RNP granules by autophagy.
    Keywords:  Cajal bodies; P-bodies; RNP granules; autophagy; neurodegenerative disease; paraspeckles; post-translational modification; stress granules
    DOI:  https://doi.org/10.3390/cells11132063
  58. Neural Regen Res. 2023 Jan;18(1): 31-37
    Sex-biased autophagy as a potential mechanism mediating sex differences in ischemic stroke outcome.
    Brian Noh, Louise D McCullough, Jose F Moruno-Manchon.
      Stroke is the second leading cause of death and a major cause of disability worldwide, and biological sex is an important determining factor in stroke incidence and pathology. From childhood through adulthood, men have a higher incidence of stroke compared with women. Abundant research has confirmed the beneficial effects of estrogen in experimental ischemic stroke but genetic factors such as the X-chromosome complement can also play an important role in determining sex differences in stroke. Autophagy is a self-degrading cellular process orchestrated by multiple core proteins, which leads to the engulfment of cytoplasmic material and degradation of cargo after autophagy vesicles fuse with lysosomes or endosomes. The levels and the activity of components of these signaling pathways and of autophagy-related proteins can be altered during ischemic insults. Ischemic stroke activates autophagy, however, whether inhibiting autophagy after stroke is beneficial in the brain is still under a debate. Autophagy is a potential mechanism that may contribute to differences in stroke progression between the sexes. Furthermore, the effects of manipulating autophagy may also differ between the sexes. Mechanisms that regulate autophagy in a sex-dependent manner in ischemic stroke remain unexplored. In this review, we summarize clinical and pre-clinical evidence for sex differences in stroke. We briefly introduce the autophagy process and summarize the effects of gonadal hormones in autophagy in the brain and discuss X-linked genes that could potentially regulate brain autophagy. Finally, we review pre-clinical studies that address the mechanisms that could mediate sex differences in brain autophagy after stroke.
    Keywords:  X-chromosome; autophagy; brain; estrogen; gonadal hormones; neurodegeneration; neuron; stroke
    DOI:  https://doi.org/10.4103/1673-5374.340406
  59. Adv Exp Med Biol. 2022 Jul 04.
    Virus, Exosome, and MicroRNA: New Insights into Autophagy.
    Javid Sadri Nahand, Arash Salmaninejad, Samaneh Mollazadeh, Seyed Saeed Tamehri Zadeh, Mehdi Rezaee, Amir Hossein Sheida, Fatemeh Sadoughi, Parisa Maleki Dana, Mahdi Rafiyan, Masoud Zamani, Seyed Pouya Taghavi, Fatemeh Dashti, Seyed Mohammad Ali Mirazimi, Hossein Bannazadeh Baghi, Mohsen Moghoofei, Mohammad Karimzadeh, Massoud Vosough, Hamed Mirzaei.
      Autophagy is known as a conserved self-eating mechanism that contributes to cells to degrade different intracellular components (i.e., macromolecular complexes, aggregated proteins, soluble proteins, organelles, and foreign bodies). Autophagy needs formation of a double-membrane structure, which is composed of the sequestered cytoplasmic contents, called autophagosome. There are a variety of internal and external factors involved in initiation and progression of autophagy process. Viruses as external factors are one of the particles that could be associated with different stages of this process. Viruses exert their functions via activation and/or inhibition of a wide range of cellular and molecular targets, which are involved in autophagy process. Besides viruses, a variety of cellular and molecular pathways that are activated and inhibited by several factors (e.g., genetics, epigenetics, and environment factors) are related to beginning and developing of autophagy mechanism. Exosomes and microRNAs have been emerged as novel and effective players anticipated in various stages of autophagy. More knowledge in these pathways and identification of accurate roles of them could help to provide better therapeutic approaches in several diseases such as cancer. We highlighted the roles of viruses, exosomes, and microRNAs in the autophagy processes.
    Keywords:  Autophagy; Cancer; Chemoresistance; Exosome; MicroRNA; Viral infection
    DOI:  https://doi.org/10.1007/5584_2022_715
  60. Nat Commun. 2022 Jul 05. 13(1): 3856
    Spatial regulation of AMPK signaling revealed by a sensitive kinase activity reporter.
    Danielle L Schmitt, Stephanie D Curtis, Anne C Lyons, Jin-Fan Zhang, Mingyuan Chen, Catherine Y He, Sohum Mehta, Reuben J Shaw, Jin Zhang.
      AMP-activated protein kinase (AMPK) is a master regulator of cellular energetics which coordinates metabolism by phosphorylating a plethora of substrates throughout the cell. But how AMPK activity is regulated at different subcellular locations for precise spatiotemporal control over metabolism is unclear. Here we present a sensitive, single-fluorophore AMPK activity reporter (ExRai AMPKAR), which reveals distinct kinetic profiles of AMPK activity at the mitochondria, lysosome, and cytoplasm. Genetic deletion of the canonical upstream kinase liver kinase B1 (LKB1) results in slower AMPK activity at lysosomes but does not affect the response amplitude at lysosomes or mitochondria, in sharp contrast to the necessity of LKB1 for maximal cytoplasmic AMPK activity. We further identify a mechanism for AMPK activity in the nucleus, which results from cytoplasmic to nuclear shuttling of AMPK. Thus, ExRai AMPKAR enables illumination of the complex subcellular regulation of AMPK signaling.
    DOI:  https://doi.org/10.1038/s41467-022-31190-x
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