bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023–04–09
fifty-four papers selected by
Viktor Korolchuk, Newcastle University
  1. A lysosome membrane regeneration pathway depends on TBC1D15 and autophagic lysosomal reformation proteins.
  2. Autophagy and cancer: basic mechanisms and inhibitor development.
  3. Emerging mechanistic insights of selective autophagy in hepatic diseases.
  4. LC3-independent autophagy is vital to prevent TNF cytotoxicity.
  5. Monitoring the Activation of Selective Autophagy via N-Terminal Arginylation.
  6. The phosphatidylinositol 3-phosphate effector FYVE3 regulates FYVE2-dependent autophagy in Arabidopsis thaliana.
  7. Comprehensive proteomic analysis of autophagosomes derived from Leishmania-infected macrophages.
  8. Autophagy and its therapeutic potential in diabetic nephropathy.
  9. Redox partner interactions in the ATG8 lipidation system in microalgae.
  10. PERK prevents rhodopsin degradation during retinitis pigmentosa by inhibiting IRE1-induced autophagy.
  11. Deceiving The Big Eaters: Salmonella Typhimurium SopB subverts host cell Xenophagy in macrophages via dual mechanisms.
  12. Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology.
  13. Aryl Hydrocarbon Receptor Maintains Hepatic Mitochondrial Homeostasis in Mice.
  14. Potential Therapeutic Targets in Ovarian Cancer: Autophagy and Metabolism.
  15. ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience.
  16. Vacuole membrane contact sites regulate liquid-ordered domain formation during glucose starvation.
  17. Editorial: Role of microglia autophagy in age-related neurodegenerative diseases.
  18. Transcriptome Discovery of Genes in the Three Phases of Autophagy That Are Upregulated During Atrial Fibrillation.
  19. An update on the molecular mechanism and pharmacological interventions for Ischemia-reperfusion injury by regulating AMPK/mTOR signaling pathway in autophagy.
  20. Bub1 and Bub3 regulate metabolic adaptation via macrolipophagy in Drosophila.
  21. RNA recruitment switches the fate of protein condensates from autophagic degradation to accumulation.
  22. Hepatocyte CD36 modulates UBQLN1-mediated proteasomal degradation of autophagic SNARE proteins contributing to septic liver injury.
  23. Novel insights into Parkin-mediated mitochondrial dysfunction and neuroinflammation in Parkinson's disease.
  24. Autophagy in hepatic ischemia-reperfusion injury.
  25. Versatile Switchable Targeted Polysiloxanes for High-Resolution Visualization of Mitochondrial and Lysosomal Interactions during Ferroptosis.
  26. The dual and emerging role of physical exercise-induced TFEB activation in the protection against Alzheimer's disease.
  27. CircEPS15, as a sponge of MIR24-3p ameliorates neuronal damage in Parkinson disease through boosting PINK1-PRKN-mediated mitophagy.
  28. Autophagy in dry eye disease: Therapeutic implications of autophagy modulators on the ocular surface.
  29. Macrotubule associated protein MAP1LC3C regulates lysosomal exocytosis and induces zinc reprogramming in renal cancer cells.
  30. Disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede Purkinje cell loss in a mouse model of Niemann-Pick Type-C disease.
  31. Mitochondria in Health, Disease, and Ageing.
  32. Autophagy regulates the release of exercise factors and their beneficial effects on spatial memory recall.
  33. A small molecule compound that inhibits blue light-induced retinal damage via activation of autophagy.
  34. A Benzohydrazide-Based Artificial Ion Channel that Modulates Chloride Ion Concentration in Cancer Cells and Induces Apoptosis by Disruption of Autophagy.
  35. Macrolide antibiotics activate the integrated stress response and promote tumor proliferation.
  36. MitoSwap - Mitophagy partnered with compensatory mitochondrial biogenesis during stem cell differentiation.
  37. Tuberous Sclerosis Complex-1 (TSC1) contributes to selective neuronal vulnerability in Alzheimer's Disease.
  38. Homocysteine accelerates hepatocyte autophagy by upregulating TFEB via DNMT3b-mediated DNA hypomethylation.
  39. Role of mammalian target of rapamycin (mTOR) signalling in oncogenesis.
  40. Bif-1c Attenuates Viral Proliferation by Regulating Autophagic Flux Blockade Induced by the Rabies Virus CVS-11 Strain in N2a Cells.
  41. Nanoplastics exposure disrupts circadian rhythm associated with dysfunction of the endolysosomal pathway and autophagy in Caenorhabditis elegans.
  42. A new glance at autophagolysosomal-dependent or -independent function of transcriptional factor EB in human cancer.
  43. Oxidative DNA Damage-induced PARP-1-mediated Autophagic Flux Disruption Contributes to Bupivacaine-induced Neurotoxicity During Pregnancy.
  44. Activation of the mTORC1 signaling cascade in the hippocampus and medial prefrontal cortex is required for the antidepressant actions of vortioxetine in mice.
  45. Control of mitochondria-associated endoplasmic reticulum membranes by protein S-palmitoylation: Novel therapeutic targets for neurodegenerative diseases.
  46. Mitophagy alleviates AIF-mediated spleen apoptosis induced by AlCl3 through Parkin stabilization in mice.
  47. An ATG4B inhibitor blocks autophagy and sensitizes Sorafenib inhibition activities in HCC tumor cells.
  48. Disruption of the Rab7-Dependent Final Common Pathway of Endosomal and Autophagic Processing Results in a Severe Podocytopathy.
  49. Acute, next-generation AMPK activation initiates a disease-resistant gene expression program in dystrophic skeletal muscle.
  50. The ubiquitin ligase HERC4 suppresses MafA transcriptional activity triggered by GSK3β in myeloma by atypical K63-linked polyubiquitination.
  51. Analyzing the Interaction of Arginylated Proteins and Nt-Arg-Mimicking Chemical Compounds to N-Recognins.
  52. Antagonizing apolipoprotein J chaperone promotes proteasomal degradation of mTOR and relieves hepatic lipid deposition.
  53. Tumor necrosis factor α-induced protein 3 mediates inflammation and neuronal autophagy in Parkinson's disease via the NFκB and mTOR pathways.
  54. Discovery of the First Raptor (Regulatory-Associated Protein of mTOR) Inhibitor as a New Type of Antiadipogenic Agent.
  1. Nat Cell Biol. 2023 Apr 06.
    A lysosome membrane regeneration pathway depends on TBC1D15 and autophagic lysosomal reformation proteins.
    Anshu Bhattacharya, Rukmini Mukherjee, Santosh Kumar Kuncha, Melinda Elaine Brunstein, Rajeshwari Rathore, Stephan Junek, Christian Münch, Ivan Dikic.
      Acute lysosomal membrane damage reduces the cellular population of functional lysosomes. However, these damaged lysosomes have a remarkable recovery potential independent of lysosomal biogenesis and remain unaffected in cells depleted in TFEB and TFE3. We combined proximity-labelling-based proteomics, biochemistry and high-resolution microscopy to unravel a lysosomal membrane regeneration pathway that depends on ATG8, the lysosomal membrane protein LIMP2, the RAB7 GTPase-activating protein TBC1D15 and proteins required for autophagic lysosomal reformation, including dynamin-2, kinesin-5B and clathrin. Following lysosomal damage, LIMP2 acts as a lysophagy receptor to bind ATG8, which in turn recruits TBC1D15 to damaged membranes. TBC1D15 interacts with ATG8 proteins on damaged lysosomes and provides a scaffold to assemble and stabilize the autophagic lysosomal reformation machinery. This potentiates the formation of lysosomal tubules and subsequent dynamin-2-dependent scission. TBC1D15-mediated lysosome regeneration was also observed in a cell culture model of oxalate nephropathy.
    DOI:  https://doi.org/10.1038/s41556-023-01125-9
  2. Cancer Sci. 2023 Apr 03.
    Autophagy and cancer: basic mechanisms and inhibitor development.
    Yutaro Hama, Yuta Ogasawara, Nobuo N Noda.
      Autophagy is a lysosomal degradation system of cytoplasmic components, and it contributes to cellular homeostasis through turnover of various biomolecules and organelles, often in a selective manner. Autophagy is closely related to cancer, but its roles in cancer are complicated. It works as either a promoter or suppressor, depending on the stage and type of cancer. In this review, we briefly summarize the basic mechanisms of autophagy and describe the complicated roles of autophagy in cancer. Moreover, we summarize the clinical trials of autophagy inhibitors targeting cancer and the development of more specific autophagy inhibitors for future clinical application.
    Keywords:  ATG; autophagy; cancer; chloroquine; inhibitor; mTORC1
    DOI:  https://doi.org/10.1111/cas.15803
  3. Front Pharmacol. 2023 ;14 1149809
    Emerging mechanistic insights of selective autophagy in hepatic diseases.
    Abdul Alim Al-Bari, Yuko Ito, Paul G Thomes, Manoj B Menon, Marina García-Macia, Raouf Fadel, Alfreda Stadlin, Nicholas Peake, MoezAlIslam Ezzat Faris, Nabil Eid, Daniel J Klionsky.
      Macroautophagy (hereafter referred to as autophagy), a highly conserved metabolic process, regulates cellular homeostasis by degrading dysfunctional cytosolic constituents and invading pathogens via the lysosomal system. In addition, autophagy selectively recycles specific organelles such as damaged mitochondria (via mitophagy), and lipid droplets (LDs; via lipophagy) or eliminates specialized intracellular pathogenic microorganisms such as hepatitis B virus (HBV) and coronaviruses (via virophagy). Selective autophagy, particularly mitophagy, plays a key role in the preservation of healthy liver physiology, and its dysfunction is connected to the pathogenesis of a wide variety of liver diseases. For example, lipophagy has emerged as a defensive mechanism against chronic liver diseases. There is a prominent role for mitophagy and lipophagy in hepatic pathologies including non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), and drug-induced liver injury. Moreover, these selective autophagy pathways including virophagy are being investigated in the context of viral hepatitis and, more recently, the coronavirus disease 2019 (COVID-19)-associated hepatic pathologies. The interplay between diverse types of selective autophagy and its impact on liver diseases is briefly addressed. Thus, modulating selective autophagy (e.g., mitophagy) would seem to be effective in improving liver diseases. Considering the prominence of selective autophagy in liver physiology, this review summarizes the current understanding of the molecular mechanisms and functions of selective autophagy (mainly mitophagy and lipophagy) in liver physiology and pathophysiology. This may help in finding therapeutic interventions targeting hepatic diseases via manipulation of selective autophagy.
    Keywords:  TFEB; autophagy; lipophagy; liver disease; mitophagy; virophagy
    DOI:  https://doi.org/10.3389/fphar.2023.1149809
  4. Autophagy. 2023 Apr 04.
    LC3-independent autophagy is vital to prevent TNF cytotoxicity.
    Dario Priem, Jon Huyghe, Mathieu Jm Bertrand.
      The (macro)autophagy field is facing a paradigm shift after the recent discovery that cytosolic cargoes can still be selectively targeted to phagophores (the precursors to autophagosomes) even in the absence of LC3 or other Atg8-protein family members. Several in vitro studies have indeed reported on the existence of an unconventional selective autophagic pathway that involves the in-situ formation of an autophagosome around the cargo through the direct selective autophagy receptor-mediated recruitment of RB1CC1/FIP200, thereby bypassing the requirement of LC3. In an article recently published in Science, we demonstrate the physiological importance of this unconventional autophagic pathway in the context of TNF (tumor necrosis factor) signaling. We show that it promotes the degradation of the cytotoxic TNFRSF1A/TNFR1 (TNF receptor superfamily member 1A) complex II that assembles upon TNF sensing and thereby protects mice from TNFRSF1A-driven embryonic lethality and skin inflammation.
    Keywords:  ATG9A; Apoptosis; LC3-independent autophagy; RB1CC1; TAX1BP1; cell death; embryogenesis; mouse development; skin disease; unconventional autophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2197760
  5. Methods Mol Biol. 2023 ;2620 243-252
    Monitoring the Activation of Selective Autophagy via N-Terminal Arginylation.
    Chang Hoon Ji, Su Bin Kim, Min Ju Lee, Yong Tae Kwon.
      In addition to generating N-degron-carrying substrates destined for proteolysis, N-terminal arginylation can globally upregulate selective macroautophagy via activation of the autophagic N-recognin and archetypal autophagy cargo receptor p62/SQSTM1/sequestosome-1. To evaluate the macroautophagic turnover of cellular substrates, including protein aggregates (aggrephagy) and subcellular organelles (organellophagy) mediated by N-terminal arginylation in vivo, we report here a protocol for assaying the activation of the autophagic Arg/N-degron pathway and degradation of cellular cargoes via N-terminal arginylation. These methods, reagents, and conditions are applicable across a wide spectrum of different cell lines, primary cultures, and/or animal tissues, thereby providing a general means for identification and validation of putative cellular cargoes degraded by Nt-arginylation-activated selective autophagy.
    Keywords:  ATE1; Autophagic flux; Detergent-insoluble/soluble fractionation; In vitro p62/SQSTM1 self-oligomerization; Nt-arginylation; Punctate formation/co-localization
    DOI:  https://doi.org/10.1007/978-1-0716-2942-0_26
  6. Front Plant Sci. 2023 ;14 1160162
    The phosphatidylinositol 3-phosphate effector FYVE3 regulates FYVE2-dependent autophagy in Arabidopsis thaliana.
    Jeong Hun Kim, Hyera Jung, Kyoungjun Song, Han Nim Lee, Taijoon Chung.
      Phosphatidylinositol 3-phosphate (PI3P) is a signaling phospholipid that play a key role in endomembrane trafficking, specifically autophagy and endosomal trafficking. However, the mechanisms underlying the contribution of PI3P downstream effectors to plant autophagy remain unknown. Known PI3P effectors for autophagy in Arabidopsis thaliana include ATG18A (Autophagy-related 18A) and FYVE2 (Fab1p, YOTB, Vac1p, and EEA1 2), which are implicated in autophagosome biogenesis. Here, we report that FYVE3, a paralog of plant-specific FYVE2, plays a role in FYVE2-dependent autophagy. Using yeast two-hybrid and bimolecular fluorescence complementation assays, we determined that the FYVE3 protein was associated with autophagic machinery containing ATG18A and FYVE2, by interacting with ATG8 isoforms. The FYVE3 protein was transported to the vacuole, and the vacuolar delivery of FYVE3 relies on PI3P biosynthesis and the canonical autophagic machinery. Whereas the fyve3 mutation alone barely affects autophagic flux, it suppresses defective autophagy in fyve2 mutants. Based on the molecular genetics and cell biological data, we propose that FYVE3 specifically regulates FYVE2-dependent autophagy.
    Keywords:  ATG8; autophagosome; autophagy; phosphatidylinositol 3-phosphate; phosphoinositide; vacuolar trafficking
    DOI:  https://doi.org/10.3389/fpls.2023.1160162
  7. PLoS One. 2023 ;18(4): e0284026
    Comprehensive proteomic analysis of autophagosomes derived from Leishmania-infected macrophages.
    Devki Nandan, Eleanor Chen, Fabian Chang, Kyung-Mee Moon, Leonard J Foster, Neil Reiner.
      Recently, autophagy has been implicated as a host defense mechanism against intracellular pathogens. On the other hand, certain intracellular pathogens such as Leishmania can manipulate the host's autophagy to promote their survival. Our recent findings regarding the regulation of autophagy by Leishmania donovani indicate that this pathogen induces non-classical autophagy in infected macrophages, independent of regulation by the mammalian target of rapamycin complex 1. This suggests the fine-tuning of autophagy to optimally promote parasite survival, possibly by the sequestration or modulation of specific autophagosome-associated proteins. To investigate how Leishmania potentially manipulates the composition of host-cell autophagosomes, we undertook a quantitative proteomic study of the human monocytic cell line THP-1 following infection with L. donovani. We used stable isotope labeling by amino acid in cell culture and liquid chromatography-tandem mass spectrometry to compare expression profiles between autophagosomes isolated from THP-1 cells infected with L. donovani or treated with known autophagy inducers. Selected proteomic results were validated by Western blotting. In this study, we showed that L. donovani modulates the composition of macrophage autophagosomes during infection when compared to autophagosomes induced by either rapamycin (selective autophagy) or starvation (non-selective autophagy). Among 1787 proteins detected in Leishmania-induced autophagosomes, 146 were significantly modulated compared to the proteome of rapamycin-induced autophagosomes, while 57 were significantly modulated compared to starvation-induced autophagosomes. Strikingly, 23 Leishmania proteins were also detected in the proteome of Leishmania-induced autophagosomes. Together, our data provide the first comprehensive insight into the proteome dynamics of host autophagosomes in response to Leishmania infection and demonstrate the complex relations between the host and pathogen at the molecular level. A comprehensive analysis of the Leishmania-induced autophagosome proteome will be instrumental in the advancement of understanding leishmaniasis.
    DOI:  https://doi.org/10.1371/journal.pone.0284026
  8. Front Endocrinol (Lausanne). 2023 ;14 1139444
    Autophagy and its therapeutic potential in diabetic nephropathy.
    Yu-Peng Han, Li-Juan Liu, Jia-Lin Yan, Meng-Yuan Chen, Xiang-Fei Meng, Xin-Ru Zhou, Ling-Bo Qian.
      Diabetic nephropathy (DN), the leading cause of end-stage renal disease, is the most significant microvascular complication of diabetes and poses a severe public health concern due to a lack of effective clinical treatments. Autophagy is a lysosomal process that degrades damaged proteins and organelles to preserve cellular homeostasis. Emerging studies have shown that disorder in autophagy results in the accumulation of damaged proteins and organelles in diabetic renal cells and promotes the development of DN. Autophagy is regulated by nutrient-sensing pathways including AMPK, mTOR, and Sirt1, and several intracellular stress signaling pathways such as oxidative stress and endoplasmic reticulum stress. An abnormal nutritional status and excess cellular stresses caused by diabetes-related metabolic disorders disturb the autophagic flux, leading to cellular dysfunction and DN. Here, we summarized the role of autophagy in DN focusing on signaling pathways to modulate autophagy and therapeutic interferences of autophagy in DN.
    Keywords:  autophagy; cellular stress; diabetic nephropathy; nutrient-sensing pathway; renal cell
    DOI:  https://doi.org/10.3389/fendo.2023.1139444
  9. Free Radic Biol Med. 2023 Apr 05. pii: S0891-5849(23)00374-X. [Epub ahead of print]
    Redox partner interactions in the ATG8 lipidation system in microalgae.
    Manuel J Mallén-Ponce, Samuel Gámez-Arcas, María Esther Pérez-Pérez.
      Autophagy is a catabolic pathway that functions as a degradative and recycling process to maintain cellular homeostasis in most eukaryotic cells, including photosynthetic organisms such as microalgae. This process involves the formation of double-membrane vesicles called autophagosomes, which engulf the material to be degraded and recycled in lytic compartments. Autophagy is mediated by a set of highly conserved autophagy-related (ATG) proteins that play a fundamental role in the formation of the autophagosome. The ATG8 ubiquitin-like system catalyzes the conjugation of ATG8 to the lipid phosphatidylethanolamine, an essential reaction in the autophagy process. Several studies identified the ATG8 system and other core ATG proteins in photosynthetic eukaryotes. However, how ATG8 lipidation is driven and regulated in these organisms is not fully understood yet. A detailed analysis of representative genomes from the entire microalgal lineage revealed a high conservation of ATG proteins in these organisms with the remarkable exception of red algae, which likely lost ATG genes before diversification. Here, we examine in silico the mechanisms and dynamic interactions between different components of the ATG8 lipidation system in plants and algae. Moreover, we also discuss the role of redox post-translational modifications in the regulation of ATG proteins and the activation of autophagy in these organisms by reactive oxygen species.
    Keywords:  ATG proteins; ATG8 lipidation system; Autophagy; Microalgae; Redox regulation
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.04.004
  10. J Cell Biol. 2023 May 01. pii: e202208147. [Epub ahead of print]222(5):
    PERK prevents rhodopsin degradation during retinitis pigmentosa by inhibiting IRE1-induced autophagy.
    Ning Zhao, Ning Li, Tao Wang.
      Chronic endoplasmic reticulum (ER) stress is the underlying cause of many degenerative diseases, including autosomal dominant retinitis pigmentosa (adRP). In adRP, mutant rhodopsins accumulate and cause ER stress. This destabilizes wild-type rhodopsin and triggers photoreceptor cell degeneration. To reveal the mechanisms by which these mutant rhodopsins exert their dominant-negative effects, we established an in vivo fluorescence reporter system to monitor mutant and wild-type rhodopsin in Drosophila. By performing a genome-wide genetic screen, we found that PERK signaling plays a key role in maintaining rhodopsin homeostasis by attenuating IRE1 activities. Degradation of wild-type rhodopsin is mediated by selective autophagy of ER, which is induced by uncontrolled IRE1/XBP1 signaling and insufficient proteasome activities. Moreover, upregulation of PERK signaling prevents autophagy and suppresses retinal degeneration in the adRP model. These findings establish a pathological role for autophagy in this neurodegenerative condition and indicate that promoting PERK activity could be used to treat ER stress-related neuropathies, including adRP.
    DOI:  https://doi.org/10.1083/jcb.202208147
  11. Microbes Infect. 2023 Apr 03. pii: S1286-4579(23)00031-X. [Epub ahead of print] 105128
    Deceiving The Big Eaters: Salmonella Typhimurium SopB subverts host cell Xenophagy in macrophages via dual mechanisms.
    Ritika Chatterjee, Debalina Chaudhuri, Subba Rao Gangi Setty, Dipshikha Chakravortty.
      Salmonella, a stealthy facultative intracellular pathogen, utilises an array of host immune evasion strategies. This facilitates successful survival via replicative niche establishment in otherwise hostile environments such as macrophages. Salmonella survives in and utilises macrophages for effective dissemination, ultimately leading to systemic infection. Bacterial xenophagy or macro-autophagy is an important host defense mechanism in macrophages. Here, we report for the first time that the Salmonella pathogenicity island-1 (SPI-1) effector SopB is involved in subverting host autophagy via dual mechanisms. SopB is a phosphoinositide phosphatase capable of altering the phosphoinositide dynamics of the host cell. Here, we demonstrate that SopB mediates escape from autophagy by inhibiting the terminal fusion of Salmonella-containing vacuoles (SCVs) with lysosomes and/or autophagosomes. We also report that SopB downregulates overall lysosomal biogenesis by modulating the Akt-transcription factor EB (TFEB) axis via restricting the latter's nuclear localisation. TFEB is a master regulator of lysosomal biogenesis and autophagy. This reduces the overall lysosome content inside host macrophages, further facilitating the survival of Salmonella in macrophages and systemic dissemination of Salmonella.
    Keywords:  Autophagy; Lysosomal biogenesis; Macrophages; Phosphatidylinositol; Salmonella-containing vacuoles TFEB
    DOI:  https://doi.org/10.1016/j.micinf.2023.105128
  12. Front Cell Neurosci. 2023 ;17 1086895
    Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology.
    Rim Diab, Federica Pilotto, Smita Saxena.
      The proper functioning of the cell clearance machinery is critical for neuronal health within the central nervous system (CNS). In normal physiological conditions, the cell clearance machinery is actively involved in the elimination of misfolded and toxic proteins throughout the lifetime of an organism. The highly conserved and regulated pathway of autophagy is one of the important processes involved in preventing and neutralizing pathogenic buildup of toxic proteins that could eventually lead to the development of neurodegenerative diseases (NDs) such as Alzheimer's disease or Amyotrophic lateral sclerosis (ALS). The most common genetic cause of ALS and frontotemporal dementia (FTD) is a hexanucleotide expansion consisting of GGGGCC (G4C2) repeats in the chromosome 9 open reading frame 72 gene (C9ORF72). These abnormally expanded repeats have been implicated in leading to three main modes of disease pathology: loss of function of the C9ORF72 protein, the generation of RNA foci, and the production of dipeptide repeat proteins (DPRs). In this review, we discuss the normal physiological role of C9ORF72 in the autophagy-lysosome pathway (ALP), and present recent research deciphering how dysfunction of the ALP synergizes with C9ORF72 haploinsufficiency, which together with the gain of toxic mechanisms involving hexanucleotide repeat expansions and DPRs, drive the disease process. This review delves further into the interactions of C9ORF72 with RAB proteins involved in endosomal/lysosomal trafficking, and their role in regulating various steps in autophagy and lysosomal pathways. Lastly, the review aims to provide a framework for further investigations of neuronal autophagy in C9ORF72-linked ALS-FTD as well as other neurodegenerative diseases.
    Keywords:  ALS-FTD; C9ORF72; RAB proteins; autophagy; autophagy-lysosomal pathway; endosomal trafficking; neurodegeneration
    DOI:  https://doi.org/10.3389/fncel.2023.1086895
  13. Mol Metab. 2023 Mar 31. pii: S2212-8778(23)00051-0. [Epub ahead of print] 101717
    Aryl Hydrocarbon Receptor Maintains Hepatic Mitochondrial Homeostasis in Mice.
    Mi Jeong Heo, Ji Ho Suh, Sung Ho Lee, Kyle L Poulsen, Yu A An, Bhagavatula Moorthy, Sean M Hartig, David D Moore, Kang Ho Kim.
       BACKGROUND & AIMS: Mitophagy removes damaged mitochondria to maintain cellular homeostasis. Aryl hydrocarbon receptor (AhR) expression in the liver plays a crucial role in supporting normal liver functions, but its impact on mitochondrial function is unclear. Here, we identified a new role of AhR in the regulation of mitophagy to control hepatic energy homeostasis.
    APPROACH &RESULTS: Transcriptomic analysis indicated that mitochondria-related gene sets were dysregulated in AhR knockout (KO) liver. In both primary mouse hepatocytes and AML12 hepatocyte cell lines, AhR inhibition strongly suppressed mitochondrial respiration rate and substrate utilization. AhR inhibition also blunted the fasting response of several essential autophagy genes and the mitophagy process. We further identified BCL2 interacting protein 3 (BNIP3), a mitophagy receptor that senses nutrient stress, as an AhR target gene. AhR is directly recruited to the Bnip3 genomic locus, and Bnip3 transcription was enhanced by AhR endogenous ligand treatment in wild-type liver and abolished entirely in AhR KO liver. Mechanistically, overexpression of Bnip3 in AhR knockdown cells mitigated the production of mitochondrial reactive oxygen species (ROS) and restored functional mitophagy.
    CONCLUSIONS: AhR regulation of the mitophagy receptor BNIP3 coordinates hepatic mitochondrial function. Loss of AhR induces mitochondrial ROS production and impairs mitochondrial respiration. These findings provide new insight into how endogenous AhR governs hepatic mitochondrial homeostasis.
    Keywords:  BNIP3; autophagy; kynurenine; max 5): mitophagy; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.molmet.2023.101717
  14. Front Biosci (Landmark Ed). 2023 03 10. 28(3): 47
    Potential Therapeutic Targets in Ovarian Cancer: Autophagy and Metabolism.
    Misung Park, Soohyun Choe, Miyoung Shin, Ayoung Kim, Kyumin Mo, Hyeonseok Kwon, Hyunho Yoon.
      Ovarian cancer (OC) is characterized by high mortality rates owing to late diagnosis and resistance to chemotherapy. Autophagy and metabolism play essential roles in the pathological process of cancer and have recently been proposed as potential targets for anticancer therapies. Autophagy is responsible for the catabolic clearance of functionally misfolded proteins and plays different roles depending on the stage and type of cancer. Thus, understanding and controlling autophagy is relevant for treating cancer. Autophagy intermediates can communicate with each other by providing substrates for glucose, amino acid, and lipid metabolism. Metabolites and metabolic regulatory genes modulate autophagy and influence the immune response. Therefore, autophagy and the functional manipulation of metabolism during starvation or overnutrition are being investigated as potential therapeutic targets. This review discusses the role of autophagy and metabolism in OC and highlights effective therapeutic strategies targeting these processes.
    Keywords:  autophagy; cancer therapeutics; metabolism; metabolites; ovarian cancer
    DOI:  https://doi.org/10.31083/j.fbl2803047
  15. J Cell Biol. 2023 May 01. pii: e201910133. [Epub ahead of print]222(5):
    ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience.
    Natalia Jiménez-Moreno, Madhu Kollareddy, Petros Stathakos, Joanna J Moss, Zuriñe Antón, Deborah K Shoemark, Richard B Sessions, Ralph Witzgall, Maeve Caldwell, Jon D Lane.
      The LIM homeodomain transcription factors LMX1A and LMX1B are essential mediators of midbrain dopaminergic neuronal (mDAN) differentiation and survival. Here we show that LMX1A and LMX1B are autophagy transcription factors that provide cellular stress protection. Their suppression dampens the autophagy response, lowers mitochondrial respiration, and elevates mitochondrial ROS, and their inducible overexpression protects against rotenone toxicity in human iPSC-derived mDANs in vitro. Significantly, we show that LMX1A and LMX1B stability is in part regulated by autophagy, and that these transcription factors bind to multiple ATG8 proteins. Binding is dependent on subcellular localization and nutrient status, with LMX1B interacting with LC3B in the nucleus under basal conditions and associating with both cytosolic and nuclear LC3B during nutrient starvation. Crucially, ATG8 binding stimulates LMX1B-mediated transcription for efficient autophagy and cell stress protection, thereby establishing a novel LMX1B-autophagy regulatory axis that contributes to mDAN maintenance and survival in the adult brain.
    DOI:  https://doi.org/10.1083/jcb.201910133
  16. FEBS Lett. 2023 Apr 04.
    Vacuole membrane contact sites regulate liquid-ordered domain formation during glucose starvation.
    Keiko Sakuragi, Philipp Schlarmann, Atsuko Ikeda, Kouichi Funato.
      Liquid-ordered (Lo) membrane domains have been proposed to play important roles in a wide variety of biological processes, such as protein sorting and cell signaling. However, the mechanisms by which they are formed and maintained remain poorly understood. Lo domains are formed in the vacuolar membrane of yeast in response to glucose starvation. Here, we show that deletion of proteins which localize to vacuole membrane contact sites caused a marked decrease in the number of cells with Lo domains. In addition to Lo domain formation, autophagy is induced upon glucose starvation. However, deletion of core autophagy proteins did not inhibit Lo domain formation. Thus, we propose that vacuolar Lo domain formation during glucose restriction is regulated by membrane contact sites but not by autophagy.
    Keywords:  Lo domain; NVJ; autophagy; glucose starvation; vCLAMP
    DOI:  https://doi.org/10.1002/1873-3468.14621
  17. Front Aging Neurosci. 2023 ;15 1175935
    Editorial: Role of microglia autophagy in age-related neurodegenerative diseases.
    Zihua Wang.
      
    Keywords:  autophagy; drug delivery; microglia; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.3389/fnagi.2023.1175935
  18. Circ Rep. 2023 Apr 10. 5(4): 114-122
    Transcriptome Discovery of Genes in the Three Phases of Autophagy That Are Upregulated During Atrial Fibrillation.
    Takahiro Kamihara, Akihiro Hirashiki, Manabu Kokubo, Atsuya Shimizu.
      Background: Autophagy may contribute to the maintenance of atrial fibrillation (AF), but no previous study has concurrently surveyed all 3 phases of autophagy, namely autophagosome formation, lysosome formation, and autophagosome-lysosome fusion. Here we aimed to identify disorders involving various phases of autophagy during AF. Methods and Results: We used bioinformatic techniques to analyze publicly available DNA microarray datasets from the left atrium (LA) and right atrium (RA) of 7 patients with AF and 6 patients with normal sinus rhythm who underwent valvular surgeries. We compared gene expression levels in the LA (AF-LA) and RA of patients with AF with those in the LA and RA of patients with normal sinus rhythm. Several differentially expressed genes in the AF-LA sample were significantly associated with the Gene Ontogeny term 'Autophagy', indicating that the expression of autophagic genes was specifically altered in this dataset. In particular, the expression of genes known or suspected to be involved in autophagosome formation (autophagy related 5 [ATG5], autophagy related 10 [ATG10], autophagy related 12 [ATG12], and light chain 3B [LC3B]), lysosome formation (lysosomal associated membrane protein 1 [LAMP1] and lysosomal associated membrane protein 2 [LAMP2]), and autophagosome-lysosome fusion (synaptosome associated protein 29 [SNAP29], SNAP associated protein [SNAPIN], and syntaxin 17 [STX17]) was significantly upregulated in the LA-AF dataset. Conclusions: Autophagy is activated excessively in, and may perpetuate, AF.
    Keywords:  Atrial fibrillation; Autophagosome; Autophagy; Computational biology; Lysosome
    DOI:  https://doi.org/10.1253/circrep.CR-22-0130
  19. Cell Signal. 2023 Mar 31. pii: S0898-6568(23)00079-7. [Epub ahead of print] 110665
    An update on the molecular mechanism and pharmacological interventions for Ischemia-reperfusion injury by regulating AMPK/mTOR signaling pathway in autophagy.
    Bin Tang, Zhijian Luo, Rong Zhang, Dongmei Zhang, Guojun Nie, Mingxing Li, Yan Dai.
      AMP-activated protein kinase (5'-adenosine monophosphate-activated protein kinase, AMPK)/mammalian target of rapamycin (mTOR) is an important signaling pathway maintaining normal cell function and homeostasis in vivo. The AMPK/mTOR pathway regulates cellular proliferation, autophagy, and apoptosis. Ischemia-reperfusion injury (IRI) is secondary damage that frequently occurs clinically in various disease processes and treatments, and the exacerbated injury during tissue reperfusion increases disease-associated morbidity and mortality. IRI arises from multiple complex pathological mechanisms, among which cell autophagy is a focus of recent research and a new therapeutic target. The activation of AMPK/mTOR signaling in IRI can modulate cellular metabolism and regulate cell proliferation and immune cell differentiation by adjusting gene transcription and protein synthesis. Thus, the AMPK/mTOR signaling pathway has been intensively investigated in studies focused on IRI prevention and treatment. In recent years, AMPK/mTOR pathway-mediated autophagy has been found to play a crucial role in IRI treatment. This article aims to elaborate the action mechanisms of AMPK/mTOR signaling pathway activation in IRI and summarize the progress of AMPK/mTOR-mediated autophagy research in the field of IRI therapy.
    Keywords:  AMPK/mTOR autophagy IRI research progress
    DOI:  https://doi.org/10.1016/j.cellsig.2023.110665
  20. Cell Rep. 2023 Apr 05. pii: S2211-1247(23)00354-6. [Epub ahead of print]42(4): 112343
    Bub1 and Bub3 regulate metabolic adaptation via macrolipophagy in Drosophila.
    Qiaoqiao Zhang, Hui Zheng, Shengye Yang, Tong Feng, Minwen Jie, Haiyang Chen, Hao Jiang.
      Lipophagy, the process of selective catabolism of lipid droplets (LDs) by autophagy, maintains lipid homeostasis and provides cellular energy under metabolic adaptation, yet its underlying mechanism remains largely ambiguous. Here, we show that the Bub1-Bub3 complex, the crucial regulator involved in the whole process of chromosome alignment and separation during mitosis, controls the fasting-induced lipid catabolism in the fat body (FB) of Drosophila. Bidirectional deviations of the Bub1 or Bub3 level affect the consumption of triacylglycerol (TAG) of fat bodies and the survival rate of adult flies under starving. Moreover, Bub1 and Bub3 work together to attenuate lipid degradation via macrolipophagy upon fasting. Thus, we uncover physiological roles of the Bub1-Bub3 complex on metabolic adaptation and lipid metabolism beyond their canonical mitotic functions, providing insights into the in vivo functions and molecular mechanisms of macrolipophagy during nutrient deprivation.
    Keywords:  CP: Metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2023.112343
  21. J Cell Biol. 2023 Jun 05. pii: e202210104. [Epub ahead of print]222(6):
    RNA recruitment switches the fate of protein condensates from autophagic degradation to accumulation.
    Hui Zheng, Kangfu Peng, Xiaomeng Gou, Chen Ju, Hong Zhang.
      Protein condensates can evade autophagic degradation under stress or pathological conditions. However, the underlying mechanisms are unclear. Here, we demonstrate that RNAs switch the fate of condensates in Caenorhabditis elegans. PGL granules undergo autophagic degradation in embryos laid under normal conditions and accumulate in embryos laid under heat stress conditions to confer stress adaptation. In heat-stressed embryos, mRNAs and RNA control factors partition into PGL granules. Depleting proteins involved in mRNA biogenesis and stability suppresses PGL granule accumulation and triggers their autophagic degradation, while loss of activity of proteins involved in RNA turnover facilitates accumulation. RNAs facilitate LLPS of PGL granules, enhance their liquidity, and also inhibit recruitment of the gelation-promoting scaffold protein EPG-2 to PGL granules. Thus, RNAs are important for controlling the susceptibility of phase-separated protein condensates to autophagic degradation. Our work provides insights into the accumulation of ribonucleoprotein aggregates associated with the pathogenesis of various diseases.
    DOI:  https://doi.org/10.1083/jcb.202210104
  22. Autophagy. 2023 Apr 04.
    Hepatocyte CD36 modulates UBQLN1-mediated proteasomal degradation of autophagic SNARE proteins contributing to septic liver injury.
    Yanping Li, Jingyuan Xu, Weiting Chen, Xingxing Wang, Zhibo Zhao, Yuqi Li, Linkun Zhang, Junkui Jiao, Qin Yang, Qiuying Ding, Ping Yang, Li Wei, Yao Chen, Yaxi Chen, Xiong Z Ruan, Lei Zhao.
      Macroautophagy/autophagy plays a protective role in sepsis-induced liver injury. As a member of class B scavenger receptors, CD36 plays important roles in various disorders, such as atherosclerosis and fatty liver disease. Here we found that the expression of CD36 in hepatocytes was increased in patients and a mouse model with sepsis, accompanied by impaired autophagy flux. Furthermore, hepatocyte cd36 knockout (cd36-HKO) markedly improved liver injury and the impairment of autophagosome-lysosome fusion in lipopolysaccharide (LPS)-induced septic mice. Ubqln1 (ubiquilin 1) overexpression (OE) in hepatocyte blocked the protective effect of cd36-HKO on LPS-induced liver injury in mice. Mechanistically, with LPS stimulation, CD36 on the plasma membrane was depalmitoylated and distributed to the lysosome, where CD36 acted as a bridge molecule linking UBQLN1 to soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and hence promoting the proteasomal degradation of SNARE proteins, resulting in fusion impairment. Overall, our data reveal that CD36 is essential for modulating the proteasomal degradation of autophagic SNARE proteins in a UBQLN1-dependent manner. Targeting CD36 in hepatocytes is effective for improving autophagic flux in sepsis and therefore represents a promising therapeutic strategy for clinical treatment of septic liver injury.
    Keywords:  CD36; autophagy; liver injury; proteasomal degradation; ubiquilin 1
    DOI:  https://doi.org/10.1080/15548627.2023.2196876
  23. Curr Opin Neurobiol. 2023 Apr 04. pii: S0959-4388(23)00045-4. [Epub ahead of print]80 102720
    Novel insights into Parkin-mediated mitochondrial dysfunction and neuroinflammation in Parkinson's disease.
    Sandro L Pereira, Dajana Grossmann, Sylvie Delcambre, Andreas Hermann, Anne Grünewald.
      Mutations in PRKN cause the second most common genetic form of Parkinson's disease (PD)-a debilitating movement disorder that is on the rise due to population aging in the industrial world. PRKN codes for an E3 ubiquitin ligase that has been well established as a key regulator of mitophagy. Together with PTEN-induced kinase 1 (PINK1), Parkin controls the lysosomal degradation of depolarized mitochondria. But Parkin's functions go well beyond mitochondrial clearance: the versatile protein is involved in mitochondria-derived vesicle formation, cellular metabolism, calcium homeostasis, mitochondrial DNA maintenance, mitochondrial biogenesis, and apoptosis induction. Moreover, Parkin can act as a modulator of different inflammatory pathways. In the current review, we summarize the latest literature concerning the diverse roles of Parkin in maintaining a healthy mitochondrial pool. Moreover, we discuss how these recent discoveries may translate into personalized therapeutic approaches not only for PRKN-PD patients but also for a subset of idiopathic cases.
    Keywords:  Biogenesis; Calcium; Inflammation; Metabolism; Mitochondria; Mitophagy; PINK1; Parkin; Parkinson's disease; mtDNA
    DOI:  https://doi.org/10.1016/j.conb.2023.102720
  24. Cell Death Discov. 2023 Apr 05. 9(1): 115
    Autophagy in hepatic ischemia-reperfusion injury.
    Benliang Mao, Wei Yuan, Fan Wu, Yong Yan, Bailin Wang.
      Hepatic ischemia-reperfusion injury (HIRI) is a major complication of liver resection or liver transplantation that can seriously affect patient's prognosis. There is currently no definitive and effective treatment strategy for HIRI. Autophagy is an intracellular self-digestion pathway initiated to remove damaged organelles and proteins, which maintains cell survival, differentiation, and homeostasis. Recent studies have shown that autophagy is involved in the regulation of HIRI. Numerous drugs and treatments can change the outcome of HIRI by controlling the pathways of autophagy. This review mainly discusses the occurrence and development of autophagy, the selection of experimental models for HIRI, and the specific regulatory pathways of autophagy in HIRI. Autophagy has considerable potential in the treatment of HIRI.
    DOI:  https://doi.org/10.1038/s41420-023-01387-0
  25. Anal Chem. 2023 Apr 04.
    Versatile Switchable Targeted Polysiloxanes for High-Resolution Visualization of Mitochondrial and Lysosomal Interactions during Ferroptosis.
    Kun Zhang, Ying Lan, Fanfan Wang, Zhiming Gou, Mei Yan, Yujing Zuo.
      Ferroptosis is an iron-dependent process that regulates cell death and is essential for maintaining normal cell and tissue survival. The explosion of reactive oxygen species characterizes ferroptosis in a significant way. Peroxynitrite (ONOO-) is one of the endogenous reactive oxygen species. Abnormal ONOO- concentrations cause damage to subcellular organelles and further interfere with organelle interactions. However, the proper conduct of organelle interactions is critical for cellular signaling and the maintenance of cellular homeostasis. Therefore, investigating the effect of ONOO- on organelle interactions during ferroptosis is a highly attractive topic. To date, it has been challenging to visualize the full range of ONOO- fluctuations in mitochondria and lysosomes during ferroptosis. In this paper, we constructed a switchable targeting polysiloxane platform. During the selective modification of NH2 groups located in the side chain, the polysiloxane platform successfully constructed fluorescent probes targeting lysosomes and mitochondria (Si-Lyso-ONOO, Si-Mito-ONOO), respectively. Real-time detection of ONOO- in lysosomes and mitochondria during ferroptosis was successfully achieved. Remarkably, the occurrence of autophagy during late ferroptosis and the interaction between mitochondria and lysosomes was observed via the differentiated responsive strategy. We expect that this switchable targeting polysiloxane functional platform will broaden the application of polymeric materials in bioimaging and provide a powerful tool for further deeper understanding of the ferroptosis process.
    DOI:  https://doi.org/10.1021/acs.analchem.2c05137
  26. J Cell Physiol. 2023 Apr 03.
    The dual and emerging role of physical exercise-induced TFEB activation in the protection against Alzheimer's disease.
    Gustavo Paroschi Morais, Ivo Vieira de Sousa Neto, Bruno Brieda Marafon, Eduardo R Ropelle, Dennys E Cintra, José R Pauli, Adelino S R da Silva.
      The mechanisms of autophagy have been related to Alzheimer's disease (AD) pathogenesis by the endosomal-lysosomal system, having a critical function in forming amyloid-β (Aβ) plaques. Nevertheless, the exact mechanisms mediating disease pathogenesis remain unclear. The transcription factor EB (TFEB), a primary transcriptional autophagy regulator, improves gene expression, mediating lysosome function, autophagic flux, and autophagosome biogenesis. In this review, we present for the first time the hypothesis of how TFEB, autophagy, and mitochondrial function are interconnected in AD, providing a logical foundation for unraveling the critical role of chronic physical exercise in this process. Aerobic exercise training promotes Adiponectin Receptor 1 (AdipoR1)/AMP-activated protein kinase (AMPK)/TFEB axis activation in the brain of the AD animal model, which contributes to alleviated Aβ deposition and neuronal apoptosis while improving cognitive function. Moreover, TFEB upregulates Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and nuclear factor erythroid 2-related factor 2 (NRF-2), improving mitochondrial biogenesis and redox status. In addition, tissue contraction activates calcineurin in skeletal muscle, which induces TFEB nuclear translocation, raising the hypothesis that the same would occur in the brain. Thus, a deep and comprehensive exploration of the TFEB could provide new directions and strategies for preventing AD. We conclude that chronic exercise can be an effective TFEB activator, inducing autophagy and mitochondrial biogenesis, representing a potential nonpharmacological strategy contributing to brain health.
    Keywords:  Alzheimer; TFEB; autophagy; brain; exercise
    DOI:  https://doi.org/10.1002/jcp.31005
  27. Autophagy. 2023 Apr 04.
    CircEPS15, as a sponge of MIR24-3p ameliorates neuronal damage in Parkinson disease through boosting PINK1-PRKN-mediated mitophagy.
    Yuanzhang Zhou, Yang Liu, Zhengwei Kang, Hang Yao, Nanshan Song, Min Wang, Chenghuan Song, Kezhong Zhang, Jianhua Ding, Juanjuan Tang, Gang Hu, Ming Lu.
      Despite growing evidence that has declared the importance of circRNAs in neurodegenerative diseases, the clinical significance of circRNAs in dopaminergic (DA) neuronal degeneration in the pathogenesis of Parkinson disease (PD) remains unclear. Here, we performed rRNA-depleted RNA sequencing and detected more than 10,000 circRNAs in the plasma samples of PD patients. In consideration of ROC and the correlation between Hohen-Yahr stage (H-Y stage) and Unified Parkinson Disease Rating Scale-motor score (UPDRS) of 40 PD patients, circEPS15 was selected for further research. Low expression of circEPS15 was found in PD patients and there was a negative positive correlation between the circEPS15 level and severity of PD motor symptoms, while overexpression of circEPS15 protected DA neurons against neurotoxin-induced PD-like neurodegeneration in vitro and in vivo. Mechanistically, circEPS15 acted as a MIR24-3p sponge to promote the stable expression of target gene PINK1, thus enhancing PINK1-PRKN-dependent mitophagy to eliminate damaged mitochondria and maintain mitochondrial homeostasis. Thus, circEPS15 rescued DA neuronal degeneration through the MIR24-3p-PINK1 axis-mediated improvement of mitochondrial function. This study reveals that circEPS15 exerts a critical role in participating in PD pathogenesis, and may give us an insight into the novel avenue to develop potential biomarkers and therapeutic targets for PD.
    Keywords:  CircEPS15; MIR24-3p; PINK1; Parkinson disease; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2196889
  28. Indian J Ophthalmol. 2023 Apr;71(4): 1285-1291
    Autophagy in dry eye disease: Therapeutic implications of autophagy modulators on the ocular surface.
    Nallathambi Jeyabalan, Aswathi M Pillai, Pooja Khamar, Rohit Shetty, Rajiv R Mohan, Arkasubhra Ghosh.
      Dry eye disease (DED) is a chronic ocular surface disorder, associated with inflammation, which can cause severe morbidity, visual compromise, and loss of quality of life, affecting up to 5-50% of the world population. In DED, ocular surface damage and tear film instability due to abnormal tear secretion lead to ocular surface pain, discomfort, and epithelial barrier disruption. Studies have shown the involvement of autophagy regulation in dry eye disease as a pathogenic mechanism along with the inflammatory response. Autophagy is a self-degradation pathway in mammalian cells that reduces the excessive inflammation driven by the secretion of inflammatory factors in tears. Specific autophagy modulators are already available for the management of DED currently. However, growing studies on autophagy regulation in DED might further encourage the development of autophagy modulating drugs that reduce the pathological response at the ocular surface. In this review, we summarize the role of autophagy in the pathogenesis of dry eye disease and explore its therapeutic application.
    Keywords:  Autophagy modulators; corneal autophagy; inflammation; ocular surface dry eye disease
    DOI:  https://doi.org/10.4103/IJO.IJO_2912_22
  29. J Biol Chem. 2023 Mar 30. pii: S0021-9258(23)00305-8. [Epub ahead of print] 104663
    Macrotubule associated protein MAP1LC3C regulates lysosomal exocytosis and induces zinc reprogramming in renal cancer cells.
    Rita Verma, Parul Aggarwal, Megan E Bischoff, James Reigle, Dina Secic, Collin Wetzel, Katherine VandenHeuvel, Jacek Biesiada, Birgit Ehmer, Julio A Landero Figueroa, David R Plas, Mario Medvedovic, Jarek Meller, Maria F Czyzyk-Krzeska.
      Microtubule Associated Protein 1 Light Chain 3 Gamma (MAP1LC3C or LC3C) is a member of the microtubule associated family of proteins that are essential in the formation of autophagosomes and lysosomal degradation of cargo. LC3C has tumor suppressing activity and its expression is dependent on kidney cancer tumor suppressors, such as von Hippel-Lindau protein (VHL) and folliculin (FLCN). Recently We demonstrated that LC3C autophagy is regulated by noncanonical upstream regulatory complexes and targets for degradation postdivision midbody rings associated with cancer cells stemness. Here we show that loss of LC3C leads to peripheral positioning of the lysosomes and lysosomal exocytosis (LE). This process is independent of the autophagic activity of LC3C. Analysis of isogenic cells with low and high LE shows substantial transcriptomic reprogramming with altered expression of Zn-related genes and activity of Polycomb Repressor Complex 2 (PRC2), accompanied by a robust decrease in intracellular Zn. Additionally, metabolomic analysis revealed alterations in amino acid steady-state levels. Cells with augmented LE show increased tumor initiation properties and form aggressive tumors in xenograft models. Immunocytochemistry identified high levels of Lysosomal Associated Membrane Protein 1 (LAMP1) on the plasma membrane of cancer cells in human clear cell renal cell carcinoma (ccRCC) and reduced levels of Zn, suggesting that LE occurs in ccRCC, potentially contributing to the loss of Zn. These data indicate that the reprogramming of lysosomal localization and Zn metabolism with implication for epigenetic remodeling in a subpopulation of tumor propagating cancer cells is an important aspect of tumor suppressing activity of LC3C.
    Keywords:  LC3C; exocytosis; lysosome; renal cancer; zinc
    DOI:  https://doi.org/10.1016/j.jbc.2023.104663
  30. Sci Rep. 2023 Apr 06. 13(1): 5665
    Disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede Purkinje cell loss in a mouse model of Niemann-Pick Type-C disease.
    Sarah Kim, Kathleen Ochoa, Sierra E Melli, Fawad A K Yousufzai, Zerian D Barrera, Aela A Williams, Gianna McIntyre, Esteban Delgado, James N Bolish, Collin M Macleod, Mary Boghos, Hayden P Lens, Alex G Ramos, Vincent B Wilson, Kelly Maloney, Zachary M Padron, Amaal H Khan, Rosa E Blanco, Ileana Soto.
      Purkinje cell (PC) loss occurs at an early age in patients and animal models of Niemann-Pick Type C (NPC), a lysosomal storage disease caused by mutations in the Npc1 or Npc2 genes. Although degeneration of PCs occurs early in NPC, little is known about how NPC1 deficiency affects the postnatal development of PCs. Using the Npc1nmf164 mouse model, we found that NPC1 deficiency significantly affected the postnatal development of PC dendrites and synapses. The developing dendrites of Npc1nmf164 PCs were significantly deficient in mitochondria and lysosomes. Furthermore, anabolic (mTORC1) and catabolic (TFEB) signaling pathways were not only perturbed but simultaneously activated in NPC1-deficient PCs, suggesting a loss of metabolic balance. We also found that mice with conditional heterozygous deletion of the Phosphatase and Tensin Homolog Deleted on Chromosome 10 gene (Pten-cHet), an inhibitor of mTORC1, showed similar early dendritic alterations in PCs to those found in Npc1-deficient mice. However, in contrast to Npc1nmf164 mice, Pten-cHet mice exhibited the overactivation of the mTORC1 pathway but with a strong inhibition of TFEB signaling, along with no dendritic mitochondrial reductions by the end of their postnatal development. Our data suggest that disruption of the lysosomal-metabolic signaling in PCs causes dendritic and synaptic developmental deficits that precede and promote their early degeneration in NPC.
    DOI:  https://doi.org/10.1038/s41598-023-32971-0
  31. Physiol Rev. 2023 Apr 06.
    Mitochondria in Health, Disease, and Ageing.
    John S Harrington, Stefan W Ryter, Maria Plataki, David R Price, Augustine M K Choi.
      Mitochondria are well-known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. While oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell-death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.
    Keywords:  Apoptosis; Inflammation; Mitochondria; Mitochondrial Dysfunction; Mitophagy
    DOI:  https://doi.org/10.1152/physrev.00058.2021
  32. Heliyon. 2023 Apr;9(4): e14705
    Autophagy regulates the release of exercise factors and their beneficial effects on spatial memory recall.
    Reine Khoury, Joelle Saad, Vanessa Jabre, Litsa Maria Ghayad, Mohamad Khalifeh, Rouba Houbeika, Perla El Ahmad, Amar Mezher, Diala El Masri, Zena Haddad, Fady Eid, Nour Barmo, Patrick Nasrallah, Sama F Sleiman, Joseph S Stephan.
      Exercise promotes learning and memory recall as well as rescues cognitive decline associated with aging. The positive effects of exercise are mediated by circulatory factors that predominantly increase Brain Derived Neurotrophic Factor (BDNF) signaling in the hippocampus. Identifying the pathways that regulate the release of the circulatory factors by various tissues during exercise and that mediate hippocampal Mus musculus Bdnf expression will allow us to harness the therapeutic potential of exercise. Here, we report that two weeks of voluntary exercise in male mice activates autophagy in the hippocampus by increasing LC3B protein levels (p = 0.0425) and that autophagy is necessary for exercise-induced spatial learning and memory retention (p < 0.001; exercise + autophagy inhibitor chloroquine CQ versus exercise). We place autophagy downstream of hippocampal BDNF signaling and identify a positive feedback activation between the pathways. We also assess whether the modulation of autophagy outside the nervous system is involved in mediating exercise's effect on learning and memory recall. Indeed, plasma collected from young exercise mice promote spatial learning (p = 0.0446; exercise versus sedentary plasma) and memory retention in aged inactive mice (p = 0.0303; exercise versus sedentary plasma), whereas plasma collected from young exercise mice that received the autophagy inhibitor chloroquine diphosphate failed to do so. We show that the release of exercise factors that reverse the symptoms of aging into the circulation is dependent on the activation of autophagy in young animals. Indeed, we show that the release of the exercise factor, beta-hydroxybutyrate (DBHB), into the circulation, is autophagy-dependent and that DBHB promotes spatial learning and memory formation (p = 0.0005) by inducing hippocampal autophagy (p = 0.0479). These results implicate autophagy in peripheral tissues and in the hippocampus in mediating the effects of exercise on learning and memory recall and identify DBHB as a candidate endogenous exercise factor whose release and positive effects are autophagy-dependent.
    Keywords:  Aging; Autophagy; BDNF; Beta-hydroxybutyrate; Exercise; Learning; Memory
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e14705
  33. Biochem Pharmacol. 2023 Apr 04. pii: S0006-2952(23)00125-9. [Epub ahead of print]211 115534
    A small molecule compound that inhibits blue light-induced retinal damage via activation of autophagy.
    Young Chae Shin, Sanha Lee, Hong Lan Jin, Xiang Fei, Sang Won Kang, Seung-Yong Seo, Kwang Won Jeong.
      Dry age-related macular degeneration (AMD) is a type of disease that causes visual impairment due to changes in the macula located in the center of the retina. The accumulation of drusen under the retina is also a characteristic of dry AMD. In this study, we identified a compound (JS-017) that can potentially degrade N-retinylidene-N-retinylethanolamine (A2E), one of the components of lipofuscin, using fluorescence-based screening, which measures A2E degradation in human retinal pigment epithelial cells. JS-017 effectively degraded A2E in ARPE-19 cells and consequently suppressed the activation of the NF-κB signaling pathway and expression of inflammatory and apoptosis genes induced by blue light (BL). Mechanistically, JS-017 induced LC3-II formation and improved autophagic flux in ARPE-19 cells. Additionally, the A2E degradation activity of JS-017 was found to be decreased in autophagy-related 5 protein-depleted ARPE-19 cells, suggesting that autophagy was required for A2E degradation mediated by JS-017. Finally, JS-017 exhibited an improvement in BL-induced retinal damage measured through fundus examination in an in vivo retinal degeneration mouse model. The thickness of the outer nuclear layer and inner/external segments, which was decreased upon exposure to BL irradiation, was also restored upon JS-017 treatment. Altogether, we demonstrated that JS-017 protected human retinal pigment epithelium (RPE) cells from A2E and BL-induced damage by degrading A2E via the activation of autophagy. The results suggest the feasibility of a novel A2E-degrading small molecule as a therapeutic agent for retinal degenerative diseases.
    DOI:  https://doi.org/10.1016/j.bcp.2023.115534
  34. J Am Chem Soc. 2023 Apr 06.
    A Benzohydrazide-Based Artificial Ion Channel that Modulates Chloride Ion Concentration in Cancer Cells and Induces Apoptosis by Disruption of Autophagy.
    Abhishek Mondal, Shreyada N Save, Susmita Sarkar, Debashis Mondal, Jagannath Mondal, Shilpy Sharma, Pinaki Talukdar.
      Fluctuations in the intracellular chloride ion concentration, mediated by synthetic ion transporters, have been known to induce cytotoxicity in cells by disrupting ionic homeostasis. However, the activity of these transporters in modulating autophagy remains largely unexplored. Here, we report a benzoylbenzohydrazide (1c) that self-assembles to form a supramolecular nanochannel lumen that allows selective and efficient transport of chloride ions across the cell membranes, disrupts ion homeostasis, and thus leads to the induction of apoptosis in cancer cells. It is important to note that the transporter was relatively nontoxic to cells of noncancerous origin. 1c was also shown to induce the deacidification of lysosomes, thereby disrupting autophagy in cancer cells. Taken together, these findings provide a rare example of an artificial ion channel that specifically targets cancer cells by induction of apoptosis via disruption of autophagy.
    DOI:  https://doi.org/10.1021/jacs.3c01451
  35. Cell Stress. 2023 Apr;7(4): 20-33
    Macrolide antibiotics activate the integrated stress response and promote tumor proliferation.
    Xin Yu, Ai-Ling Tian, Ping Wang, Juanjuan Li, Juan Wu, Bei Li, Zhou Liu, Siqing Liu, Zhijie Gao, Si Sun, Shengrong Sun, Yi Tu, Qi Wu.
      Macrolide antibiotics are widely used antibacterial agents that are associated with autophagy inhibition. This study aimed to investigate the association between macrolide antibiotics and malignant tumors, as well as the effect on autophagy, reactive oxygen species (ROS) accumulation and integrated stress response (ISR). The meta-analysis indicated a modestly higher risk of cancer in macrolide antibiotic ever-users compared to non-users. Further experiments showed that macrolides block autophagic flux by inhibiting lysosomal acidification. Additionally, azithromycin, a representative macrolide antibiotic, induced the accumulation of ROS, and stimulated the ISR and the activation of transcription factor EB (TFEB) and TFE3 in a ROS-dependent manner. Finally, animal experiments confirmed that azithromycin promoted tumor progression in vivo, which could be receded by N-acetylcysteine, an inhibitor of ROS and ISR. Overall, this study reveals the potential role of macrolide antibiotics in malignant progression and highlights the need for further investigation into their effects.
    Keywords:  ER stress; ROS; autophagy; azithromycin; cancer; macrolide antibiotic
    DOI:  https://doi.org/10.15698/cst2023.04.278
  36. Autophagy Rep. 2022 ;1(1): 210-213
    MitoSwap - Mitophagy partnered with compensatory mitochondrial biogenesis during stem cell differentiation.
    Priyanka Gajwani, Jalees Rehman.
      Differentiating stem cells must adapt their mitochondrial metabolism to fit the needs of the mature differentiated cell. In a recent study, we observed that during differentiation to an endothelial phenotype, pluripotent stem cell mitochondria are removed by mitophagy, triggering compensatory mitochondrial biogenesis to replenish the mitochondrial pool. We identified the mitochondrial phosphatase PGAM5 as the link between mitophagy and transcription of the mitochondrial biogenesis regulator PPARGC1A/PGC1α in the nucleus. Swapping of mitochondria through the coupled processes of mitophagy and mitochondrial biogenesis lead to enhanced metabolic reprogramming in the differentiated cell.
    Keywords:  CTNNB1/β-catenin; PINK1; PPARGC1A/PGC1α; differentiation; endothelium; mitochondrial biogenesis; mitofusin 2; mitophagy; stem cells
    DOI:  https://doi.org/10.1080/27694127.2022.2071549
  37. Neuropathol Appl Neurobiol. 2023 Apr 05. e12904
    Tuberous Sclerosis Complex-1 (TSC1) contributes to selective neuronal vulnerability in Alzheimer's Disease.
    Bryan A Adriaanse, Sinead Brady, Minghui Wang, Daniel J Beard, Jonathan I Spencer, Jonathan Pansieri, Brad A Sutherland, Margaret M Esiri, Alastair M Buchan, Zameel Cader, Bin Zhang, Gabriele C DeLuca.
       AIMS: Selective neuronal vulnerability of hippocampal Cornu Ammonis (CA)-1 neurons is a pathological hallmark of Alzheimer's Disease (AD) with an unknown underlying mechanism. We interrogated the expression of Tuberous Sclerosis Complex-1 (TSC1; hamartin) and mTOR-related proteins in hippocampal CA1 and CA3 subfields.
    METHODS: A human post-mortem cohort of mild (n=7) and severe (n=10) AD and non-neurological controls (n=9) was used for quantitative and semi-quantitative analyses. We also developed an in vitro TSC1-knockdown model in rat hippocampal neurons, while transcriptomic analyses of TSC1-knockdown neuronal cultures were performed.
    RESULTS: We found a selective increase of TSC1 cytoplasmic inclusions in human AD CA1 neurons with hyperactivation of one of TSC1's downstream targets, the mammalian target of rapamycin complex-1 (mTORC1), suggesting that TSC1 is no longer active in AD. TSC1-knockdown experiments showed accelerated cell death independent of amyloid-beta toxicity. Transcriptomic analyses of TSC1 knockdown neuronal cultures revealed signatures that were significantly enriched for AD-related pathways.
    CONCLUSIONS: Our combined data point to TSC1 dysregulation as a key driver of selective neuronal vulnerability in the AD hippocampus. Future work aimed at identifying targets amenable to therapeutic manipulation is urgently needed to halt selective neurodegeneration, and by extension, debilitating cognitive impairment characteristic of AD.
    Keywords:  Alzheimer’s Disease; molecular biology; neurodegeneration; neuropathology
    DOI:  https://doi.org/10.1111/nan.12904
  38. Acta Biochim Biophys Sin (Shanghai). 2023 Apr 25.
    Homocysteine accelerates hepatocyte autophagy by upregulating TFEB via DNMT3b-mediated DNA hypomethylation.
    Anning Yang, Wen Zeng, Hongwen Zhang, Yinju Hao, Qingqing Wang, Yue Sun, Shangkun Quan, Ning Ding, Xiaoling Yang, Jianmin Sun, Huiping Zhang, Bin Liu, Yun Jiao, Kai Wu, Yideng Jiang.
      Autophagy plays a critical role in the physiology and pathophysiology of hepatocytes. High level of homocysteine (Hcy) promotes autophagy in hepatocytes, but the underlying mechanism is still unknown. Here, we investigate the relationship between Hcy-induced autophagy level and the expression of nuclear transcription factor EB (TFEB). The results show that Hcy-induced autophagy level is mediated by upregulation of TFEB. Silencing of TFEB decreases the level of autophagy-related protein LC3BII/I and increases p62 expression level in hepatocytes after exposure to Hcy. Moreover, the effect of Hcy on the expression of TFEB is regulated by hypomethylation of the TFEB promoter catalyzed by DNA methyltransferase 3b (DNMT3b). In summary, this study shows that Hcy can activate autophagy by inhibiting DNMT3b-mediated DNA methylation and upregulating TFEB expression. These findings provide another new mechanism for Hcy-induced autophagy in hepatocytes.
    Keywords:  DNA methylation; DNA methyltransferase 3b; TFEB; autophagy; homocysteine
    DOI:  https://doi.org/10.3724/abbs.2023060
  39. Life Sci. 2023 Apr 05. pii: S0024-3205(23)00296-5. [Epub ahead of print] 121662
    Role of mammalian target of rapamycin (mTOR) signalling in oncogenesis.
    Mohamed El-Tanani, Hamdi Nsairat, Alaa A Aljabali, Ángel Serrano-Aroca-Angel, Vijay Mishra, Yachana Mishra, Gowhar A Naikoo, Walhan Alshaer, Murtaza M Tambuwala.
      The signalling system known as mammalian target of rapamycin (mTOR) is believed to be required for several biological activities involving cell proliferation. The serine-threonine kinase identified as mTOR recognises PI3K-AKT stress signals. It is well established in the scientific literature that the deregulation of the mTOR pathway plays a crucial role in cancer growth and advancement. This review focuses on the normal functions of mTOR as well as its abnormal roles in cancer development.
    Keywords:  Apoptosis; Pathological angiogenesis; Rapamycin and rapalogues; Signalling cascade; mTOR
    DOI:  https://doi.org/10.1016/j.lfs.2023.121662
  40. Microbiol Spectr. 2023 Apr 04. e0307922
    Bif-1c Attenuates Viral Proliferation by Regulating Autophagic Flux Blockade Induced by the Rabies Virus CVS-11 Strain in N2a Cells.
    Pengfei Hou, Yidi Guo, Hongli Jin, Jingxuan Sun, Yujie Bai, Wujian Li, Ling Li, Zengguo Cao, Fangfang Wu, Haili Zhang, Yuanyuan Li, Songtao Yang, Xianzhu Xia, Pei Huang, Hualei Wang.
      Bax-interacting factor-1 (Bif-1) is a multifunctional protein involved in apoptosis, autophagy, and mitochondrial morphology. However, the associations between Bif-1 and viruses are poorly understood. As discrete Bif-1 isoforms are selectively expressed and exert corresponding effects, we evaluated the effects of neuron-specific/ubiquitous Bif-1 isoforms on rabies virus (RABV) proliferation. First, infection with the RABV CVS-11 strain significantly altered Bif-1 expression in mouse neuroblastoma (N2a) cells, and Bif-1 knockdown in turn promoted RABV replication. Overexpression of neuron-specific Bif-1 isoforms (Bif-1b/c/e) suppressed RABV replication. Moreover, our study showed that Bif-1c colocalized with LC3 and partially alleviated the incomplete autophagic flux induced by RABV. Taken together, our data reveal that neuron-specific Bif-1 isoforms impair the RABV replication process by abolishing autophagosome accumulation and blocking autophagic flux induced by the RABV CVS-11 strain in N2a cells. IMPORTANCE Autophagy can be triggered by viral infection and replication. Autophagosomes are generated and affect RABV replication, which differs by viral strain and infected cell type. Bax-interacting factor-1 (Bif-1) mainly has a proapoptotic function but is also involved in autophagosome formation. However, the association between Bif-1-involved autophagy and RABV infection remains unclear. In this study, our data reveal that a neuron-specific Bif-1 isoform, Bif-1c, impaired viral replication by unchoking autophagosome accumulation induced by RABV in N2a cells to a certain extent. Our study reveals for the first time that Bif-1 is involved in modulating autophagic flux and plays a crucial role in RABV replication, establishing Bif-1 as a potential therapeutic target for rabies.
    Keywords:  Bif-1c; RABV; autophagy flux; replication
    DOI:  https://doi.org/10.1128/spectrum.03079-22
  41. J Hazard Mater. 2023 Mar 28. pii: S0304-3894(23)00590-3. [Epub ahead of print]452 131308
    Nanoplastics exposure disrupts circadian rhythm associated with dysfunction of the endolysosomal pathway and autophagy in Caenorhabditis elegans.
    Chan-Wei Yu, Yi-Chun Wu, Vivian Hsiu-Chuan Liao.
      Nanoplastics (NPs), an emerging pollutant, have raised great safety concerns due to their widespread applications and continuous release into the environment, which lead to potential human and environmental risks. Recently, polystyrene NPs (100 nm; 100 mg/L) exposure has been reported to disrupt circadian rhythms under five days temperature entrainment and be associated with stress resistance decline in Caenorhabditis elegans. This study explored the possible relationship between circadian rhythm disruption and endocytosis and autophagy under polystyrene NPs exposure in C. elegans. We show that the disrupted circadian rhythm induced by NPs exposure reduced stress resistance via endocytosis and autophagy impairment. Furthermore, we found that most NPs taken up by intestinal cells were localized to early endosomes, late endosomes, and lysosomes and delivered to autophagosomes. In addition, the disruption of circadian rhythm inhibited NPs localization to these organelles. These findings indicate that NPs exposure disrupts circadian rhythm and alters its subcellular trafficking, leading to enhanced toxicity in C. elegans. Our results shed light on the prominent role of NPs exposure in circadian rhythm disruption associated with endocytosis and autophagy impairments, which may be conserved in higher animals such as humans.
    Keywords:  Autophagy; Caenorhabditis elegans; Circadian rhythms; Endocytosis; Nanoplastics; Subcellular localization
    DOI:  https://doi.org/10.1016/j.jhazmat.2023.131308
  42. Acta Pharmacol Sin. 2023 Apr 03.
    A new glance at autophagolysosomal-dependent or -independent function of transcriptional factor EB in human cancer.
    Ting Wang, Yi Qin, Zeng Ye, De-Sheng Jing, Gui-Xiong Fan, Meng-Qi Liu, Qi-Feng Zhuo, Shun-Rong Ji, Xue-Min Chen, Xian-Jun Yu, Xiao-Wu Xu, Zheng Li.
      Autophagy-lysosome system plays a variety of roles in human cancers. In addition to being implicated in metabolism, it is also involved in tumor immunity, remodeling the tumor microenvironment, vascular proliferation, and promoting tumor progression and metastasis. Transcriptional factor EB (TFEB) is a major regulator of the autophagy-lysosomal system. With the in-depth studies on TFEB, researchers have found that it promotes various cancer phenotypes by regulating the autophagolysosomal system, and even in an autophagy-independent way. In this review, we summarize the recent findings about TFEB in various types of cancer (melanoma, pancreatic ductal adenocarcinoma, renal cell carcinoma, colorectal cancer, breast cancer, prostate cancer, ovarian cancer and lung cancer), and shed some light on the mechanisms by which it may serve as a potential target for cancer treatment.
    Keywords:  Mammalian Target Of Rapamycin Complex 1; TFEB Protein; autophagy-lysosomal system; metastasis; neoplasm; tumor progression
    DOI:  https://doi.org/10.1038/s41401-023-01078-7
  43. Curr Neuropharmacol. 2023 Apr 04.
    Oxidative DNA Damage-induced PARP-1-mediated Autophagic Flux Disruption Contributes to Bupivacaine-induced Neurotoxicity During Pregnancy.
    Jiaming Luo, Lei Zeng, Ji Li, Shiyuan Xu, Wei Zhao.
       OBJECTIVE: Severe neurologic complications after spinal anesthesia are rare but highly distressing, especially in pregnant women. Bupivacaine is widely used in spinal anesthesia, but its neurotoxic effects have gained attention.
    METHODS: Furthermore, the etiology of bupivacaine-mediated neurotoxicity in obstetric patients re- mains unclear. Female C57BL/6 mice were intrathecally injected with 0.75% bupivacaine on the 18th day of pregnancy. We used immunohistochemistry to examine DNA damage after bupivacaine treat- ment in pregnant mice and measured γ-H2AX (Ser139) and 8-OHdG in the spinal cord. A PARP-1 in- hibitor (PJ34) and autophagy inhibitor (3-MA) were administered with bupivacaine in pregnant mice. Parp-1flox/flox mice were crossed with Nes-Cre transgenic mice to obtain neuronal conditional knock- down mice. Then, LC3B and P62 staining were performed to evaluate autophagic flux in the spinal cords of pregnant wild-type (WT) and Parp-1-/- mice. We performed transmission electron microscopy (TEM) to evaluate autophagosomes.
    RESULTS: The present study showed that oxidative stress-mediated DNA damage and neuronal injury were increased after bupivacaine treatment in the spinal cords of pregnant mice. Moreover, PARP-1 was significantly activated, and autophagic flux was disrupted. Further studies revealed that PARP-1 knockdown and autophagy inhibitors could alleviate bupivacaine-mediated neurotoxicity in pregnant mice.
    CONCLUSION: Bupivacaine may cause neuronal DNA damage and PARP-1 activation in pregnant mice. PARP-1 further obstructed autophagic flux and ultimately led to neurotoxicity.
    Keywords:  Autophagy flux; PARP-1; bupivacaine; neuronal DNA damage.; neurotoxicity; pregnancy
    DOI:  https://doi.org/10.2174/1570159X21666230404102122
  44. Int J Neuropsychopharmacol. 2023 Apr 07. pii: pyad017. [Epub ahead of print]
    Activation of the mTORC1 signaling cascade in the hippocampus and medial prefrontal cortex is required for the antidepressant actions of vortioxetine in mice.
    Wei-Yu Li, Tian-Shun Shi, Jie Huang, Yan-Mei Chen, Wei Guan, Bo Jiang, Cheng-Niu Wang.
       BACKGROUND: Although thought as a multimodal-acting antidepressant targeting at the serotonin system, more and more other molecules are being reported to participate in the antidepressant mechanism of vortioxetine. A previous report has shown that vortioxetine administration enhanced the expression of rapamycin complex 1 (mTORC1) in neurons. It has been well demonstrated that mTORC1 participates in not only the pathogenesis of depression but also the pharmacological mechanisms of many antidepressants. Therefore, we speculate that the antidepressant mechanism of vortioxetine may require mTORC1.
    METHODS: Two mice models of depression (chronic social defeat stress and chronic unpredictable mild stress) and western blotting were first used together to examine whether vortioxetine administration produced reversal effects against the chronic stress-induced down-regulation in the whole mTORC1 signaling cascade in both the hippocampus and medial prefrontal cortex. Then, LY294002, U0126, and rapamycin were used together to explore whether the antidepressant effects of vortioxetine in mice models of depression were attenuated by pharmacological blockade of the mTORC1 system. Furthermore, LV-mTORC1-shRNA-EGFP was adopted to examine if genetic blockade of mTORC1 also abolished the antidepressant actions of vortioxetine in mice.
    RESULTS: Vortioxetine administration produced significant reversal effects against the chronic stress-induced down-regulation in the whole mTORC1 signaling cascade in both the hippocampus and medial prefrontal cortex. Both pharmacological and genetic blockade of the mTORC1 system notably attenuated the antidepressant effects of vortioxetine in mice.
    CONCLUSIONS: Activation of the mTORC1 system in the hippocampus and medial prefrontal cortex is required for the antidepressant actions of vortioxetine in mice.
    Keywords:  Chronic social defeat stress; Chronic unpredictable mild stress; Depression; Mammalian target of rapamycin complex 1; Vortioxetine
    DOI:  https://doi.org/10.1093/ijnp/pyad017
  45. Ageing Res Rev. 2023 Mar 31. pii: S1568-1637(23)00079-X. [Epub ahead of print]87 101920
    Control of mitochondria-associated endoplasmic reticulum membranes by protein S-palmitoylation: Novel therapeutic targets for neurodegenerative diseases.
    Qiangqiang He, Meiyu Qu, Tingyu Shen, Jiakun Su, Yana Xu, Chengyun Xu, Muhammad Qasim Barkat, Jibao Cai, Haibin Zhu, Ling-Hui Zeng, Ximei Wu.
      Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic coupling structures between mitochondria and the endoplasmic reticulum (ER). As a new subcellular structure, MAMs combine the two critical organelle functions. Mitochondria and the ER could regulate each other via MAMs. MAMs are involved in calcium (Ca2+) homeostasis, autophagy, ER stress, lipid metabolism, etc. Researchers have found that MAMs are closely related to metabolic syndrome and neurodegenerative diseases (NDs). The formation of MAMs and their functions depend on specific proteins. Numerous protein enrichments, such as the IP3R-Grp75-VDAC complex, constitute MAMs. The changes in these proteins govern the interaction between mitochondria and the ER; they also affect the biological functions of MAMs. S-palmitoylation is a reversible protein post-translational modification (PTM) that mainly occurs on protein cysteine residues. More and more studies have shown that the S-palmitoylation of proteins is closely related to their membrane localization. Here, we first briefly describe the composition and function of MAMs, reviewing the component and biological roles of MAMs mediated by S-palmitoylation, elaborating on S-palmitoylated proteins in Ca2+ flux, lipid rafts, and so on. We try to provide new insight into the molecular basis of MAMs-related diseases, mainly NDs. Finally, we propose potential drug compounds targeting S-palmitoylation.
    Keywords:  Ca(2+); Lipid rafts; MAMs; Neurodegenerative diseases; S-palmitoylation
    DOI:  https://doi.org/10.1016/j.arr.2023.101920
  46. Food Chem Toxicol. 2023 Apr 05. pii: S0278-6915(23)00164-3. [Epub ahead of print] 113762
    Mitophagy alleviates AIF-mediated spleen apoptosis induced by AlCl3 through Parkin stabilization in mice.
    Miao Song, Jian Zhang, Siming Huo, Xuliang Zhang, Yilong Cui, Yanfei Li.
      Aluminium (Al) accumulates in the spleen and causes spleen apoptosis. Mitochondrial dyshomeostasis represents primary mechanisms of spleen apoptosis induced by Al. Apoptosis-inducing factor (AIF) is located in the gap of the mitochondrial membrane and can be released into the nucleus, leading to apoptosis. Phosphatase and tensin homolog (PTEN)-induced putative kinase1 (PINK1)/E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy maintains mitochondrial homeostasis by removing damaged mitochondria, but its function in AIF-mediated spleen apoptosis induced by Al is not clear. In our study, aluminium trichloride (AlCl3) was diluted in water for 90 d and administered to 75 male C57BL/6N mice at 0, 44.8, 59.8, 89.7, and 179.3 mg/kg body weight. AlCl3 triggered PINK1/Parkin pathway-mediated mitophagy, induced AIF release and AIF-mediated spleen apoptosis. AlCl3 was administered to sixty male C57BL/6N mice of wild type and Parkin knockout for 90 d at 0 and 179.3 mg/kg body weight. The results indicated that Parkin deficiency decreased mitophagy, aggravated mitochondrial damage, AIF release and AIF-mediated spleen apoptosis induced by AlCl3. According to our results, PINK1/Parkin-mediated mitophagy and AIF-mediated spleen apoptosis are caused by AlCl3, whereas mitophagy is protective in AIF-mediated apoptosis induced by AlCl3.
    Keywords:  AIF; Aluminium trichloride; Apoptosis; Mitophagy; PINK1/Parkin; Spleen
    DOI:  https://doi.org/10.1016/j.fct.2023.113762
  47. Bioorg Med Chem. 2023 Mar 27. pii: S0968-0896(23)00110-4. [Epub ahead of print]84 117262
    An ATG4B inhibitor blocks autophagy and sensitizes Sorafenib inhibition activities in HCC tumor cells.
    Yanqiu Xie, Shijie Fan, Dongxuan Ni, Wei Wan, Pan Xu, Yiluan Ding, Ruihan Zhang, Jing Lu, Naixia Zhang, Yuanyuan Zhang, Weilie Xiao, Kehao Zhao, Cheng Luo.
      Autophagy related 4B (ATG4B) which regulates autophagy by promoting the formation of autophagosome through reversible modification of LC3, is closely related to cancer cell growth and drug resistance, and therefore is an attractive therapeutic target. Recently, ATG4B inhibitors have been reported, yet with drawbacks including weak potency. To discover more promising ATG4B inhibitors, we developed a high-throughput screening (HTS) assay and identified a new ATG4B inhibitor named DC-ATG4in. DC-ATG4in directly binds to ATG4B and inhibits its enzyme activity with an IC50 of 3.08 ± 0.47 μM. We further confirmed that DC-ATG4in is an autophagy inhibitor and blocks autophagy induced by Sorafenib in Hepatocellular Carcinoma (HCC) cells. More importantly, combination of DC-ATG4in with Sorafenib synergized the cancer cell killing effect and proliferation inhibition activities on HCC cells. Our data suggested that inactivation of autophagy via ATG4B inhibition may be a viable strategy to sensitize existing targeted therapy such as Sorafenib in the future.
    Keywords:  ATG4B inhibitor; Combination therapy; DC-ATG4in; Hepatocellular Carcinoma; Sorafenib
    DOI:  https://doi.org/10.1016/j.bmc.2023.117262
  48. J Am Soc Nephrol. 2023 Apr 05.
    Disruption of the Rab7-Dependent Final Common Pathway of Endosomal and Autophagic Processing Results in a Severe Podocytopathy.
    Kristin Vöing, Ulf Michgehl, Nils David Mertens, Cara Picciotto, Mee-Ling Maywald, Jonas Goretzko, Sofie Waimann, Kevin Gilhaus, Manuel Rogg, Christoph Schell, Jürgen Klingauf, Yaroslav Tsytsyura, Uwe Hansen, Veerle van Marck, Aimee L Edinger, Beate Vollenbröker, Ursula Rescher, Daniela Anne Braun, Britta George, Thomas Weide, Hermann Pavenstädt.
       BACKGROUND: Endocytosis, recycling, and degradation of proteins are essential functions of mammalian cells, especially for terminally differentiated cells with limited regeneration rates, such as podocytes. How disturbances within these trafficking pathways may act as factors in proteinuric glomerular diseases is poorly understood.
    METHODS: To explore how disturbances in trafficking pathways may act as factors in proteinuric glomerular diseases, we focused on Rab7, a highly conserved GTPase that controls the homeostasis of late endolysosomal and autophagic processes. We generated mouse and Drosophila in vivo models lacking Rab7 exclusively in podocytes or nephrocytes, and performed histologic and ultrastructural analyses. To further investigate Rab7 function on lysosomal and autophagic structures, we used immortalized human cell lines depleted for Rab.
    RESULTS: Depletion of Rab7 in mice, Drosophila, and immortalized human cell lines resulted in an accumulation of diverse vesicular structures resembling multivesicular bodies, autophagosomes, and autoendolysosomes. Mice lacking Rab7 developed a severe and lethal renal phenotype with early-onset proteinuria and global or focal segmental glomerulosclerosis, accompanied by an altered distribution of slit diaphragm proteins. Remarkably, structures resembling multivesicular bodies began forming within 2 weeks after birth, prior to the glomerular injuries. In Drosophila nephrocytes, rab7 knockdown resulted in the accumulation of vesicles and reduced slit diaphragms. In vitro, RAB7 knockout led to similar enlarged vesicles and altered lysosomal pH values, accompanied by an accumulation of lysosomal marker proteins.
    CONCLUSIONS: Disruption within the final common pathway of endocytic and autophagic processes may be a novel and insufficiently understood mechanism regulating podocyte health and disease.
    DOI:  https://doi.org/10.1681/ASN.0000000000000126
  49. FASEB J. 2023 05;37(5): e22863
    Acute, next-generation AMPK activation initiates a disease-resistant gene expression program in dystrophic skeletal muscle.
    Sean Y Ng, Andrew I Mikhail, Stephanie R Mattina, Alexander Manta, Ian J Diffey, Vladimir Ljubicic.
      Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disorder characterized by muscle weakness and wasting. Previous proof-of-concept studies demonstrate that the dystrophic phenotype can be mitigated with the pharmacological stimulation of AMP-activated protein kinase (AMPK). However, first-generation AMPK activators have failed to translate from bench to bedside due to either their lack of potency or toxic, off-target effects. The identification of safe and efficacious molecules that stimulate AMPK in dystrophic muscle is of particular importance as it may broaden the therapeutic landscape for DMD patients regardless of their specific dystrophin mutation. Here, we demonstrate that a single dose of the next generation, orally-bioactive AMPK agonist MK-8722 (MK) to mdx mice evoked skeletal muscle AMPK and extensive downstream stimulation within 12 h post-treatment. Specifically, MK elicited a gene expression profile indicative of a more disease-resistant slow, oxidative phenotype including increased peroxisome proliferator-activated receptor ɣ coactivator-1⍺ activity and utrophin levels. In addition, we observed augmented autophagy signaling downstream of AMPK, as well as elevations in critical autophagic genes such as Map1lc3 and Sqstm1 subsequent to the myonuclear accumulation of the master regulator of the autophagy gene program, transcription factor EB. Lastly, we show that pharmacological AMPK stimulation normalizes the expression of myogenic regulatory factors and amends activated muscle stem cell content in mdx muscle. Our results indicate that AMPK activation via MK enhances disease-mitigating mechanisms in dystrophic muscle and prefaces further investigation on the chronic effects of novel small molecule AMPK agonists.
    Keywords:  PGC-1α; autophagy; muscular dystrophy; myogenic regulatory factors; utrophin
    DOI:  https://doi.org/10.1096/fj.202201846RR
  50. J Biol Chem. 2023 Apr 05. pii: S0021-9258(23)00317-4. [Epub ahead of print] 104675
    The ubiquitin ligase HERC4 suppresses MafA transcriptional activity triggered by GSK3β in myeloma by atypical K63-linked polyubiquitination.
    Zubin Zhang, Mei Li, Peng Lin, Ying Ren, Yuanming He, Siyu Wang, Yujia Xu, Biyin Cao, Guanghui Wang, Michael F Moran, Xinliang Mao.
      MafA and c-Maf are close members of the Maf transcription factor family and indicators of poor prognosis of multiple myeloma (MM). Our previous study finds that the ubiquitin ligase HERC4 induces c-Maf degradation but stabilizes MafA, and the mechanism is elusive. In the present study we find that HERC4 interacts with MafA and mediates its K63-linked polyubiquitination at K33. Moreover, HERC4 inhibits MafA phosphorylation and its transcriptional activity triggered by glycogen synthase kinase 3β (GSK3β). The K33R MafA variant prevents HERC4 from inhibiting MafA phosphorylation and increases MafA transcriptional activity. Further analyses reveal that MafA can also activate the STAT3 signaling but it is suppressed by HERC4. Lastly, we demonstrate that lithium chloride, a GSK3β inhibitor, can upregulate HERC4 and synergizes dexamethasone, a typical anti-MM drug, in inhibiting MM cell proliferation and xenograft growth in nude mice. These findings thus highlight a novel regulation of MafA oncogenic activity in MM and provide the rationale by targeting HERC4/GSK3β/MafA for the treatment of MM.
    Keywords:  GSK3β; HERC4; K63-linked polyubiquitination; MafA; multiple myeloma
    DOI:  https://doi.org/10.1016/j.jbc.2023.104675
  51. Methods Mol Biol. 2023 ;2620 253-262
    Analyzing the Interaction of Arginylated Proteins and Nt-Arg-Mimicking Chemical Compounds to N-Recognins.
    Chang Hoon Ji, Min Ju Lee, Su Bin Kim, Yong Tae Kwon.
      Characterizing and measuring the interactome of N-degrons and N-recognins are critical to the identification and verification of putative N-terminally arginylated native proteins and small-molecule chemicals that structurally and physiologically mimic the N-terminal arginine residue. This chapter focuses on in vitro and in vivo assays to confirm the putative interaction, and measure the binding affinity, between Nt-Arg-carrying natural (or Nt-Arg-mimicking synthetic) ligands and proteasomal or autophagic N-recognins carrying the UBR box or the ZZ domain. These methods, reagents, and conditions are applicable across a wide spectrum of different cell lines, primary cultures, and/or animal tissues, allowing for the qualitative analysis and quantitative measurement of the interaction of arginylated proteins and N-terminal arginine-mimicking chemical compounds to their respective N-recognins.
    Keywords:  ATE1; Microscale thermophoresis (MST); Nt-arginine-mimicking chemical compound; Nt-arginylation; Pull-down assay
    DOI:  https://doi.org/10.1007/978-1-0716-2942-0_27
  52. Hepatology. 2023 Jan 03.
    Antagonizing apolipoprotein J chaperone promotes proteasomal degradation of mTOR and relieves hepatic lipid deposition.
    Shuangdi Duan, Nong Qin, Jiayi Pi, Pei Sun, Yating Gao, Lamei Liu, Zenghui Li, Ya Li, Liyang Shi, Qiang Gao, Ye Qiu, Songqing Tang, Chun-Hsiang Wang, Tzu-Ying Chen, Sin-Tian Wang, Kung-Chia Young, Hung-Yu Sun.
       BACKGROUND AND AIMS: Overnutrition-induced activation of mammalian target of rapamycin (mTOR) dysregulates intracellular lipid metabolism and contributes to hepatic lipid deposition. Apolipoprotein J (ApoJ) is a molecular chaperone and participates in pathogen-induced and nutrient-induced lipid accumulation. This study investigates the mechanism of ApoJ-regulated ubiquitin-proteasomal degradation of mTOR, and a proof-of-concept ApoJ antagonist peptide is proposed to relieve hepatic steatosis.
    APPROACH AND RESULTS: By using omics approaches, upregulation of ApoJ was found in high-fat medium-fed hepatocytes and livers of patients with NAFLD. Hepatic ApoJ level associated with the levels of mTOR and protein markers of autophagy and correlated positively with lipid contents in the liver of mice. Functionally, nonsecreted intracellular ApoJ bound to mTOR kinase domain and prevented mTOR ubiquitination by interfering FBW7 ubiquitin ligase interaction through its R324 residue. In vitro and in vivo gain-of-function or loss-of-function analysis further demonstrated that targeting ApoJ promotes proteasomal degradation of mTOR, restores lipophagy and lysosomal activity, thus prevents hepatic lipid deposition. Moreover, an antagonist peptide with a dissociation constant (Kd) of 2.54 µM interacted with stress-induced ApoJ and improved hepatic pathology, serum lipid and glucose homeostasis, and insulin sensitivity in mice with NAFLD or type II diabetes mellitus.
    CONCLUSIONS: ApoJ antagonist peptide might be a potential therapeutic against lipid-associated metabolic disorders through restoring mTOR and FBW7 interaction and facilitating ubiquitin-proteasomal degradation of mTOR.
    DOI:  https://doi.org/10.1097/HEP.0000000000000185
  53. Neurosci Lett. 2023 Apr 03. pii: S0304-3940(23)00180-5. [Epub ahead of print] 137223
    Tumor necrosis factor α-induced protein 3 mediates inflammation and neuronal autophagy in Parkinson's disease via the NFκB and mTOR pathways.
    Chi Ma, Xinya Wei, Fengjun Wang, Tianqi Zhang, Yuanming Jiang, Zhaojun Meng, Zhuobo Zhang.
      This study aimed to probe the function of tumor necrosis factor α-induced protein 3 (TNFAIP3) in the pathogenesis of Parkinson disease (PD) with its association with autophagy and inflammatory response. TNFAIP3 was reduced in the SN of PD patients (the GSE54282 dataset) and mice and in the MPP+-treated SK-N-SH cells. TNFAIP3 inhibited inflammatory response and enhanced autophagy, thereby alleviating PD in mice. NFκB and mTOR pathways were activated in the SN of PD mice and MPP+-treated cells. TNFAIP3 blocked the two pathways by preventing the p65 nuclear translocation and stabilizing DEPTOR, an endogenous inhibitor of mTOR. NFκB activator LPS and mTOR activator MHY1485 reversed the effects of TNFAIP3 on mitigation of injury in PD mice and in SK-N-SH cells induced with MPP+. Altogether, TNFAIP3 played a neuroprotective role in MPTP-induced mice by restricting NFκB and mTOR pathways.
    Keywords:  Autophagy; Inflammatory response; NFκB pathway; Parkinson’s disease; TNFAIP3; mTOR pathway
    DOI:  https://doi.org/10.1016/j.neulet.2023.137223
  54. J Med Chem. 2023 Apr 04.
    Discovery of the First Raptor (Regulatory-Associated Protein of mTOR) Inhibitor as a New Type of Antiadipogenic Agent.
    Xue-Long Yan, Yue-Hua Pan, Run-Zhu Fan, Qin-Qin Song, Shen Li, Jia-Luo Huang, Wei Li, Dong Huang, Fang-Yu Yuan, Gui-Hua Tang, Yong Rao, Zhi-Shu Huang, Sheng Yin.
      Raptor, a regulatory-associated protein of mTOR, has been genetically proved to be an important regulator in lipogenesis. However, its druggable potential is rarely investigated, largely due to the lack of an inhibitor. In this study, the antiadipogenic screening of a daphnane diterpenoid library followed by target fishing led to the identification of a Raptor inhibitor, 1c (5/7/6 carbon ring with orthoester and chlorine functionalities). Pharmacodynamic studies verified that 1c is a potent and tolerable antiadipogenic agent in vitro and in vivo. Mechanistic studies revealed that the targeting of Raptor by 1c could block the formation of mTORC1 and then downregulate the downstream S6K1- and 4E-BP1-mediated C/EBPs/PPARγ signaling, eventually retarding adipocyte cell differentiation at the early stage. These findings suggest that Raptor can be explored as a novel therapeutic target for obesity and its related complications, and 1c as the first Raptor inhibitor may provide a new therapeutic option for these conditions.
    DOI:  https://doi.org/10.1021/acs.jmedchem.3c00067
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