bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023‒02‒12
sixty papers selected by
Viktor Korolchuk, Newcastle University
  1. Mitochondrial cargo export in exosomes: Possible pathways and implication in disease biology.
  2. Chaperoning the Driver of Filovirus Egress to a Dead End.
  3. Effect of the Ketone Body, D-β-Hydroxybutyrate, on Sirtuin2-Mediated Regulation of Mitochondrial Quality Control and the Autophagy-Lysosomal Pathway.
  4. A selective type of autophagy to maintain glioma stem cell activity.
  5. Recent Update and Drug Target in Molecular and Pharmacological Insights into Autophagy Modulation in Cancer Treatment and Future Progress.
  6. Gemcitabine promotes autophagy and lysosomal function through ERK- and TFEB-dependent mechanisms.
  7. Autophagy as a Therapeutic Target for Chronic Kidney Disease and the Roles of TGF-β1 in Autophagy and Kidney Fibrosis.
  8. Excessive Protein Accumulation and Impaired Autophagy in the Hippocampus of Angelman Syndrome Modeled in Mice.
  9. Autophagy Requirements for Eye Lens Differentiation and Transparency.
  10. Chloroplast Envelopes Play a Role in the Formation of Autophagy-Related Structures in Plants.
  11. Current and potential roles of RNA modification-mediated autophagy dysregulation in cancer.
  12. Exploring the Complex Link between Autophagy, Regulated Cell Death, and Cell Fate Pathways in Cancer Pathogenesis and Therapy.
  13. Shuffled ATG8 interacting motifs form an ancestral bridge between UFMylation and autophagy.
  14. Rab7a-mTORC1 signaling-mediated cholesterol trafficking from the lysosome to mitochondria ameliorates hepatic lipotoxicity induced by aflatoxin B1 exposure.
  15. DNAJB12 and Hsp70 Mediate Triage of Misfolded Membrane Proteins for Proteasomal versus Lysosomal Degradation.
  16. To Kill or to Be Killed: How Does the Battle between the UPS and Autophagy Maintain the Intracellular Homeostasis in Eukaryotes?
  17. Role of ceramides and sphingolipidsin Parkinson's disease.
  18. Mitophagy is a novel protective mechanism for drug-tolerant persister (DTP) cancer cells.
  19. Sirtuins and their influence on autophagy.
  20. The role of LRRK2 in intracellular organelle dynamics.
  21. Targeting chaperone-mediated autophagy for Parkinson's disease therapy.
  22. Coronaviruses, Lysosomes, and Secondary Bacterial Infections: Coronaviruses Outsmart the Host.
  23. Natural compounds from botanical drugs targeting mTOR signaling pathway as promising therapeutics for atherosclerosis: A review.
  24. Perturbation of Autophagy by a Beclin 1-Targeting Stapled Peptide Induces Mitochondria Stress and Inhibits Proliferation of Pancreatic Cancer Cells.
  25. Molecular interplay between NOX1 and autophagy in cadmium-induced prostate carcinogenesis.
  26. Autotaxin (ATX) inhibits autophagy leading to exaggerated disruption of intestinal epithelial barrier in colitis.
  27. Autophagy: A challengeable paradox in cancer treatment.
  28. AlphaFold2-multimer guided high-accuracy prediction of typical and atypical ATG8-binding motifs.
  29. A small-molecule drug inhibits autophagy gene expression through the central regulator TFEB.
  30. Zebrafish maoc1 Attenuates Spring Viremia of Carp Virus Propagation by Promoting Autophagy-Lysosome-Dependent Degradation of Viral Phosphoprotein.
  31. Snf1/AMPK fine-tunes TORC1 signaling in response to glucose starvation.
  32. Pexophagy in plants: a mechanism to remit cells from oxidative damage caused under high-intensity light.
  33. Targeting and regulation of autophagy in hepatocellular carcinoma: revisiting the molecular interactions and mechanisms for new therapy approaches.
  34. Mitochondrial-Derived Vesicles-Link to Extracellular Vesicles and Implications in Cardiovascular Disease.
  35. Liver specific disruption of Glutaredoxin 3 leads to iron accumulation and impaired cellular iron homeostasis.
  36. PARP1 promotes NLRP3 activation via blocking TFEB-mediated autophagy in rotenone-induced neurodegeneration.
  37. Lysosomal dysfunction in diabetic cardiomyopathy.
  38. Baicalin mitigated IL-1β-Induced osteoarthritis chondrocytes damage through activating mitophagy.
  39. The Ubiquitin Proteasome System as a Therapeutic Area in Parkinson's Disease.
  40. Stromal Interaction Molecule 1-Mediated Store-Operated Calcium Entry Promotes Autophagy Through AKT/Mammalian Target of Rapamycin Pathway in Hippocampal Neurons After Ischemic Stroke.
  41. Lysosomes as a Target of Anticancer Therapy.
  42. P38 Mediates Tumor Suppression through Reduced Autophagy and Actin Cytoskeleton Changes in NRAS-Mutant Melanoma.
  43. Acid ceramidase involved in pathogenic cascade leading to accumulation of α-synuclein in iPSC model of GBA1-associated Parkinson's disease.
  44. G-quadruplex ligands as potent regulators of lysosomes.
  45. Proteotoxic stress-induced autophagy is regulated by the NRF2 pathway via extracellular vesicles.
  46. Physiological Roles of Hippo Signaling Pathway and Autophagy in Dementia.
  47. Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis.
  48. Xanthohumol alleviates oxidative stress and impaired autophagy in experimental severe acute pancreatitis through inhibition of AKT/mTOR.
  49. Myristic acid as a checkpoint to regulate STING-dependent autophagy and interferon responses by promoting N-myristoylation.
  50. Autophagy Meets Aging: An Overview.
  51. RRP Regulates Autophagy through the AMPK Pathway to Alleviate the Effect of Cell Senescence on Atherosclerosis.
  52. Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress.
  53. The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.
  54. RhoA rescues cardiac senescence by regulating Parkin-mediated mitophagy.
  55. Neurovascular development in Pten and Tsc2 mouse mutants.
  56. Inhibition of Klf10 Attenuates Oxidative Stress-Induced Senescence of Chondrocytes via Modulating Mitophagy.
  57. Axonal transport of autophagosomes is regulated by dynein activators JIP3/JIP4 and ARF/RAB GTPases.
  58. Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex.
  59. PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products.
  60. Autophagy-dependent ferroptosis in kidney disease.
  1. J Cell Physiol. 2023 Feb 06.
    Mitochondrial cargo export in exosomes: Possible pathways and implication in disease biology.
    Aman Sharma.
      Exosome biogenesis occurs parallel to multiple endocytic traffic routes. These coexisting routes drive cargo loading in exosomes via overlapping of exosome biogenesis with endosomal pathways. One such pathway is autophagy which captures damaged intracellular organelles or their components in an autophagosome vesicle and route them for lysosomal degradation. However, in case of a noncanonical fusion event between autophagosome and maturing multivesicular body (MVB)-a site for exosome biogenesis, the autophagic cargo is putatively loaded in exosomes and subsequent released out of the cell via formation of an "amphisome" like structure. Similarly, during "mitophagy" or mitochondrial (mt) autophagy, amphisome formation routes mitophagy cargo to exosomes. These mt-cargo enriched exosomes or mt-enREXO are often positive for LC3 protein-an autophagic flux marker, and potent regulators of paracrine signaling with both homeostatic and pathological roles. Here, I review this emerging concept and discuss how intracellular autophagic routes helps in generation of mt-enREXO and utility of these vesicles in paracrine cellular signaling and diagnostic areas.
    Keywords:  cancer; exosomes; heart disease; mitochondria cargo
    DOI:  https://doi.org/10.1002/jcp.30967
  2. Autophagy. 2023 Feb 10.
    Chaperoning the Driver of Filovirus Egress to a Dead End.
    Jingjing Liang, Marija A Djurkovic, Olena Shtanko, Ronald N Harty.
      Ebola virus (EBOV) and Marburg virus (MARV) are zoonotic, virulent pathogens that cause sporadic and global outbreaks of severe hemorrhagic fever. Re-emergence of these filoviruses remains a global public health threat, highlighting the need for novel countermeasures to control and treat future disease outbreaks. The EBOV VP40 matrix protein drives virion assembly and egress. We recently reported that BAG3 and HSPA/HSP70, two central components of chaperone-assisted selective autophagy (CASA), target VP40 for autophagic sequestration and degradation, thereby inhibiting virus egress and spread. In addition, we found that expression of the EBOV glycoprotein (GP) activates MTORC1, the gateway regulator of autophagy. Notably, pharmacological suppression of MTORC1 signaling by rapamycin activates autophagy and blocks filovirus egress. These findings highlight the MTORC1-CASA axis as a regulator of filovirus egress and suggest new opportunities for antiviral development and intervention.
    Keywords:  BAG3; Ebola virus; HSP70; MTORC1; VP40; chaperone-assisted selective autophagy; filovirus
    DOI:  https://doi.org/10.1080/15548627.2023.2178781
  3. Cells. 2023 Feb 02. pii: 486. [Epub ahead of print]12(3):
    Effect of the Ketone Body, D-β-Hydroxybutyrate, on Sirtuin2-Mediated Regulation of Mitochondrial Quality Control and the Autophagy-Lysosomal Pathway.
    Juan Carlos Gómora-García, Teresa Montiel, Melanie Hüttenrauch, Ashley Salcido-Gómez, Lizbeth García-Velázquez, Yazmin Ramiro-Cortés, Juan Carlos Gomora, Susana Castro-Obregón, Lourdes Massieu.
      Mitochondrial activity and quality control are essential for neuronal homeostasis as neurons rely on glucose oxidative metabolism. The ketone body, D-β-hydroxybutyrate (D-BHB), is metabolized to acetyl-CoA in brain mitochondria and used as an energy fuel alternative to glucose. We have previously reported that D-BHB sustains ATP production and stimulates the autophagic flux under glucose deprivation in neurons; however, the effects of D-BHB on mitochondrial turnover under physiological conditions are still unknown. Sirtuins (SIRTs) are NAD+-activated protein deacetylases involved in the regulation of mitochondrial biogenesis and mitophagy through the activation of transcription factors FOXO1, FOXO3a, TFEB and PGC1α coactivator. Here, we aimed to investigate the effect of D-BHB on mitochondrial turnover in cultured neurons and the mechanisms involved. Results show that D-BHB increased mitochondrial membrane potential and regulated the NAD+/NADH ratio. D-BHB enhanced FOXO1, FOXO3a and PGC1α nuclear levels in an SIRT2-dependent manner and stimulated autophagy, mitophagy and mitochondrial biogenesis. These effects increased neuronal resistance to energy stress. D-BHB also stimulated the autophagic-lysosomal pathway through AMPK activation and TFEB-mediated lysosomal biogenesis. Upregulation of SIRT2, FOXOs, PGC1α and TFEB was confirmed in the brain of ketogenic diet (KD)-treated mice. Altogether, the results identify SIRT2, for the first time, as a target of D-BHB in neurons, which is involved in the regulation of autophagy/mitophagy and mitochondrial quality control.
    Keywords:  autophagy; ketone bodies; lysosomal biogenesis; mitophagy; sirtuin2
    DOI:  https://doi.org/10.3390/cells12030486
  4. Stem Cell Investig. 2023 ;10 1
    A selective type of autophagy to maintain glioma stem cell activity.
    Khushbu Patel, Esperanza Arias.
      
    Keywords:  Chaperone-mediated autophagy (CMA); glioblastoma; proteostasis; stem cell
    DOI:  https://doi.org/10.21037/sci-2022-047
  5. Cells. 2023 Jan 31. pii: 458. [Epub ahead of print]12(3):
    Recent Update and Drug Target in Molecular and Pharmacological Insights into Autophagy Modulation in Cancer Treatment and Future Progress.
    Md Ataur Rahman, Abu Saim Mohammad Saikat, Md Saidur Rahman, Mobinul Islam, Md Anowar Khasru Parvez, Bonglee Kim.
      Recent evidence suggests that autophagy is a governed catabolic framework enabling the recycling of nutrients from injured organelles and other cellular constituents via a lysosomal breakdown. This mechanism has been associated with the development of various pathologic conditions, including cancer and neurological disorders; however, recently updated studies have indicated that autophagy plays a dual role in cancer, acting as a cytoprotective or cytotoxic mechanism. Numerous preclinical and clinical investigations have shown that inhibiting autophagy enhances an anticancer medicine's effectiveness in various malignancies. Autophagy antagonists, including chloroquine and hydroxychloroquine, have previously been authorized in clinical trials, encouraging the development of medication-combination therapies targeting the autophagic processes for cancer. In this review, we provide an update on the recent research examining the anticancer efficacy of combining drugs that activate cytoprotective autophagy with autophagy inhibitors. Additionally, we highlight the difficulties and progress toward using cytoprotective autophagy targeting as a cancer treatment strategy. Importantly, we must enable the use of suitable autophagy inhibitors and coadministration delivery systems in conjunction with anticancer agents. Therefore, this review briefly summarizes the general molecular process behind autophagy and its bifunctional role that is important in cancer suppression and in encouraging tumor growth and resistance to chemotherapy and metastasis regulation. We then emphasize how autophagy and cancer cells interacting with one another is a promising therapeutic target in cancer treatment.
    Keywords:  autophagic cell death; autophagy; autophagy activators; autophagy inhibitors; cancer
    DOI:  https://doi.org/10.3390/cells12030458
  6. Cell Death Discov. 2023 Feb 06. 9(1): 45
    Gemcitabine promotes autophagy and lysosomal function through ERK- and TFEB-dependent mechanisms.
    Benoît Marchand, Marc-Antoine Poulin, Christine Lawson, Lee-Hwa Tai, Steve Jean, Marie-Josée Boucher.
      Gemcitabine is a first-line treatment agent for pancreatic ductal adenocarcinoma (PDAC). Contributing to its cytotoxicity, this chemotherapeutic agent is primarily a DNA replication inhibitor that also induces DNA damage. However, its therapeutic effects are limited owing to chemoresistance. Evidence in the literature points to a role for autophagy in restricting the efficacy of gemcitabine. Autophagy is a catabolic process in which intracellular components are delivered to degradative organelles lysosomes. Interfering with this process sensitizes PDAC cells to gemcitabine. It is consequently inferred that autophagy and lysosomal function need to be tightly regulated to maintain homeostasis and provide resistance to environmental stress, such as those imposed by chemotherapeutic drugs. However, the mechanism(s) through which gemcitabine promotes autophagy remains elusive, and the impact of gemcitabine on lysosomal function remains largely unexplored. Therefore, we applied complementary approaches to define the mechanisms triggered by gemcitabine that support autophagy and lysosome function. We found that gemcitabine elicited ERK-dependent autophagy in PDAC cells, but did not stimulate ERK activity or autophagy in non-tumoral human pancreatic epithelial cells. Gemcitabine also promoted transcription factor EB (TFEB)-dependent lysosomal function in PDAC cells. Indeed, treating PDAC cells with gemcitabine caused expansion of the lysosomal network, as revealed by Lysosome associated membrane protein-1 (LAMP1) and LysoTracker staining. More specific approaches have shown that gemcitabine promotes the activity of cathepsin B (CTSB), a cysteine protease playing an active role in lysosomal degradation. We showed that lysosomal function induced by gemcitabine depends on TFEB, the master regulator of autophagy and lysosomal biogenesis. Interfering with TFEB function considerably limited the clonogenic growth of PDAC cells and hindered the capacity of TFEB-depleted PDAC cells to develop orthotopic tumors.
    DOI:  https://doi.org/10.1038/s41420-023-01342-z
  7. Cells. 2023 Jan 26. pii: 412. [Epub ahead of print]12(3):
    Autophagy as a Therapeutic Target for Chronic Kidney Disease and the Roles of TGF-β1 in Autophagy and Kidney Fibrosis.
    Miss Ruby, Cody C Gifford, RamendraPati Pandey, V Samuel Raj, Venkata S Sabbisetti, Amrendra K Ajay.
      Autophagy is a lysosomal protein degradation system that eliminates cytoplasmic components such as protein aggregates, damaged organelles, and even invading pathogens. Autophagy is an evolutionarily conserved homoeostatic strategy for cell survival in stressful conditions and has been linked to a variety of biological processes and disorders. It is vital for the homeostasis and survival of renal cells such as podocytes and tubular epithelial cells, as well as immune cells in the healthy kidney. Autophagy activation protects renal cells under stressed conditions, whereas autophagy deficiency increases the vulnerability of the kidney to injury, resulting in several aberrant processes that ultimately lead to renal failure. Renal fibrosis is a condition that, if chronic, will progress to end-stage kidney disease, which at this point is incurable. Chronic Kidney Disease (CKD) is linked to significant alterations in cell signaling such as the activation of the pleiotropic cytokine transforming growth factor-β1 (TGF-β1). While the expression of TGF-β1 can promote fibrogenesis, it can also activate autophagy, which suppresses renal tubulointerstitial fibrosis. Autophagy has a complex variety of impacts depending on the context, cell types, and pathological circumstances, and can be profibrotic or antifibrotic. Induction of autophagy in tubular cells, particularly in the proximal tubular epithelial cells (PTECs) protects cells against stresses such as proteinuria-induced apoptosis and ischemia-induced acute kidney injury (AKI), whereas the loss of autophagy in renal cells scores a significant increase in sensitivity to several renal diseases. In this review, we discuss new findings that emphasize the various functions of TGF-β1 in producing not just renal fibrosis but also the beneficial TGF-β1 signaling mechanisms in autophagy.
    Keywords:  ATG; TGF-β1; autophagy; chronic kidney disease; mTOR; proximal tubular epithelial cells
    DOI:  https://doi.org/10.3390/cells12030412
  8. Biol Psychiatry. 2022 Dec 05. pii: S0006-3223(22)01796-6. [Epub ahead of print]
    Excessive Protein Accumulation and Impaired Autophagy in the Hippocampus of Angelman Syndrome Modeled in Mice.
    Francesca Aria, Kiran Pandey, Cristina M Alberini.
      BACKGROUND: Angelman syndrome (AS), a neurodevelopmental disorder caused by abnormalities of the 15q11.2-q13.1 chromosome region, is characterized by impairment of cognitive and motor functions, sleep problems, and seizures. How the genetic defects of AS produce these neurological symptoms is unclear. Mice modeling AS (AS mice) accumulate activity-regulated cytoskeleton-associated protein (ARC/ARG3.1), a neuronal immediate early gene (IEG) critical for synaptic plasticity. This accumulation suggests an altered protein metabolism.METHODS: Focusing on the dorsal hippocampus (dHC), a brain region critical for memory formation and cognitive functions, we assessed levels and tissue distribution of IEGs, de novo protein synthesis, and markers of protein synthesis, endosomes, autophagy, and synaptic functions in AS mice at baseline and following learning. We also tested autophagic flux and memory retention following autophagy-promoting treatment.
    RESULTS: AS dHC exhibited accumulation of IEGs ARC, FOS, and EGR1; autophagy proteins MLP3B, SQSTM1, and LAMP1; and reduction of the endosomal protein RAB5A. AS dHC also had increased levels of de novo protein synthesis, impaired autophagic flux with accumulation of autophagosome, and altered synaptic protein levels. Contextual fear conditioning significantly increased levels of IEGs and autophagy proteins, de novo protein synthesis, and autophagic flux in the dHC of normal mice, but not in AS mice. Enhancing autophagy in the dHC alleviated AS-related memory and autophagic flux impairments.
    CONCLUSIONS: A major biological deficit of AS brain is a defective protein metabolism, particularly that dynamically regulated by learning, resulting in stalled autophagy and accumulation of neuronal proteins. Activating autophagy ameliorates AS cognitive impairments and dHC protein accumulation.
    Keywords:  Angelman syndrome; Autophagy; Hippocampus; Immediate early genes; Mouse; Protein synthesis
    DOI:  https://doi.org/10.1016/j.biopsych.2022.11.016
  9. Cells. 2023 Feb 01. pii: 475. [Epub ahead of print]12(3):
    Autophagy Requirements for Eye Lens Differentiation and Transparency.
    Lisa Brennan, M Joseph Costello, J Fielding Hejtmancik, A Sue Menko, S Amer Riazuddin, Alan Shiels, Marc Kantorow.
      Recent evidence points to autophagy as an essential cellular requirement for achieving the mature structure, homeostasis, and transparency of the lens. Collective evidence from multiple laboratories using chick, mouse, primate, and human model systems provides evidence that classic autophagy structures, ranging from double-membrane autophagosomes to single-membrane autolysosomes, are found throughout the lens in both undifferentiated lens epithelial cells and maturing lens fiber cells. Recently, key autophagy signaling pathways have been identified to initiate critical steps in the lens differentiation program, including the elimination of organelles to form the core lens organelle-free zone. Other recent studies using ex vivo lens culture demonstrate that the low oxygen environment of the lens drives HIF1a-induced autophagy via upregulation of essential mitophagy components to direct the specific elimination of the mitochondria, endoplasmic reticulum, and Golgi apparatus during lens fiber cell differentiation. Pioneering studies on the structural requirements for the elimination of nuclei during lens differentiation reveal the presence of an entirely novel structure associated with degrading lens nuclei termed the nuclear excisosome. Considerable evidence also indicates that autophagy is a requirement for lens homeostasis, differentiation, and transparency, since the mutation of key autophagy proteins results in human cataract formation.
    Keywords:  autophagy; cataract; differentiation; lens
    DOI:  https://doi.org/10.3390/cells12030475
  10. Plants (Basel). 2023 Jan 18. pii: 443. [Epub ahead of print]12(3):
    Chloroplast Envelopes Play a Role in the Formation of Autophagy-Related Structures in Plants.
    Makoto Yanagisawa, Simon D X Chuong.
      Autophagy is a degradation process of cytoplasmic components that is conserved in eukaryotes. One of the hallmark features of autophagy is the formation of double-membrane structures known as autophagosomes, which enclose cytoplasmic content destined for degradation. Although the membrane source for the formation of autophagosomes remains to be determined, recent studies indicate the involvement of various organelles in autophagosome biogenesis. In this study, we examined the autophagy process in Bienertia sinuspersici: one of four terrestrial plants capable of performing C4 photosynthesis in a single cell (single-cell C4 species). We demonstrated that narrow tubules (stromule-like structures) 30-50 nm in diameter appear to extend from chloroplasts to form the membrane-bound structures (autophagosomes or autophagy-related structures) in chlorenchyma cells of B. sinuspersici during senescence and under oxidative stress. Immunoelectron microscopic analysis revealed the localization of stromal proteins to the stromule-like structures, sequestering portions of the cytoplasm in chlorenchyma cells of oxidative stress-treated leaves of B. sinuspersici and Arabidopsis thaliana. Moreover, the fluorescent marker for autophagosomes GFP-ATG8, colocalized with the autophagic vacuole maker neutral red in punctate structures in close proximity to the chloroplasts of cells under oxidative stress conditions. Together our results implicate a role for chloroplast envelopes in the autophagy process induced during senescence or under certain stress conditions in plants.
    Keywords:  autophagic vacuole; autophagosome; autophagy; chloroplast envelopes; stromules
    DOI:  https://doi.org/10.3390/plants12030443
  11. Arch Biochem Biophys. 2023 Feb 07. pii: S0003-9861(23)00041-3. [Epub ahead of print]736 109542
    Current and potential roles of RNA modification-mediated autophagy dysregulation in cancer.
    Hua Huang, Ruining Pan, Sijia Wang, Yifei Guan, Yue Zhao, Xinhui Liu.
      Autophagy, a cellular lysosomal degradation and survival pathway, supports nutrient recycling and adaptation to metabolic stress and participates in various stages of tumor development, including tumorigenesis, metastasis, and malignant state maintenance. Among the various factors contributing to the dysregulation of autophagy in cancer, RNA modification can regulate autophagy by directly affecting the expression of core autophagy proteins. We propose that autophagy disorder mediated by RNA modification is an important mechanism for cancer development. Therefore, this review mainly discusses the role of RNA modification-mediated autophagy regulation in tumorigenesis. We summarize the molecular basis of autophagy and the core proteins and complexes at different stages of autophagy, especially those involved in cancer development. Moreover, we describe the crosstalk of RNA modification and autophagy and review the recent advances and potential role of the RNA modification/autophagy axis in the development of multiple cancers. Furthermore, the dual role of the RNA modification/autophagy axis in cancer drug resistance is discussed. A comprehensive understanding and extensive exploration of the molecular crosstalk of RNA modifications with autophagy will provide important insights into tumor pathophysiology and provide more options for cancer therapeutic strategies.
    Keywords:  Anticancer drug resistance; Autophagy; Cancer; RNA modification; m(6)A
    DOI:  https://doi.org/10.1016/j.abb.2023.109542
  12. Cells. 2023 Feb 03. pii: 498. [Epub ahead of print]12(3):
    Exploring the Complex Link between Autophagy, Regulated Cell Death, and Cell Fate Pathways in Cancer Pathogenesis and Therapy.
    Mohammad Amin Moosavi, Mojgan Djavaheri-Mergny.
      Autophagy is a catabolic lysosomal-dependent pathway involved in the degradation of cellular materials, supplying precursor compounds and energy for macromolecule synthesis and metabolic needs [...].
    DOI:  https://doi.org/10.3390/cells12030498
  13. EMBO J. 2023 Feb 10. e112053
    Shuffled ATG8 interacting motifs form an ancestral bridge between UFMylation and autophagy.
    Lorenzo Picchianti, Víctor Sánchez de Medina Hernández, Ni Zhan, Nicholas At Irwin, Roan Groh, Madlen Stephani, Harald Hornegger, Rebecca Beveridge, Justyna Sawa-Makarska, Thomas Lendl, Nenad Grujic, Christin Naumann, Sascha Martens, Thomas A Richards, Tim Clausen, Silvia Ramundo, G Elif Karagöz, Yasin Dagdas.
      UFMylation involves the covalent modification of substrate proteins with UFM1 (Ubiquitin-fold modifier 1) and is important for maintaining ER homeostasis. Stalled translation triggers the UFMylation of ER-bound ribosomes and activates C53-mediated autophagy to clear toxic polypeptides. C53 contains noncanonical shuffled ATG8-interacting motifs (sAIMs) that are essential for ATG8 interaction and autophagy initiation. However, the mechanistic basis of sAIM-mediated ATG8 interaction remains unknown. Here, we show that C53 and sAIMs are conserved across eukaryotes but secondarily lost in fungi and various algal lineages. Biochemical assays showed that the unicellular alga Chlamydomonas reinhardtii has a functional UFMylation pathway, refuting the assumption that UFMylation is linked to multicellularity. Comparative structural analyses revealed that both UFM1 and ATG8 bind sAIMs in C53, but in a distinct way. Conversion of sAIMs into canonical AIMs impaired binding of C53 to UFM1, while strengthening ATG8 binding. Increased ATG8 binding led to the autoactivation of the C53 pathway and sensitization of Arabidopsis thaliana to ER stress. Altogether, our findings reveal an ancestral role of sAIMs in UFMylation-dependent fine-tuning of C53-mediated autophagy activation.
    Keywords:  ER-phagy; UFMylation; phylogenomics; ribosome stalling; selective autophagy
    DOI:  https://doi.org/10.15252/embj.2022112053
  14. Chemosphere. 2023 Feb 06. pii: S0045-6535(23)00338-7. [Epub ahead of print] 138071
    Rab7a-mTORC1 signaling-mediated cholesterol trafficking from the lysosome to mitochondria ameliorates hepatic lipotoxicity induced by aflatoxin B1 exposure.
    Jin-Xian Lin, Chi-Yu Xu, Xin-Mou Wu, Lin Che, Ting-Yu Li, Su-Min Mo, Dong-Bei Guo, Zhong-Ning Lin, Yu-Chun Lin.
      Aflatoxin B1 (AFB1) is a common contaminant in many foodstuffs and is considered a public health concern worldwide due to its hepatotoxicity caused by lipid metabolism disorders. However, the molecular mechanism underlying AFB1-induced lipotoxicity-dependent liver injury via regulating cholesterol metabolism remains unclear. We established a cholesterol trafficking disorder-mediated hepatic lipotoxicity model with AFB1 mixture exposure in vitro (HepaRG and HepG2 cells, 1.6 μM for 36 h) and in vivo (C57BL/6 mice, 3 mg kg-1, i.g., every other day for 6 weeks). In vitro, the interaction between lysosomal Niemann-Pick type C1 (NPC1) protein and mitochondrial translocator protein (TSPO) regulated lipotoxicity induced by AFB1 mixture exposure, including lysosomal membrane permeabilization and mitochondria-dependent necroptosis. Moreover, the downregulation of lysosomal Ras-associated protein 7a (Rab7a) enhanced the mammalian target of rapamycin complex 1 (mTORC1)-mediated disorders of cholesterol trafficking from the lysosome to mitochondria. Furthermore, cholesterol trafficking disorder-mediated hepatic lipotoxicity induced by the low-dose level of AFB1 exposure was relieved by genetic or pharmaceutic activation of Rab7a to inhibit mTORC1 in vitro and ex vivo. In vivo, mTORC1 inhibitor (Torin1, 4 mg kg-1, i.p., every other day for 3 weeks) alleviated the cholesterol trafficking disorder-mediated hepatic lipotoxicity via upregulating the molecular machinery of lysosomes and mitochondria contacts mediated by NPC1 and TSPO interaction in the low dose of AFB1 exposure. Altogether, our data suggested a novel mechanism that lysosomal Rab7a-mTORC1 signaling determines the cholesterol trafficking regulated by NPC1-TSPO from the lysosome to mitochondria, which promotes hepatic lipotoxicity via lysosomal quality control and mitochondria-dependent necroptosis signaling pathways in chemical mixture exposure.
    Keywords:  Aflatoxin B1 (AFB1); Cholesterol trafficking; Hepatic lipotoxicity; Lysosomes and mitochondria contacts; Mammalian target of rapamycin complex 1 (mTORC1); Ras-associated protein 7a (Rab7a)
    DOI:  https://doi.org/10.1016/j.chemosphere.2023.138071
  15. Autophagy Rep. 2022 ;1(1): 559-562
    DNAJB12 and Hsp70 Mediate Triage of Misfolded Membrane Proteins for Proteasomal versus Lysosomal Degradation.
    Andrew Kennedy, Douglas M Cyr.
      The endoplasmic reticulum (ER) fills the cell with a continuous network of sealed membrane tubules and sheets. The ER is subdivided into microdomains mediating one-third of total protein biosynthesis, oxidative protein folding, secretion, protein quality control, calcium signaling, marcoautophagy/autophagy, stress sensing, and apoptosis. Defects in ER-calcium homeostasis underlie several diseases. Damage to the ER by misfolded membrane proteins is suppressed by specific HSPA/Hsp70 and DNAJ/Hsp40 chaperone pairs that select intermediates for ubiquitination and ER-associated degradation (ERAD) via the proteasome. The ER-transmembrane Hsp40 chaperone DNAJB12 and HSPA/Hsp70 also target toxic intermediates of misfolded membrane proteins for ER-associated autophagy (ERAA). DNAJB12-HSPA/Hsp70 maintain membrane protein degradation intermediates in detergent-soluble and degradation-competent states. DNAJB12-HSPA/Hsp70 also interact with the autophagy initiation kinase ULK1 on ER tubules containing ERAD-resistant misfolded membrane proteins (ERAD-RMPs). Omegasomes are ER microdomains where the autophagosome precursor or phagophore (PG) forms. ER tubules loaded with ERAD-RMPs enter omegasomes where they are converted into ER-connected PG (ER-PG). The Atg8 (autophagy related 8)-family member GABARAP (GABA type A receptor-associated protein) facilitates transfer of ERAD-RMPs from ER-PGs to autolysosomes (AL) that dock transiently with omegasomes. This article describes a model for DNAJB12-HSPA/Hsp70 action during the conformation-dependent triage in the ER of misfolded membrane proteins for folding versus proteasomal or AL degradation.
    DOI:  https://doi.org/10.1080/27694127.2022.2139335
  16. Int J Mol Sci. 2023 Jan 22. pii: 2221. [Epub ahead of print]24(3):
    To Kill or to Be Killed: How Does the Battle between the UPS and Autophagy Maintain the Intracellular Homeostasis in Eukaryotes?
    Peifeng Yu, Zhihua Hua.
      The ubiquitin-26S proteasome system and autophagy are two major protein degradation machineries encoded in all eukaryotic organisms. While the UPS is responsible for the turnover of short-lived and/or soluble misfolded proteins under normal growth conditions, the autophagy-lysosomal/vacuolar protein degradation machinery is activated under stress conditions to remove long-lived proteins in the forms of aggregates, either soluble or insoluble, in the cytoplasm and damaged organelles. Recent discoveries suggested an integrative function of these two seemly independent systems for maintaining the proteome homeostasis. One such integration is represented by their reciprocal degradation, in which the small 76-amino acid peptide, ubiquitin, plays an important role as the central signaling hub. In this review, we summarized the current knowledge about the activity control of proteasome and autophagosome at their structural organization, biophysical states, and turnover levels from yeast and mammals to plants. Through comprehensive literature studies, we presented puzzling questions that are awaiting to be solved and proposed exciting new research directions that may shed light on the molecular mechanisms underlying the biological function of protein degradation.
    Keywords:  autophagy; biophysical state; development; liquid–liquid phase separation; proteasome; protein degradation; stress; ubiquitin; ubiquitylation
    DOI:  https://doi.org/10.3390/ijms24032221
  17. J Mol Biol. 2023 Feb 08. pii: S0022-2836(23)00056-6. [Epub ahead of print] 168000
    Role of ceramides and sphingolipidsin Parkinson's disease.
    Melissa Vos, Christine Klein, Andrew A Hicks.
      Sphingolipids, including the basic ceramide, are a subset of bioactive lipids that consist of many different species. Sphingolipids are indispensable for proper neuronal function, and an increasing number of studies have emerged on the complexity and importance of these lipids in (almost) all biological processes. These include regulation of mitochondrial function, autophagy, and endosomal trafficking, which are affected in Parkinson's disease (PD). PD is the second most common neurodegenerative disorder and is characterized by the loss of dopaminergic neurons. Currently, PD cannot be cured due to the lack of knowledge of the exact pathogenesis. Nonetheless, important advances have identified molecular changes in mitochondrial function, autophagy, and endosomal function. Furthermore, recent studies have identified ceramide alterations in patients suffering from PD, and in PD models, suggesting a critical interaction between sphingolipids and related cellular processes in PD. For instance, autosomal recessive forms of PD cause mitochondrial dysfunction, including energy production or mitochondrial clearance, that is directly influenced by manipulating sphingolipids. Additionally, endo-lysosomal recycling is affected by genes that cause autosomal dominant forms of the disease, such as VPS35 and SNCA. Furthermore, endo-lysosomal recycling is crucial for transporting sphingolipids to different cellular compartments where they will execute their functions. This review will discuss mitochondrial dysfunction, defects in autophagy, and abnormal endosomal activity in PD and the role sphingolipids play in these vital molecular processes.
    Keywords:  Parkinson’s disease; Sphingolipids; autophagy; ceramide; endosome; mitochondria
    DOI:  https://doi.org/10.1016/j.jmb.2023.168000
  18. Autophagy. 2023 Feb 06.
    Mitophagy is a novel protective mechanism for drug-tolerant persister (DTP) cancer cells.
    Yun Li, Hengxing Chen, Daning Lu, H Phillip Koeffler, Yin Zhang, Dong Yin.
      Drug-tolerant persister (DTP) cancer cells drive residual tumor and relapse. However, the mechanisms underlying DTP state development are largely unexplored. In a recent study, we determined that PINK1-mediated mitophagy favors DTP generation in the context of MAPK inhibition therapy. DTP cells that persist in the presence of a MAPK inhibitor exhibit mitochondria-dependent metabolism. During DTP state development, MYC depletion alleviates the transcriptional repression of PINK1, resulting in PINK1 upregulation and mitophagy activation. PINK1-mediated mitophagy is essential for mitochondrial homeostasis in DTP cells. Either knockdown of PINK1 or mitophagy inhibition eradicates DTP cells and achieves complete responses to MAPK inhibition therapy. This study reveals a novel role of mitophagy as a protective mechanism for DTP development.
    Keywords:  Drug-tolerant persister; MAPK inhibitor; PINK1; mitophagy; quiescent cancer cells
    DOI:  https://doi.org/10.1080/15548627.2023.2177398
  19. J Cell Biochem. 2023 Feb 06.
    Sirtuins and their influence on autophagy.
    Marius W Baeken.
      Sirtuins and autophagy are well-characterized agents that can promote longevity and protect individual organisms from age-associated diseases like neurodegenerative disorders. In recent years, more and more data has been obtained that discerned potential overlaps and crosstalk between Sirtuin proteins and autophagic activity. This review aims to summarize the advances within the field for each individual Sirtuin in mammalian systems. In brief, most Sirtuins have been implicated in promoting autophagy, with Sirtuin 1 and Sirtuin 6 showing the highest immediate involvement, while Sirtuin 4 and Sirtuin 5 only demonstrate occasional influence. The way Sirtuins regulate autophagy, however, is very diverse, as they have been shown to regulate gene expression of autophagy-associated genes and posttranslational modifications of proteins, with consequences for the activity and cellular localization of these proteins. They have also been shown to determine specific proteins for autophagic degradation. Overall, much data has been accumulated over recent years, yet many open questions remain. Especially although the dynamic between Sirtuin proteins and the immediate regulation of autophagic players like Light Chain 3B has been confirmed, many of these proteins have various orthologues in mammalian systems, and research so far has not exceeded the bona fide components of autophagy.
    Keywords:  HDAC; SIRT1; acetylation; autophagy; sirtuins
    DOI:  https://doi.org/10.1002/jcb.30377
  20. J Mol Biol. 2023 Feb 08. pii: S0022-2836(23)00054-2. [Epub ahead of print] 167998
    The role of LRRK2 in intracellular organelle dynamics.
    C Alexander Boecker.
      Pathogenic mutations in the leucine rich repeat kinase 2 (LRRK2) gene hyperactivate LRRK2 kinase activity and lead to the development of Parkinson's disease (PD). Membrane recruitment of LRRK2 and the identification of RAB GTPases as bona fide LRRK2 substrates strongly indicate that LRRK2 regulates intracellular trafficking. This review highlights the current literature on the role of LRRK2 in intracellular organelle dynamics. With a focus on the effects of LRRK2 on microtubule function, mitochondrial dynamics, the autophagy-lysosomal pathway, and synaptic vesicle trafficking, it summarizes our current understanding of how intracellular dynamics are altered upon pathogenic LRRK2 hyperactivation.
    Keywords:  Parkinson’s disease; RAB GTPases; autophagosomes; lysosomes; mitochondria
    DOI:  https://doi.org/10.1016/j.jmb.2023.167998
  21. Neural Regen Res. 2023 Aug;18(8): 1723-1724
    Targeting chaperone-mediated autophagy for Parkinson's disease therapy.
    Yi-Ting Wang, Jia-Hong Lu.
      
    DOI:  https://doi.org/10.4103/1673-5374.363831
  22. DNA Cell Biol. 2023 Feb 10.
    Coronaviruses, Lysosomes, and Secondary Bacterial Infections: Coronaviruses Outsmart the Host.
    Xiaohua Peng, Charles S Dela Cruz, Lokesh Sharma.
      Lysosomes are key organelles that contribute to homeostatic functions such as autophagy-mediated recycling of cellular components and innate immune response through phagocytosis-mediated pathogen killing during infections. Viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has developed unique adaptation to not only avoid lysosome-mediated destruction but also actively utilize lysosomal machinery to both enter and exit cells. To survive the highly hostile lysosomal environment, coronaviruses deacidify the lysosomes, potentially by manipulating H+ ion exchange across the lysosomal lumen, ensuring coronavirus survival. At the same time, this deacidification not only impairs cellular homeostatic functions such as autophagy but also renders the host susceptible to secondary bacterial infections. Furthermore, lysosomal enzymes promote extensive cell death and tissue damage during secondary bacterial infections. Thus, targeting lysosomal pathways provide a great opportunity to limit both viral replication and subsequent negative impact on host immunity against secondary bacterial infections.
    Keywords:  COVID-19; coronavirus; lysosomes; secondary bacterial infections
    DOI:  https://doi.org/10.1089/dna.2023.0002
  23. Front Pharmacol. 2023 ;14 1083875
    Natural compounds from botanical drugs targeting mTOR signaling pathway as promising therapeutics for atherosclerosis: A review.
    Qian Wu, Qianyu Lv, Xiao'an Liu, Xuejiao Ye, Linlin Cao, Manshi Wang, Junjia Li, Yingtian Yang, Lanlan Li, Shihan Wang.
      Atherosclerosis (AS) is a chronic inflammatory disease that is a major cause of cardiovascular diseases (CVDs), including coronary artery disease, hypertension, myocardial infarction, and heart failure. Hence, the mechanisms of AS are still being explored. A growing compendium of evidence supports that the activity of the mechanistic/mammalian target of rapamycin (mTOR) is highly correlated with the risk of AS. The mTOR signaling pathway contributes to AS progression by regulating autophagy, cell senescence, immune response, and lipid metabolism. Various botanical drugs and their functional compounds have been found to exert anti- AS effects by modulating the activity of the mTOR signaling pathway. In this review, we summarize the pathogenesis of AS based on the mTOR signaling pathway from the aspects of immune response, autophagy, cell senescence, and lipid metabolism, and comb the recent advances in natural compounds from botanical drugs to inhibit the mTOR signaling pathway and delay AS development. This review will provide a new perspective on the mechanisms and precision treatments of AS.
    Keywords:  atherosclerosis; autophagy; cell senescence; herbal medicine; mTOR; mechanism; rapamycin
    DOI:  https://doi.org/10.3389/fphar.2023.1083875
  24. Cancers (Basel). 2023 Feb 02. pii: 953. [Epub ahead of print]15(3):
    Perturbation of Autophagy by a Beclin 1-Targeting Stapled Peptide Induces Mitochondria Stress and Inhibits Proliferation of Pancreatic Cancer Cells.
    Na Li, Xiaozhe Zhang, Jingyi Chen, Shan Gao, Lei Wang, Yanxiang Zhao.
      Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, with a dismal five-year survival rate of less than 10%. PDAC possesses prominent genetic alterations in the oncogene KRAS and tumor suppressors p53, SMAD4 and CDKN2A. However, efforts to develop targeted drugs against these molecules have not been successful, and novel therapeutic modalities for PDAC treatment are urgently needed. Autophagy is an evolutionarily conserved self-degradative process that turns over intracellular components in a lysosome-dependent manner. The role of autophagy in PDAC is complicated and context-dependent. Elevated basal autophagy activity has been detected in multiple human PDAC cell lines and primary tumors resected from patients. However, clinical trials using chloroquine (CQ) to inhibit autophagy failed to show therapeutic efficacy. Here we show that a Beclin 1-targeting stapled peptide (Tat-SP4) developed in our lab further enhanced autophagy in multiple PDAC cell lines possessing high basal autophagy activity. Tat-SP4 also triggered faster endolysosomal degradation of EGFR and induced significant mitochondria stress as evidenced by partial loss of Δψ, increased level of ROS and reduced OXPHOS activity. Tat-SP4 exerted a potent anti-proliferative effect in PDAC cell lines in vitro and prohibited xenograft tumor growth in vivo. Intriguingly, excessive autophagy has been reported to trigger a unique form of cell death termed autosis. Tat-SP4 does induce autosis-like features in PDAC cells, including mitochondria stress and non-apoptotic cell death. Overall, our study suggests that autophagy perturbation by a Beclin 1-targeting peptide and the resulting autosis may offer a new strategy for PDAC drug discovery.
    Keywords:  EGFR; PDAC; autophagy; stapled peptide
    DOI:  https://doi.org/10.3390/cancers15030953
  25. Free Radic Biol Med. 2023 Feb 08. pii: S0891-5849(23)00056-4. [Epub ahead of print]
    Molecular interplay between NOX1 and autophagy in cadmium-induced prostate carcinogenesis.
    Ashish Tyagi, Balaji Chandrasekaran, Ajit K Navin, Vaibhav Shukla, Becaa V Baby, Murali K Ankem, Chendil Damodaran.
      Chronic exposure to cadmium (Cd), a class I carcinogen, leads to malignant transformation of normal prostate epithelial cells. The constant generation of Cd-induced ROS and resulting ER stress induces cellular responses that are needed for cell survival, and autophagy has an important role in this process. However, the mechanisms that regulate Cd-induced ROS and how these differ in terms of acute and chronic cadmium exposure remain unexplained. Here, we show that acute or chronic Cd exposure facilitates NOX1 assembly by activating its cytosolic regulators p47phox and p67phox in RWPE-1 cells. Upregulation of NOX1 complex proteins and generation of ROS activates unfolded protein response (UPR) via phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2 alpha (eIF2α), and selective translation of activating transcription factor 4 (ATF4). Chronic Cd exposure constantly activates NOX1 complex and generates consistent ROS and ER stress that led to defective autophagy, wherein ATG5 expression is downregulated in contrast to acute Cd exposure. As a result, selective/defective autophagy creates depletion of autophagosome-lysosome fusion that gives a survival advantage to transforming cells, which is not available to RWPE-1 cells acutely exposed to Cd. Knockdown of key molecules in a lockstep manner directly affects the most downstream autophagy pathways in transforming cells. Overall, this study demonstrates that assembly of NOX1 complex proteins is indispensable for Cd-induced persistent ROS and controls ER stress-induced defective autophagy in mice and humans.
    Keywords:  Autophagy; Cadmium; ER stress; NADPH Oxidase; Prostate cancer; ROS; Transformation
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.02.007
  26. Biochim Biophys Acta Mol Basis Dis. 2023 Feb 04. pii: S0925-4439(23)00011-X. [Epub ahead of print] 166647
    Autotaxin (ATX) inhibits autophagy leading to exaggerated disruption of intestinal epithelial barrier in colitis.
    Wenjie Shi, Kaixin Peng, Hongbing Yu, Zi Wang, Shuhong Xia, Siqi Xiao, Dean Tian, Bruce A Vallance, Qin Yu.
      Inflammatory bowel disease (IBD) is an immune-mediated disease. Autotaxin (ATX) is associated with increased inflammatory molecules, however, its effect on IBD is not well understood. Autophagy plays an important role in IBD, whether ATX and autophagy act in concert in IBD remains unknown. This study is to explore the possible mechanisms of ATX affecting autophagy leading to the disruption of intestinal epithelial barrier, thereby exacerbating colitis. The expression of ATX was upregulated in UC patients and dextran sulfate sodium (DSS)-induced colitis mice. Here, we described that providing an ATX inhibitor during DSS colitis increased autophagy and ameliorated colonic inflammation. Conversely, intrarectal administration with recombinant (r)ATX increased colitis and decreased autophagy. This pro-colitic effect was attenuated in mice treated with rapamycin, resulting in increased autophagy activity and mild colitis. Moreover, the inhibitory effect of rATX on autophagy was confirmed in vitro and was reversed by the addition of rapamycin. The damaging effects of ATX on epithelial barrier function were reversed by ATX inhibitor or rapamycin treatment. In sum, our results show that ATX can inhibit autophagy through the mTOR pathway, resulting in exaggerated damage to the intestinal epithelial barrier during colitis. These findings suggest that ATX may be a key pro-colitic factor, and represent a potential therapeutic target for treating IBD in the future.
    Keywords:  Autophagy; Autotaxin; Colitis; Epithelial barrier; mTOR pathway
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166647
  27. Cancer Med. 2023 Feb 09.
    Autophagy: A challengeable paradox in cancer treatment.
    Farnaz Ahmadi-Dehlaghi, Parisa Mohammadi, Elahe Valipour, Pouya Pournaghi, Sarah Kiani, Kamran Mansouri.
      OBJECTIVE: Autophagy is an intracellular degradation pathway conserved in all eukaryotes from yeast to humans. This process plays a quality-control role by destroying harmful cellular components under normal conditions, maintaining cell survival, and establishing cellular adaptation under stressful conditions. Hence, there are various studies indicating dysfunctional autophagy as a factor involved in the development and progression of various human diseases, including cancer. In addition, the importance of autophagy in the development of cancer has been highlighted by paradoxical roles, as a cytoprotective and cytotoxic mechanism. Despite extensive research in the field of cancer, there are many questions and challenges about the roles and effects suggested for autophagy in cancer treatment. The aim of this study was to provide an overview of the paradoxical roles of autophagy in different tumors and related cancer treatment options.METHODS: In this study, to find articles, a search was made in PubMed and Google scholar databases with the keywords Autophagy, Autophagy in Cancer Management, and Drug Design.
    RESULTS: According to the investigation, some studies suggest that several advanced cancers are dependent on autophagy for cell survival, so when cancer cells are exposed to therapy, autophagy is induced and suppresses the anti-cancer effects of therapeutic agents and also results in cell resistance. However, enhanced autophagy from using anti-cancer drugs causes autophagy-mediated cell death in several cancers. Because autophagy also plays roles in both tumor suppression and promotion further research is needed to determine the precise mechanism of this process in cancer treatment.
    CONCLUSION: We concluded in this article, autophagy manipulation may either promote or hinder the growth and development of cancer according to the origin of the cancer cells, the type of cancer, and the behavior of the cancer cells exposed to treatment. Thus, before starting treatment it is necessary to determine the basal levels of autophagy in various cancers.
    Keywords:  angiogenesis; autophagy; cancer biology; cancer management; drug design; signal transduction
    DOI:  https://doi.org/10.1002/cam4.5577
  28. PLoS Biol. 2023 Feb;21(2): e3001962
    AlphaFold2-multimer guided high-accuracy prediction of typical and atypical ATG8-binding motifs.
    Tarhan Ibrahim, Virendrasinh Khandare, Federico Gabriel Mirkin, Yasin Tumtas, Doryen Bubeck, Tolga O Bozkurt.
      Macroautophagy/autophagy is an intracellular degradation process central to cellular homeostasis and defense against pathogens in eukaryotic cells. Regulation of autophagy relies on hierarchical binding of autophagy cargo receptors and adaptors to ATG8/LC3 protein family members. Interactions with ATG8/LC3 are typically facilitated by a conserved, short linear sequence, referred to as the ATG8/LC3 interacting motif/region (AIM/LIR), present in autophagy adaptors and receptors as well as pathogen virulence factors targeting host autophagy machinery. Since the canonical AIM/LIR sequence can be found in many proteins, identifying functional AIM/LIR motifs has proven challenging. Here, we show that protein modelling using Alphafold-Multimer (AF2-multimer) identifies both canonical and atypical AIM/LIR motifs with a high level of accuracy. AF2-multimer can be modified to detect additional functional AIM/LIR motifs by using protein sequences with mutations in primary AIM/LIR residues. By combining protein modelling data from AF2-multimer with phylogenetic analysis of protein sequences and protein-protein interaction assays, we demonstrate that AF2-multimer predicts the physiologically relevant AIM motif in the ATG8-interacting protein 2 (ATI-2) as well as the previously uncharacterized noncanonical AIM motif in ATG3 from potato (Solanum tuberosum). AF2-multimer also identified the AIM/LIR motifs in pathogen-encoded virulence factors that target ATG8 members in their plant and human hosts, revealing that cross-kingdom ATG8-LIR/AIM associations can also be predicted by AF2-multimer. We conclude that the AF2-guided discovery of autophagy adaptors/receptors will substantially accelerate our understanding of the molecular basis of autophagy in all biological kingdoms.
    DOI:  https://doi.org/10.1371/journal.pbio.3001962
  29. Proc Natl Acad Sci U S A. 2023 Feb 14. 120(7): e2213670120
    A small-molecule drug inhibits autophagy gene expression through the central regulator TFEB.
    Yuqi Lin, Qiqi Shi, Guang Yang, Fuchun Shi, Yang Zhou, Tongtong Wang, Peng Xu, Peifeng Li, Zaizhou Liu, Hanyin Sun, Zhixin Zhao, Ke Ding, Zhen Wang, Haizhong Feng, Biao Yu, Pengfei Fang, Jing Wang.
      Autophagy supports the fast growth of established tumors and promotes tumor resistance to multiple treatments. Inhibition of autophagy is a promising strategy for tumor therapy. However, effective autophagy inhibitors suitable for clinical use are currently lacking. There is a high demand for identifying novel autophagy drug targets and potent inhibitors with drug-like properties. The transcription factor EB (TFEB) is the central transcriptional regulator of autophagy, which promotes lysosomal biogenesis and functions and systematically up-regulates autophagy. Despite extensive evidence that TFEB is a promising target for autophagy inhibition, no small molecular TFEB inhibitors were reported. Here, we show that an United States Food and Drug Administration (FDA)-approved drug Eltrombopag (EO) binds to the basic helix-loop-helix-leucine zipper domain of TFEB, specifically the bottom surface of helix-loop-helix to clash with DNA recognition, and disrupts TFEB-DNA interaction in vitro and in cellular context. EO selectively inhibits TFEB's transcriptional activity at the genomic scale according to RNA sequencing analyses, blocks autophagy in a dose-dependent manner, and increases the sensitivity of glioblastoma to temozolomide in vivo. Together, this work reveals that TFEB is targetable and presents the first direct TFEB inhibitor EO, a drug compound with great potential to benefit a wide range of cancer therapies by inhibiting autophagy.
    Keywords:  Eltrombopag; autophagy; cancer therapy; high-throughput screen; transcription factor EB
    DOI:  https://doi.org/10.1073/pnas.2213670120
  30. J Virol. 2023 Feb 06. e0133822
    Zebrafish maoc1 Attenuates Spring Viremia of Carp Virus Propagation by Promoting Autophagy-Lysosome-Dependent Degradation of Viral Phosphoprotein.
    Yanan Song, Sijia Fan, Dawei Zhang, Jun Li, Zhi Li, Ziyi Li, Wuhan Xiao, Jing Wang.
      Spring viremia of carp virus (SVCV) is the causative agent of spring viremia of carp (SVC), an important infectious disease that causes high mortality in aquaculture cyprinids. How the host defends against SVCV infection and the underlying mechanisms are still elusive. In this study, we identify that a novel gene named maoc1 is induced by SVCV infection. maoc1-deficient zebrafish are more susceptible to SVCV infection, with higher virus replication and antiviral gene induction. Further assays indicate that maoc1 interacts with the P protein of SVCV to trigger P protein degradation through the autophagy-lysosomal pathway, leading to the restriction of SVCV propagation. These findings reveal a unique zebrafish defense machinery in response to SVCV infection. IMPORTANCE SVCV P protein plays an essential role in the virus replication and viral immune evasion process. Here, we identify maoc1 as a novel SVCV-inducible gene and demonstrate its antiviral capacity through attenuating SVCV replication, by directly binding to P protein and mediating its degradation via the autophagy-lysosomal pathway. Therefore, this study not only reveals an essential role of maoc1 in fighting against SVCV infection but also demonstrates an unusual host defense mechanism in response to invading viruses.
    Keywords:  SVCV; autophagy; maoc1; phosphoprotein; propagation
    DOI:  https://doi.org/10.1128/jvi.01338-22
  31. Elife. 2023 Feb 07. pii: e84319. [Epub ahead of print]12
    Snf1/AMPK fine-tunes TORC1 signaling in response to glucose starvation.
    Marco Caligaris, Raffaele Nicastro, Zehan Hu, Farida Tripodi, Johannes Erwin Hummel, Benjamin Pillet, Marie-Anne Deprez, Joris Winderickx, Sabine Rospert, Paola Coccetti, Jörn Dengjel, Claudio De Virgilio.
      The AMP-activated protein kinase (AMPK) and the target of rapamycin complex 1 (TORC1) are central kinase modules of two opposing signaling pathways that control eukaryotic cell growth and metabolism in response to the availability of energy and nutrients. Accordingly, energy depletion activates AMPK to inhibit growth, while nutrients and high energy levels activate TORC1 to promote growth. Both in mammals and lower eukaryotes such as yeast, the AMPK and TORC1 pathways are wired to each other at different levels, which ensures homeostatic control of growth and metabolism. In this context, a previous study (Hughes Hallet et. al, 2015) reported that AMPK in yeast, i.e. Snf1, prevents the transient TORC1 reactivation during the early phase following acute glucose starvation, but the underlying mechanism has remained elusive. Using a combination of unbiased mass spectrometry (MS)-based phosphoproteomics, genetic, biochemical, and physiological experiments, we show here that Snf1 temporally maintains TORC1 inactive in glucose-starved cells primarily through the TORC1-regulatory protein Pib2. Our data, therefore, extend the function of Pib2 to a hub that integrates both glucose and, as reported earlier, glutamine signals to control TORC1. We further demonstrate that Snf1 phosphorylates the TORC1 effector kinase Sch9 within its N-terminal region and thereby antagonizes the phosphorylation of a C-terminal TORC1-target residue within Sch9 itself that is critical for its activity. The consequences of Snf1-mediated phosphorylation of Pib2 and Sch9 are physiologically additive and sufficient to explain the role of Snf1 in short-term inhibition of TORC1 in acutely glucose-starved cells.
    Keywords:  S. cerevisiae; biochemistry; cell biology; chemical biology
    DOI:  https://doi.org/10.7554/eLife.84319
  32. Autophagy. 2023 Feb 09. 1-3
    Pexophagy in plants: a mechanism to remit cells from oxidative damage caused under high-intensity light.
    Shino Goto-Yamada, Kazusato Oikawa, Yasuko Hayashi, Shoji Mano, Kenji Yamada, Mikio Nishimura.
      Light is essential for plant growth, but excessive light energy produces reactive oxygen species (ROS), which can seriously damage cells. Mutants defective in ATG (autophagy related) genes show light intensity-dependent leaf damage and ROS accumulation. We found that autophagy is one of the crucial systems in protecting plants from ROS-induced damage by removing oxidative peroxisomes. Damaged peroxisomes are targeted by the PtdIns3P marker and specifically engulfed by phagophores labeled by ATG18a-GFP. Under high-intensity light, huge peroxisome aggregates are induced and captured by vacuolar membranes. Research provides a deeper understanding of plant stress response to light irradiation.
    Keywords:  Autophagy; ROS; microautophagy; peroxisome; pexophagy; plant
    DOI:  https://doi.org/10.1080/15548627.2023.2175570
  33. Cell Commun Signal. 2023 Feb 09. 21(1): 32
    Targeting and regulation of autophagy in hepatocellular carcinoma: revisiting the molecular interactions and mechanisms for new therapy approaches.
    Mehrdad Hashemi, Niloufar Nadafzadeh, Mohammad Hassan Imani, Romina Rajabi, Setayesh Ziaolhagh, Seyedeh Delaram Bayanzadeh, Raheleh Norouzi, Reihaneh Rafiei, Zeinab Khazaei Koohpar, Behnaz Raei, Mohammad Arad Zandieh, Shokooh Salimimoghadam, Maliheh Entezari, Afshin Taheriazam, Athanasios Alexiou, Marios Papadakis, Shing Cheng Tan.
      Autophagy is an evolutionarily conserved process that plays a role in regulating homeostasis under physiological conditions. However, dysregulation of autophagy is observed in the development of human diseases, especially cancer. Autophagy has reciprocal functions in cancer and may be responsible for either survival or death. Hepatocellular carcinoma (HCC) is one of the most lethal and common malignancies of the liver, and smoking, infection, and alcohol consumption can lead to its development. Genetic mutations and alterations in molecular processes can exacerbate the progression of HCC. The function of autophagy in HCC is controversial and may be both tumor suppressive and tumor promoting. Activation of autophagy may affect apoptosis in HCC and is a regulator of proliferation and glucose metabolism. Induction of autophagy may promote tumor metastasis via induction of EMT. In addition, autophagy is a regulator of stem cell formation in HCC, and pro-survival autophagy leads to cancer cell resistance to chemotherapy and radiotherapy. Targeting autophagy impairs growth and metastasis in HCC and improves tumor cell response to therapy. Of note, a large number of signaling pathways such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs regulate autophagy in HCC. Moreover, regulation of autophagy (induction or inhibition) by antitumor agents could be suggested for effective treatment of HCC. In this paper, we comprehensively review the role and mechanisms of autophagy in HCC and discuss the potential benefit of targeting this process in the treatment of the cancer. Video Abstract.
    Keywords:  Autophagy; Chemoresistance; Hepatocellular carcinoma; Metastasis; Stemness
    DOI:  https://doi.org/10.1186/s12964-023-01053-z
  34. Int J Mol Sci. 2023 Jan 30. pii: 2637. [Epub ahead of print]24(3):
    Mitochondrial-Derived Vesicles-Link to Extracellular Vesicles and Implications in Cardiovascular Disease.
    Jonas Heyn, Marina Augusto Heuschkel, Claudia Goettsch.
      Mitochondria are dynamic organelles regulating metabolism, cell death, and energy production. Therefore, maintaining mitochondrial health is critical for cellular homeostasis. Mitophagy and mitochondrial reorganization via fission and fusion are established mechanisms for ensuring mitochondrial quality. In recent years, mitochondrial-derived vesicles (MDVs) have emerged as a novel cellular response. MDVs are shed from the mitochondrial surface and can be directed to lysosomes or peroxisomes for intracellular degradation. MDVs may contribute to cardiovascular disease (CVD) which is characterized by mitochondrial dysfunction. In addition, evidence suggests that mitochondrial content is present in extracellular vesicles (EVs). Herein, we provide an overview of the current knowledge on MDV formation and trafficking. Moreover, we review recent findings linking MDV and EV biogenesis and discuss their role in CVD. Finally, we discuss the role of vesicle-mediated mitochondrial transfer and its potential cardioprotective effects.
    Keywords:  cardiovascular disease; extracellular vesicles; mitochondria; mitochondrial transfer; mitochondrial-derived vesicles
    DOI:  https://doi.org/10.3390/ijms24032637
  35. Biochem Biophys Res Commun. 2023 Jan 30. pii: S0006-291X(23)00148-1. [Epub ahead of print]649 39-46
    Liver specific disruption of Glutaredoxin 3 leads to iron accumulation and impaired cellular iron homeostasis.
    Ninghui Cheng, Jimmonique Donelson, Ghislain Breton, Paul A Nakata.
      The role mammalian glutaredoxin 3 (Grx3) plays in iron homeostasis is poorly understood. Here we report the generation and characterization of a Grx3 liver-specific knockout (LKO) mouse strain. Grx3 LKO and WT mice had similar growth however, the LKO mice had elevated iron concentration and ROS production leading to impaired liver function and altered cytosolic and nuclear Fe-S cluster assembly. The expression of hepatic FTH1 and other iron homeostasis genes appeared to correlate with the elevation in iron concentration. Interestingly, this increase in hepatic FTH1 showed an inverse correlation with the abundance of autophagy pathway proteins. These findings suggest a crucial role for Grx3 in regulating hepatocyte iron homeostasis by controlling cellular storage protein turnover and recycling via the autophagy pathway.
    Keywords:  Autophagy; Fe–S cluster Assembly; Glutaredoxin; Iron homeostasis; Liver
    DOI:  https://doi.org/10.1016/j.bbrc.2023.01.095
  36. Ecotoxicol Environ Saf. 2023 Feb 08. pii: S0147-6513(23)00134-3. [Epub ahead of print]252 114630
    PARP1 promotes NLRP3 activation via blocking TFEB-mediated autophagy in rotenone-induced neurodegeneration.
    He Zhang, Zhefan Xie, Yongming Peng, Ailun Xie, Chunlai Fu, Dongyan Zheng, ZiWei Cai, Jiahong Zhong, Qiang Ming, Mingque Li, Renjian Lu, Xin Liu, Jialong Chen.
      Rotenone, a widely used pesticide, causes dopaminergic neurons loss and increase the risk of Parkinson's disease (PD). However, few studies link the role of PARP1 to neuroinflammatory response and autophagy dysfunction in rotenone-induced neurodegeneration. Here, we identified that PARP1 overactivation caused by rotenone led to autophagy dysfunction and NLRP3-mediated inflammation. Further results showed that PARP1 inhibition could reduce NLRP3-mediated inflammation, which was effectively eliminated by TFEB knockdown. Moreover, PARP1 poly(ADP-ribosyl)ated TFEB that reduced autophagy. Of note, PARP1 inhibition could rescue rotenone-induced dopaminergic neurons loss. Overall, our study revealed that PARP1 blocks autophagy through poly (ADP-ribosyl)ating TFEB and inhibited NLRP3 degradation, which suggests that intervention of PARP1-TFEB-NLRP3 signaling can be a new treatment strategy for rotenone-induced neurodegeneration.
    Keywords:  Autophagy; NLRP3; PARP1; Rotenone; TFEB
    DOI:  https://doi.org/10.1016/j.ecoenv.2023.114630
  37. Front Aging. 2023 ;4 1113200
    Lysosomal dysfunction in diabetic cardiomyopathy.
    Satoru Kobayashi, Younghee Hahn, Brett Silverstein, Mandeep Singh, Adeline Fleitz, Jennifer Van, Hongling Chen, Qiangrong Liang.
      Diabetes is a major risk factor for a variety of cardiovascular complications, while diabetic cardiomyopathy, a disease specific to the myocardium independent of vascular lesions, is an important causative factor for increased risk of heart failure and mortality in diabetic populations. Lysosomes have long been recognized as intracellular trash bags and recycling facilities. However, recent studies have revealed that lysosomes are sophisticated signaling hubs that play remarkably diverse roles in adapting cell metabolism to an ever-changing environment. Despite advances in our understanding of the physiological roles of lysosomes, the events leading to lysosomal dysfunction and how they relate to the overall pathophysiology of the diabetic heart remain unclear and are under intense investigation. In this review, we summarize recent advances regarding lysosomal injury and its roles in diabetic cardiomyopathy.
    Keywords:  autophagy; cardiomyopathy; cardiovascular; diabetes; lysosomal membrane damage; lysosome
    DOI:  https://doi.org/10.3389/fragi.2023.1113200
  38. Chem Biol Drug Des. 2023 Feb 08.
    Baicalin mitigated IL-1β-Induced osteoarthritis chondrocytes damage through activating mitophagy.
    Jun He, Jian He.
      Mitophagy is related to chondrocyte homeostasis and plays a key role in the progress of osteoarthritis (OA). Baicalin has a protective effect on OA chondrocytes, the aim of this study was to explore whether the effect of Baicalin on IL-1β-induced chondrocyte injury is related to the regulation of mitophagy. The expression of collagen II in chondrocytes was detected to identify chondrocytes. The effects of different concentrations of Baicalin (10, 20 and 40 μM), autophagy inhibitor (3-Methyladenine), autophagy activator (rapamycin) and Baicalin combined with PI3K agonist (740Y-P) on the viability (cell counting kit 8), apoptosis (flow cytometry), autophagy activation (Monodansylcadaverine staining) and mitochondrial membrane potential (JC-1 kit) of IL-1β induced-chondrocytes were evaluated. The co-localization of autophagosome and mitochondria was determined by immunofluorescence. Apoptosis-, autophagy-, PI3K/AKT/mTOR pathway- and mitophagy-related proteins were detected by western blot. Our result revealed that Baicalin and rapamycin facilitated cell viability, autophagy and mitophagy, elevated mitochondrial membrane potential and suppressed apoptosis of IL-1β-induced rat chondrocytes. In addition, Baicalin and rapamycin upregulated the levels of Bcl-2, Beclin 1, LC3-II/LC3-I, p-Drp1, PINK1 and Parkin as well as downregulated the levels of Bax, cleaved-caspase-3, P62, p-PI3K/PI3K, p-mTOR/mTOR and Drp1 in IL-1β-induced rat chondrocytes. However, 3-Methyladenine did the opposite effects of Baicalin and 740Y-P reversed the effects of Baicalin on IL-1β-induced rat chondrocytes. In conclusion, Baicalin activated mitophagy in IL-1β induced-chondrocytes by inhibiting PI3K/AKT/mTOR pathway and activating PINK1/Parkin and PINK1/Drp-1 pathway, thereby reducing the chondrocyte injury.
    Keywords:  Baicalin; PI3K/AKT/mTOR; chondrocytes; mitophagy; osteoarthritis
    DOI:  https://doi.org/10.1111/cbdd.14215
  39. Neuromolecular Med. 2023 Feb 05.
    The Ubiquitin Proteasome System as a Therapeutic Area in Parkinson's Disease.
    Kumar Suresh, Michael Mattern, Matthew S Goldberg, Tauseef R Butt.
      Parkinson's disease (PD) is the most common neurodegenerative movement disorder. There are no available therapeutics that slow or halt the progressive loss of dopamine-producing neurons, which underlies the primary clinical symptoms. Currently approved PD drugs can provide symptomatic relief by increasing brain dopamine content or activity; however, the alleviation is temporary, and the effectiveness diminishes with the inevitable progression of neurodegeneration. Discovery and development of disease-modifying neuroprotective therapies has been hampered by insufficient understanding of the root cause of PD-related neurodegeneration. The etiology of PD involves a combination of genetic and environmental factors. Although a single cause has yet to emerge, genetic, cell biological and neuropathological evidence implicates mitochondrial dysfunction and protein aggregation. Postmortem PD brains show pathognomonic Lewy body intraneuronal inclusions composed of aggregated α-synuclein, indicative of failure to degrade misfolded protein. Mutations in the genes that code for α-synuclein, as well as the E3 ubiquitin ligase Parkin, cause rare inherited forms of PD. While many ubiquitin ligases label proteins with ubiquitin chains to mark proteins for degradation by the proteasome, Parkin has been shown to mark dysfunctional mitochondria for degradation by mitophagy. The ubiquitin proteasome system participates in several aspects of the cell's response to mitochondrial damage, affording numerous therapeutic opportunities to augment mitophagy and potentially stop PD progression. This review examines the role and therapeutic potential of such UPS modulators, exemplified by both ubiquitinating and deubiquitinating enzymes.
    Keywords:  Mitochondria; Mitophagy; Neurodegeneration; Parkin; Parkinson’s disease; Ubiquitin
    DOI:  https://doi.org/10.1007/s12017-023-08738-1
  40. Neuroscience. 2023 Feb 03. pii: S0306-4522(23)00061-1. [Epub ahead of print]
    Stromal Interaction Molecule 1-Mediated Store-Operated Calcium Entry Promotes Autophagy Through AKT/Mammalian Target of Rapamycin Pathway in Hippocampal Neurons After Ischemic Stroke.
    Hongchen Zhang, Wenyu Xie, Yuan Feng, Jialiang Wei, Changbin Yang, Peng Luo, Yuefan Yang, Peng Zhao, Xiaofan Jiang, Wenbin Liang, Shuhui Dai, Xia Li.
      The pathophysiological process of neuronal injury due to cerebral ischemia is complex among which disturbance of calcium homeostasis and autophagy are two major pathogenesis. However, it remains ambiguous whether the two factors are independent. Stromal interaction molecule 1 (STIM1) is the most important Ca2+ sensor mediating the store-operated Ca2+ entry (SOCE) through interacting with Orai1 and has recently been proven to participate in autophagy in multiple cells. In this study, we aimed to investigate the potential role of STIM1-induced SOCE on autophagy and whether its regulator function contributes to neuronal injury under hypoxic conditions using in vivo transient middle cerebral artery occlusion (tMCAO) model and in vitro oxygen and glucose deprivation (OGD) primary cultured neuron model respectively. The present data indicated that STIM1 induces autophagic flux impairment in neurons through promoting SOCE and inhibiting AKT/mTOR signaling pathway. Pharmacological inhibition of SOCE or downregulation of STIM1 with siRNA suppressed the autophagic activity in neurons. Moreover, stim1 knockdown attenuated neurological deficits and brain damage after tMCAO, which could be reversed by AKT/mTOR pathway inhibitor AZD5363. Together, the modulation of STIM1 on autophagic activation indicated the potential link between Ca2+ homeostasis and autophagy which provided evidence that STIM1 could be a promising therapeutic target for ischemic stroke.
    Keywords:  SOCE; STIM1; autophagy; ischemic stroke; neuron
    DOI:  https://doi.org/10.1016/j.neuroscience.2023.01.036
  41. Int J Mol Sci. 2023 Jan 22. pii: 2176. [Epub ahead of print]24(3):
    Lysosomes as a Target of Anticancer Therapy.
    Wojciech Trybus, Ewa Trybus, Teodora Król.
      Lysosomes are organelles containing acidic hydrolases that are responsible for lysosomal degradation and the maintenance of cellular homeostasis. They play an important role in autophagy, as well as in various cell death pathways, such as lysosomal and apoptotic death. Various agents, including drugs, can induce lysosomal membrane permeability, resulting in the translocation of acidic hydrolases into the cytoplasm, which promotes lysosomal-mediated death. This type of death may be of great importance in anti-cancer therapy, as both cancer cells with disturbed pathways leading to apoptosis and drug-resistant cells can undergo it. Important compounds that damage the lysosomal membrane include lysosomotropic compounds, antihistamines, immunosuppressants, DNA-damaging drugs, chemotherapeutics, photosensitizers and various plant compounds. An interesting approach in the treatment of cancer and the search for ways to overcome the chemoresistance of cancer cells may also be combining lysosomotropic compounds with targeted modulators of autophagy to induce cell death. These compounds may be an alternative in oncological treatment, and lysosomes may become a promising therapeutic target for many diseases, including cancer. Understanding the functional relationships between autophagy and apoptosis and the possibilities of their regulation, both in relation to normal and cancer cells, can be used to develop new and more effective anticancer therapies.
    Keywords:  apoptosis; autophagy; cathepsins; lysosomal membrane permeability; lysosomes
    DOI:  https://doi.org/10.3390/ijms24032176
  42. Cancers (Basel). 2023 Jan 31. pii: 877. [Epub ahead of print]15(3):
    P38 Mediates Tumor Suppression through Reduced Autophagy and Actin Cytoskeleton Changes in NRAS-Mutant Melanoma.
    Ishani Banik, Adhideb Ghosh, Erin Beebe, Blaž Burja, Mojca Frank Bertoncelj, Christopher M Dooley, Enni Markkanen, Reinhard Dummer, Elisabeth M Busch-Nentwich, Mitchell P Levesque.
      Hotspot mutations in the NRAS gene are causative genetic events associated with the development of melanoma. Currently, there are no FDA-approved drugs directly targeting NRAS mutations. Previously, we showed that p38 acts as a tumor suppressor in vitro and in vivo with respect to NRAS-mutant melanoma. We observed that because of p38 activation through treatment with the protein synthesis inhibitor, anisomycin leads to a transient upregulation of several targets of the cAMP pathway, representing a stressed cancer cell state that is often observed by therapeutic doses of MAPK inhibitors in melanoma patients. Meanwhile, genetically induced p38 or its stable transduction leads to a distinct cellular transcriptional state. Contrary to previous work showing an association of invasiveness with high p38 levels in BRAF-mutated melanoma, there was no correlation of p38 expression with NRAS-mutant melanoma invasion, highlighting the difference in BRAF and NRAS-driven melanomas. Although the role of p38 has been reported to be that of both tumor suppressor and oncogene, we show here that p38 specifically plays the role of a tumor suppressor in NRAS-mutant melanoma. Both the transient and stable activation of p38 elicits phosphorylation of mTOR, reported to be a master switch in regulating autophagy. Indeed, we observed a correlation between elevated levels of phosphorylated mTOR and a reduction in LC3 conversion (LCII/LCI), indicative of suppressed autophagy. Furthermore, a reduction in actin intensity in p38-high cells strongly suggests a role of mTOR in regulating actin and a remodeling in the NRAS-mutant melanoma cells. Therefore, p38 plays a tumor suppressive role in NRAS-mutant melanomas at least partially through the mechanism of mTOR upregulation, suppressed autophagy, and reduced actin polymerization. One or more combinations of MEK inhibitors with either anisomycin, rapamycin, chloroquine/bafilomycin, and cytochalasin modulate p38 activation, mTOR phosphorylation, autophagy, and actin polymerization, respectively, and they may provide an alternate route to targeting NRAS-mutant melanoma.
    Keywords:  NRAS mutation; anisomycin; autophagy; mTOR; melanoma; p38 tumor suppressor
    DOI:  https://doi.org/10.3390/cancers15030877
  43. Hum Mol Genet. 2023 Feb 08. pii: ddad025. [Epub ahead of print]
    Acid ceramidase involved in pathogenic cascade leading to accumulation of α-synuclein in iPSC model of GBA1-associated Parkinson's disease.
    Manoj Kumar, Manasa P Srikanth, Michela Deleidi, Penelope J Hallett, Ole Isacson, Ricardo A Feldman.
      Bi-allelic mutations in GBA1, the gene that encodes β-glucocerebrosidase (GCase), cause Gaucher disease (GD), whereas mono-allelic mutations do not cause overt pathology. Yet mono- or bi-allelic GBA1 mutations are the highest known risk factor for Parkinson's disease (PD). GCase deficiency results in the accumulation of glucosylceramide (GluCer) and its deacylated metabolite glucosylsphingosine (GluSph). Brains from patients with neuronopathic GD (nGD) have high levels of GluSph, and elevation of this lipid in GBA1-associated PD has been reported. To uncover the mechanisms involved in GBA1-associated PD, we used human induced pluripotent stem cell (hiPSC)-derived dopaminergic (DA) neurons from patients harboring heterozygote mutations in GBA1 (GBA1/PD-DA neurons). We found that compared to gene-edited isogenic controls, GBA1/PD-DA neurons exhibit mTORC1 hyperactivity, a block in autophagy, an increase in the levels of phosphorylated α-synuclein (129), and α-synuclein aggregation. These alterations were prevented by incubation with mTOR inhibitors. Inhibition of acid ceramidase, the lysosomal enzyme that deacylates GluCer to GluSph, prevented mTOR hyperactivity, restored autophagic flux, and lowered α-synuclein levels, suggesting that GluSph was responsible for these alterations. Incubation of gene-edited WT controls with exogenous GluSph recapitulated the mTOR/α-synuclein abnormalities of GBA1/PD neurons, and these phenotypic alterations were prevented when GluSph treatment was in the presence of mTOR inhibitors. We conclude that GluSph causes an aberrant activation of mTORC1, suppressing normal lysosomal functions, including the clearance of pathogenic α-synuclein species. Our results implicate acid ceramidase in the pathogenesis of GBA1-associated PD, suggesting that this enzyme is a potential therapeutic target for treating synucleinopathies caused by GCase deficiency.
    DOI:  https://doi.org/10.1093/hmg/ddad025
  44. Autophagy. 2023 Feb 05. 1-15
    G-quadruplex ligands as potent regulators of lysosomes.
    Lucille Ferret, Karla Alvarez-Valadez, Jennifer Rivière, Alexandra Muller, Natalia Bohálová, Luo Yu, Lionel Guittat, Vaclav Brázda, Guido Kroemer, Jean-Louis Mergny, Mojgan Djavaheri-Mergny.
      Guanine-quadruplex structures (G4) are unusual nucleic acid conformations formed by guanine-rich DNA and RNA sequences and known to control gene expression mechanisms, from transcription to protein synthesis. So far, a number of molecules that recognize G4 have been developed for potential therapeutic applications in human pathologies, including cancer and infectious diseases. These molecules are called G4 ligands. When the biological effects of G4 ligands are studied, the analysis is often limited to nucleic acid targets. However, recent evidence indicates that G4 ligands may target other cellular components and compartments such as lysosomes and mitochondria. Here, we summarize our current knowledge of the regulation of lysosome by G4 ligands, underlying their potential functional impact on lysosome biology and autophagic flux, as well as on the transcriptional regulation of lysosomal genes. We outline the consequences of these effects on cell fate decisions and we systematically analyzed G4-prone sequences within the promoter of 435 lysosome-related genes. Finally, we propose some hypotheses about the mechanisms involved in the regulation of lysosomes by G4 ligands.
    Keywords:  Autophagy; TFEB; guanine-quadruplex; lysosome membrane permeabilization; transcriptional regulation
    DOI:  https://doi.org/10.1080/15548627.2023.2170071
  45. Cell Stress Chaperones. 2023 Feb 11.
    Proteotoxic stress-induced autophagy is regulated by the NRF2 pathway via extracellular vesicles.
    Yuka Okusha, Ayesha Murshid, Stuart K Calderwood.
      Protein homeostasis involves a number of overlapping mechanisms, including the autophagy program, that can lead to the resolution of protein damage. We aimed in this study to examine mechanisms of autophagy in the proteotoxic stress response. We found that such stress results in a rapid elevation in the rate of autophagy in mammalian cells. Induction of this process occurred coincidentally with the increased release of extracellular vesicles (EVs) into the extracellular microenvironment. We next found that purified EVs that had been released from stressed cells were capable of directly increasing autophagic flux in recipient cells. The EVs contained a range of cargo proteins, including HSP70, BAG3, and activated transcription factor phospho-NRF2 (pNRF2). NRF2 regulates the activation of both the oxidative stress response and autophagy genes. Both heat shock and exposure of cells to proteotoxic stress-induced EVs increased the intracellular levels of pNRF2 in cells. Heat shock-induced proteotoxicity also led to increases in the levels of proteins in the oxidative stress response, including HO-1 and NQO1, as well as the key autophagy proteins LC3, ATG5, and ATG7, known to be regulated by NRF2. Increases in these autophagy proteins were dependent on the expression of NRF2 and were ablated by NRF2 knockdown.
    Keywords:  Autophagy; Extracellular vesicles (EVs); Heat shock (HS); LC3; NRF2; Proteotoxic stress
    DOI:  https://doi.org/10.1007/s12192-023-01326-z
  46. Curr Aging Sci. 2023 Feb 06.
    Physiological Roles of Hippo Signaling Pathway and Autophagy in Dementia.
    Andreas Christoper, Herry Herman, Rizky Abdulah, Felix Zulhendri, Ardo Sanjaya, Ronny Lesmana.
      BACKGROUND: Dementia is a neurocognitive disorder associated with the aging brain and mainly affects the hippocampus and cerebral cortex. The Hippo signaling pathway and autophagy proteins have been found to be perturbed in the brain affected by dementia processes.OBJECTIVE: This systematic review aims to elaborate on the involvement of the Hippo signaling pathway and autophagy in modulating the progression and severity of dementia in aging.
    METHODS: Searches were conducted on MEDLINE, Google Scholar, Scopus, and Web of Science databases.
    RESULTS: The Hippo signaling pathway is dependent upon the transcriptional co-activator YAP/TAZ, which forms complexes with TEAD in the nucleus in order to maintain cell homeostasis. When the expression YAP/TAZ is reduced, transcriptional repression-induced atypical cell death, ballooning cell death, and necrosis will consequently occur in the neurons. Moreover, the autophagic proteins, such as LC3, ATG proteins, and Beclin, are reduced, resulting in the disruption of autophagosome formation and accumulation and the spread of misfolded proteins in the brain suffering from dementia.
    CONCLUSION: The impairment of the Hippo signaling pathway and autophagy in the dementia process in aging should be considered since it might predict the severity, treatment, and prevention of dementia. PROSPERO registration number CRD42022337445.
    Keywords:  Aging; Autophagy; Brain; Dementia; Hippo signaling pathway; Neurodegeneration.
    DOI:  https://doi.org/10.2174/1874609816666230206144212
  47. Cell Metab. 2023 Feb 07. pii: S1550-4131(23)00003-7. [Epub ahead of print]35(2): 345-360.e7
    Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis.
    Joonho Suh, Na-Kyung Kim, Wonn Shim, Seung-Hoon Lee, Hyo-Jeong Kim, Eunyoung Moon, Hiromi Sesaki, Jae Hyuck Jang, Jung-Eun Kim, Yun-Sil Lee.
      Mitochondrial components have been abundantly detected in bone matrix, implying that they are somehow transported extracellularly to regulate osteogenesis. Here, we demonstrate that mitochondria and mitochondrial-derived vesicles (MDVs) are secreted from mature osteoblasts to promote differentiation of osteoprogenitors. We show that osteogenic induction stimulates mitochondrial fragmentation, donut formation, and secretion of mitochondria through CD38/cADPR signaling. Enhancing mitochondrial fission and donut formation through Opa1 knockdown or Fis1 overexpression increases mitochondrial secretion and accelerates osteogenesis. We also show that mitochondrial fusion promoter M1, which induces Opa1 expression, impedes osteogenesis, whereas osteoblast-specific Opa1 deletion increases bone mass. We further demonstrate that secreted mitochondria and MDVs enhance bone regeneration in vivo. Our findings suggest that mitochondrial morphology in mature osteoblasts is adapted for extracellular secretion, and secreted mitochondria and MDVs are critical promoters of osteogenesis.
    Keywords:  FIS1; M1; OPA1; donut mitochondria; mitochondria; mitochondrial secretion; mitochondrial transplantation; mitochondrial-derived vesicles; osteoblasts; osteogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2023.01.003
  48. Front Pharmacol. 2023 ;14 1105726
    Xanthohumol alleviates oxidative stress and impaired autophagy in experimental severe acute pancreatitis through inhibition of AKT/mTOR.
    Yaru Huangfu, Xiuxian Yu, Chengyu Wan, Yuda Zhu, Zeliang Wei, Fan Li, Yilan Wang, Kun Zhang, Shiyi Li, Yuman Dong, Yangying Li, Hai Niu, Guang Xin, Wen Huang.
      Severe acute pancreatitis (SAP) is a lethal gastrointestinal disorder, yet no specific and effective treatment is available. Its pathogenesis involves inflammatory cascade, oxidative stress, and autophagy dysfunction. Xanthohumol (Xn) displays various medicinal properties, including anti-inflammation, antioxidative, and enhancing autophagic flux. However, it is unclear whether Xn inhibits SAP. This study investigated the efficacy of Xn on sodium taurocholate (NaT)-induced SAP (NaT-SAP) in vitro and in vivo. First, Xn attenuated biochemical and histopathological responses in NaT-SAP mice. And Xn reduced NaT-induced necrosis, inflammation, oxidative stress, and autophagy impairment. The mTOR activator MHY1485 and the AKT activator SC79 partly reversed the treatment effect of Xn. Overall, this is an innovative study to identify that Xn improved pancreatic injury by enhancing autophagic flux via inhibition of AKT/mTOR. Xn is expected to become a novel SAP therapeutic agent.
    Keywords:  acute pancreatitis; autophagy; inflammation; oxidative stress; xanthohumol
    DOI:  https://doi.org/10.3389/fphar.2023.1105726
  49. Nat Commun. 2023 Feb 07. 14(1): 660
    Myristic acid as a checkpoint to regulate STING-dependent autophagy and interferon responses by promoting N-myristoylation.
    Mutian Jia, Yuanyuan Wang, Jie Wang, Danhui Qin, Mengge Wang, Li Chai, Yue Fu, Chunyuan Zhao, Chengjiang Gao, Jihui Jia, Wei Zhao.
      Stimulator of interferon gene (STING)-triggered autophagy is crucial for the host to eliminate invading pathogens and serves as a self-limiting mechanism of STING-induced interferon (IFN) responses. Thus, the mechanisms that ensure the beneficial effects of STING activation are of particular importance. Herein, we show that myristic acid, a type of long-chain saturated fatty acid (SFA), specifically attenuates cGAS-STING-induced IFN responses in macrophages, while enhancing STING-dependent autophagy. Myristic acid inhibits HSV-1 infection-induced innate antiviral immune responses and promotes HSV-1 replication in mice in vivo. Mechanistically, myristic acid enhances N-myristoylation of ARF1, a master regulator that controls STING membrane trafficking. Consequently, myristic acid facilitates STING activation-triggered autophagy degradation of the STING complex. Thus, our work identifies myristic acid as a metabolic checkpoint that contributes to immune homeostasis by balancing STING-dependent autophagy and IFN responses. This suggests that myristic acid and N-myristoylation are promising targets for the treatment of diseases caused by aberrant STING activation.
    DOI:  https://doi.org/10.1038/s41467-023-36332-3
  50. Cells. 2023 Feb 02. pii: 489. [Epub ahead of print]12(3):
    Autophagy Meets Aging: An Overview.
    Anna Picca, Emanuele Marzetti, Christiaan Leeuwenburgh.
      Aging is characterized by biological disarrangements that increase vulnerability to stressors, the development of chronic diseases (e [...].
    DOI:  https://doi.org/10.3390/cells12030489
  51. Oxid Med Cell Longev. 2023 ;2023 9645789
    RRP Regulates Autophagy through the AMPK Pathway to Alleviate the Effect of Cell Senescence on Atherosclerosis.
    Dekun Liu, Yueyue Song, Tinging Song, Lin Lin, Lei Zhang, Qiong Yang, Xingchen Niu, Dan Liang, Jiufeng Yin, Wenqing Yang, Dan Zhang.
      Autophagy is closely associated with atherosclerosis and other cardiovascular diseases (CVD). Compound Danshen prescription is widely used as a clinical antiatherosclerotic drug. In our previous studies, we have shown that the combined active component, ginsenoside Rg1-notoginsenoside R1-protocatechualdehyde (RRP), can effectively alleviate endothelial dysfunction and reduce atherosclerotic plaques. However, the association between cellular senescence, caused by reduced autophagy, and atherosclerosis remains unclear. In this study, we investigated whether RRP can enhance autophagy and alleviate cell senescence through the AMPK pathway. Our results showed that RRP reduced the secretion of inflammatory factors in the serum of atherosclerotic mice, enhanced autophagy, and alleviated aortic aging in mice, thus reducing atherosclerotic plaques. In human aortic endothelial cells (HAECs), RRP effectively enhanced autophagy and inhibited senescence by activating the AMPK pathway. When AMPKα was silenced, the effect of RRP was inhibited, thus reversing its antiaging effect. Overall, our results show that RRP regulates autophagy through the AMPK pathway, thereby inhibiting cell senescence and alleviating the progression of atherosclerosis, suggesting that RRP may be a potential candidate drug for the treatment of atherosclerosis.
    DOI:  https://doi.org/10.1155/2023/9645789
  52. Cell Host Microbe. 2023 Jan 31. pii: S1931-3128(23)00031-8. [Epub ahead of print]
    Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress.
    Maria Naama, Shahar Telpaz, Aya Awad, Shira Ben-Simon, Sarina Harshuk-Shabso, Sonia Modilevsky, Elad Rubin, Jasmin Sawaed, Lilach Zelik, Mor Zigdon, Nofar Asulin, Sondra Turjeman, Michal Werbner, Supapit Wongkuna, Rachel Feeney, Bjoern O Schroeder, Abraham Nyska, Meital Nuriel-Ohayon, Shai Bel.
      Colonic goblet cells are specialized epithelial cells that secrete mucus to physically separate the host and its microbiota, thus preventing bacterial invasion and inflammation. How goblet cells control the amount of mucus they secrete is unclear. We found that constitutive activation of autophagy in mice via Beclin 1 enables the production of a thicker and less penetrable mucus layer by reducing endoplasmic reticulum (ER) stress. Accordingly, genetically inhibiting Beclin 1-induced autophagy impairs mucus secretion, while pharmacologically alleviating ER stress results in excessive mucus production. This ER-stress-mediated regulation of mucus secretion is microbiota dependent and requires the Crohn's-disease-risk gene Nod2. Overproduction of mucus alters the gut microbiome, specifically expanding mucus-utilizing bacteria, such as Akkermansia muciniphila, and protects against chemical and microbial-driven intestinal inflammation. Thus, ER stress is a cell-intrinsic switch that limits mucus secretion, whereas autophagy maintains intestinal homeostasis by relieving ER stress.
    Keywords:  Beclin 1; ER stress; Nod2; autophagy; colitis; goblet cell; inflammatory bowel diseases; microbiota; mucus; unfolded protein response
    DOI:  https://doi.org/10.1016/j.chom.2023.01.006
  53. Nat Commun. 2023 Feb 06. 14(1): 638
    The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.
    Rakesh Ganji, Joao A Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S Clemen, Conrad C Weihl, John G Purdy, Steve P Gygi, Malavika Raman.
      The intimate association between the endoplasmic reticulum (ER) and mitochondrial membranes at ER-Mitochondria contact sites (ERMCS) is a platform for critical cellular processes, particularly lipid synthesis. How contacts are remodeled and the impact of altered contacts on lipid metabolism remains poorly understood. We show that the p97 AAA-ATPase and its adaptor ubiquitin-X domain adaptor 8 (UBXD8) regulate ERMCS. The p97-UBXD8 complex localizes to contacts and its loss increases contacts in a manner that is dependent on p97 catalytic activity. Quantitative proteomics and lipidomics of ERMCS demonstrates alterations in proteins regulating lipid metabolism and a significant change in membrane lipid saturation upon UBXD8 deletion. Loss of p97-UBXD8 increased membrane lipid saturation via SREBP1 and the lipid desaturase SCD1. Aberrant contacts can be rescued by unsaturated fatty acids or overexpression of SCD1. We find that the SREBP1-SCD1 pathway is negatively impacted in the brains of mice with p97 mutations that cause neurodegeneration. We propose that contacts are exquisitely sensitive to alterations to membrane lipid composition and saturation.
    DOI:  https://doi.org/10.1038/s41467-023-36298-2
  54. J Biol Chem. 2023 Feb 07. pii: S0021-9258(23)00125-4. [Epub ahead of print] 102993
    RhoA rescues cardiac senescence by regulating Parkin-mediated mitophagy.
    Joanne Ern Chi Soh, Akio Shimizu, Md Rasel Molla, Dimitar P Zankov, Le Kim Chi Nguyen, Mahbubur Rahman Khan, Wondwossen Wale Tesega, Si Chen, Misa Tojo, Yoshito Ito, Akira Sato, Masahito Hitosugi, Shigeru Miyagawa, Hisakazu Ogita.
      Heart failure is one of the leading causes of death worldwide. RhoA, a small GTPase, governs actin dynamics in various tissue and cell types, including cardiomyocytes; however, its involvement in cardiac function has not been fully elucidated. Here we generated cardiomyocyte-specific RhoA conditional knockout (cKO) mice, which demonstrated a significantly shorter lifespan with left ventricular dilation and severely impaired ejection fraction. We found that the cardiac tissues of the cKO mice exhibited structural disorganization with fibrosis, and also exhibited enhanced senescence compared with control mice. In addition, we show that cardiomyocyte mitochondria were structurally abnormal in the aged cKO hearts. Clearance of damaged mitochondria by mitophagy was remarkably inhibited in both cKO cardiomyocytes and RhoA-knockdown HL-1 cultured cardiomyocytes. In RhoA-depleted cardiomyocytes, we reveal that the expression of Parkin, an E3 ubiquitin ligase that plays a crucial role in mitophagy, was reduced, and expression of N-Myc, a negative regulator of Parkin, was increased. We further reveal that the RhoA-Rho kinase axis induced N-Myc phosphorylation, which led to N-Myc degradation and Parkin upregulation. Re-expression of Parkin in RhoA-depleted cardiomyocytes restored mitophagy, reduced mitochondrial damage, attenuated cardiomyocyte senescence, and rescued cardiac function both in vitro and in vivo. Finally, we found that patients with idiopathic dilated cardiomyopathy (DCM) without causal mutations for DCM showed reduced cardiac expression of RhoA and Parkin. These results suggest that RhoA promotes Parkin-mediated mitophagy as an indispensable mechanism contributing to cardioprotection in the aging heart.
    Keywords:  Ras homolog gene family; cardiomyocyte; cardiomyopathy; member A (RhoA); mitophagy; parkin; senescence; signal transduction
    DOI:  https://doi.org/10.1016/j.jbc.2023.102993
  55. eNeuro. 2023 Feb 09. pii: ENEURO.0340-22.2023. [Epub ahead of print]
    Neurovascular development in Pten and Tsc2 mouse mutants.
    Mary Dusing, Candi L LaSarge, Angela White, Lilian G Jerow, Christina Gross, Steve C Danzer.
      Hyperactivation of the mTOR signaling pathway is linked to more than a dozen neurological diseases, causing a range of pathologies, including excess neuronal growth, disrupted neuronal migration, cortical dysplasia, epilepsy and autism. The mTOR pathway also regulates angiogenesis. For the present study, therefore, we queried whether loss of Pten or Tsc2, both mTOR negative regulators, alters brain vasculature in three mouse models: one with Pten loss restricted to hippocampal dentate granule cells (DGC-Pten KOs), a second with widespread Pten loss from excitatory forebrain neurons (FB-Pten KOs) and a third with focal loss of Tsc2 from cortical excitatory neurons (f-Tsc2 KOs). Total hippocampal vessel length and volume per dentate gyrus were dramatically increased in DGC-Pten knockouts. DGC-Pten knockouts had larger dentate gyri overall, however, and when normalized to these larger structures, vessel density was preserved. In addition, tests of blood-brain barrier integrity did not reveal increased permeability. FB-Pten KOs recapitulated the findings in the more restricted DGC-Pten KOs, with increased vessel area, but preserved vessel density. FB-Pten KOs did, however, exhibit elevated levels of the angiogenic factor VegfA. In contrast to findings with Pten, focal loss of Tsc2 from cortical excitatory neurons produced a localized increase in vessel density. Together, these studies demonstrate that hypervascularization is not a consistent feature of mTOR hyperactivation models and suggest that loss of different mTOR pathway regulatory genes exert distinct effects on angiogenesis.Significance StatementHere, we examined three mouse models to determine whether mTOR hyperactivation consistently drives brain hypervascularization. Both focal loss of Pten from dentate granule cells, and widespread loss from forebrain produced larger brain structures and corresponding increases in vascular growth, but normal vessel density. By contrast, focal cortical Tsc2 lesions exhibited significantly increased vessel density. Findings indicate that hypervascularization is not characteristic of all mTOR hyperactivation models and suggest vascular changes may be driven by gene-specific effects.
    Keywords:  Angiogenesis; Focal Cortical Dysplasia; Vegf; mTOR; mtoropathy; tuberous sclerosis
    DOI:  https://doi.org/10.1523/ENEURO.0340-22.2023
  56. Molecules. 2023 Jan 17. pii: 924. [Epub ahead of print]28(3):
    Inhibition of Klf10 Attenuates Oxidative Stress-Induced Senescence of Chondrocytes via Modulating Mitophagy.
    Jie Shang, Nan Lin, Rong Peng, Ning Jiang, Biao Wu, Baizhou Xing, Shiyuan Lin, Xianghe Xu, Huading Lu.
      Osteoarthritis (OA) is the most prevalent degenerative joint disease in the elderly. Accumulation of evidence has suggested that chondrocyte senescence plays a significant role in OA development. Here, we show that Krüppel-like factor 10 (Klf10), also named TGFβ inducible early gene-1 (TIEG1), is involved in the pathology of chondrocyte senescence. Knocking down the Klf10 in chondrocytes attenuated the tert-butyl hydroperoxide (TBHP)-induced senescence, inhibited generation of reactive oxygen species (ROS), and maintained mitochondrial homeostasis by activating mitophagy. These findings suggested that knocking down Klf10 inhibited senescence-related changes in chondrocytes and improved cartilage homeostasis, indicating that Klf10 may be a therapeutic target for protecting cartilage against OA.
    Keywords:  Klf10; autophagy; mitochondria; osteoarthritis; senescence
    DOI:  https://doi.org/10.3390/molecules28030924
  57. bioRxiv. 2023 Jan 29. pii: 2023.01.28.526044. [Epub ahead of print]
    Axonal transport of autophagosomes is regulated by dynein activators JIP3/JIP4 and ARF/RAB GTPases.
    Sydney E Cason, Erika L F Holzbaur.
      Neuronal autophagosomes, "self-eating" degradative organelles, form at presynaptic sites in the distal axon and are transported to the soma to recycle their cargo. During transit, autophagic vacuoles (AVs) mature through fusion with lysosomes to acquire the enzymes necessary to breakdown their cargo. AV transport is driven primarily by the microtubule motor cytoplasmic dynein in concert with dynactin and a series of activating adaptors that change depending on organelle maturation state. The transport of mature AVs is regulated by the scaffolding proteins JIP3 and JIP4, both of which activate dynein motility in vitro. AV transport is also regulated by ARF6 in a GTP-dependent fashion. While GTP-bound ARF6 promotes the formation of the JIP3/4-dynein-dynactin complex, RAB10 competes with the activity of this complex by increasing kinesin recruitment to axonal AVs and lysosomes. These interactions highlight the complex coordination of motors regulating organelle transport in neurons.Summary: Mature autophagosomes in the axon are transported by the microtubule motor dynein, activated by JNK-interacting proteins 3 and 4 (JIP3/4). This motility is regulated by the small GTPases ARF6 and RAB10. The tight regulation of autolysosomal transport is essential for intracellular recycling to maintain neuronal homeostasis.
    DOI:  https://doi.org/10.1101/2023.01.28.526044
  58. Science. 2023 Feb 09. eade8873
    Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex.
    Julian F Ehrmann, Daniel B Grabarczyk, Maria Heinke, Luiza Deszcz, Robert Kurzbauer, Otto Hudecz, Alexandra Shulkina, Rebeca Gogova, Anton Meinhart, Gijs A Versteeg, Tim Clausen.
      Inhibitor of apoptosis proteins (IAPs) bind to pro-apoptotic proteases, keeping them inactive and preventing cell death. The atypical ubiquitin ligase BIRC6 is the only essential IAP, additionally functioning as a suppressor of autophagy. We performed a structure-function analysis of BIRC6 in complex with caspase-9, HTRA2, SMAC, and LC3B which are critical apoptosis and autophagy proteins. Cryo-electron microscopy structures show that BIRC6 forms a megadalton crescent shape that arcs around a spacious cavity containing receptor sites for client proteins. Multivalent binding of SMAC obstructs client binding, impeding ubiquitination of both autophagy and apoptotic substrates. Based on these data, we discuss how the BIRC6/SMAC complex can act as a stress-induced hub to regulate apoptosis and autophagy drivers.
    DOI:  https://doi.org/10.1126/science.ade8873
  59. Cell Death Dis. 2023 Feb 07. 14(2): 88
    PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products.
    Wei Li, Wang-Sheng Jiang, Ya-Ru Su, Ke-Wu Tu, Lin Zou, Cong-Rui Liao, Qian Wu, Zi-Han Wang, Zhao-Ming Zhong, Jian-Ting Chen, Si-Yuan Zhu.
      Osteoblast apoptosis plays an important role in age-related bone loss and osteoporosis. Our previous study revealed that advanced oxidation protein products (AOPPs) could induce nicotinamide adenine dinucleotide phosphate oxidase (NOX)-derived reactive oxygen species (ROS) production, cause mitochondrial membrane potential (ΔΨm) depolarization, trigger the mitochondria-dependent intrinsic apoptosis pathway, and lead to osteoblast apoptosis and ultimately osteopenia and bone microstructural destruction. In this study, we found that AOPPs also induced mitochondrial ROS (mtROS) generation in osteoblastic MC3T3-E1 cells, which was closely related to NOX-derived ROS, and aggravated the oxidative stress condition, thereby further promoting apoptosis. Removing excessive ROS and damaged mitochondria is the key factor in reversing AOPP-induced apoptosis. Here, by in vitro studies, we showed that rapamycin further activated PINK1/Parkin-mediated mitophagy in AOPP-stimulated MC3T3-E1 cells and significantly alleviated AOPP-induced cell apoptosis by eliminating ROS and damaged mitochondria. Our in vivo studies revealed that PINK1/Parkin-mediated mitophagy could decrease the plasma AOPP concentration and inhibit AOPP-induced osteoblast apoptosis, thus ameliorating AOPP accumulation-related bone loss, bone microstructural destruction and bone mineral density (BMD) loss. Together, our study indicated that therapeutic strategies aimed at upregulating osteoblast mitophagy and preserving mitochondrial function might have potential for treating age-related osteoporosis.
    DOI:  https://doi.org/10.1038/s41419-023-05595-5
  60. Front Med (Lausanne). 2022 ;9 1071864
    Autophagy-dependent ferroptosis in kidney disease.
    Yuanting Yang, Jiayi Cheng, Qisheng Lin, Zhaohui Ni.
      Ferroptosis is a new type of cell death caused by the lack of glutathione peroxidase 4 (GPX4) and the imbalance of cellular redox. It is characterized by the accumulation of lipid peroxides on cell membranes. Multiple regulatory pathways of ferroptosis include the GPX4, glutamate-cystine antiporter (System Xc-), lipid metabolism, and iron metabolism pathways. Recent studies have reported that autophagy-dependent ferroptosis (ferroptosis meditated by ferritinophagy, lipophagy, and clockophagy) plays a significant role in the occurrence of several diseases, including diseases affecting the nerves, liver, lungs, and kidneys. This review provides an overview of research progress made on autophagy-dependent ferroptosis in kidney diseases.
    Keywords:  acute kidney injury; autophagy; cell death; ferroptosis; kidney disease
    DOI:  https://doi.org/10.3389/fmed.2022.1071864
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