Autophagy最新文献

{"title":"Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function.","authors":"Chih-Yao Chung, Kritarth Singh, Preethi Sheshadri, Gabriel E Valdebenito, Anitta R Chacko, María Alicia Costa Besada, Xiao Fei Liang, Lida Kabir, Robert D S Pitceathly, Gyorgy Szabadkai, Michael R Duchen","doi":"10.1080/15548627.2024.2437908","DOIUrl":"https://doi.org/10.1080/15548627.2024.2437908","url":null,"abstract":"<p><p>Mitochondrial DNA (mtDNA) encodes genes essential for oxidative phosphorylation. The m.3243A>G mutation causes severe disease, including myopathy, lactic acidosis and stroke-like episodes (MELAS) and is the most common pathogenic mtDNA mutation in humans. We have previously shown that the mutation is associated with constitutive activation of the PI3K-AKT-MTORC1 axis. Inhibition of this pathway in patient fibroblasts reduced the mutant load, rescued mitochondrial bioenergetic function and reduced glucose dependence. We have now investigated the mechanisms that select against the mutant mtDNA under these conditions. Basal macroautophagy/autophagy and lysosomal degradation of mitochondria were suppressed in the mutant cells. Pharmacological inhibition of any step of the PI3K-AKT-MTORC1 pathway activated mitophagy and progressively reduced m.3243A>G mutant load over weeks. Inhibition of autophagy with bafilomycin A₁ or chloroquine prevented the reduction in mutant load, suggesting that mitophagy was necessary to remove the mutant mtDNA. Inhibition of the pathway was associated with metabolic remodeling - mitochondrial membrane potential and respiratory rate improved even before a measurable fall in mutant load and proved crucial for mitophagy. Thus, maladaptive activation of the PI3K-AKT-MTORC1 axis and impaired autophagy play a major role in shaping the presentation and progression of disease caused by the m.3243A>G mutation. Our findings highlight a potential therapeutic target for this otherwise intractable disease.<b>Abbreviation</b>: ΔΨ_m: mitochondrial membrane potential; 2DG: 2-deoxy-D-glucose; ANOVA: analysis of variance; ARMS-qPCR: amplification-refractory mutation system quantitative polymerase chain reaction; Baf A1: bafilomycin A₁; BSA: bovine serum albumin; CQ: chloroquine; Cybrid: cytoplasmic hybrid; CYCS: cytochrome c, somatic; DCA: dichloroacetic acid; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethylsulfoxide; EGFP: enhanced green fluorescent protein; LC3B-I: carboxy terminus cleaved microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated microtubule-associated protein 1 light chain 3 beta; LY: LY290042; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; MFC: mitochondrial fragmentation count; mt-Keima: mitochondrial-targeted mKeima; mtDNA: mitochondrial DNA/mitochondrial genome; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OA: oligomycin+antimycin A; OxPhos: oxidative phosphorylation; DPBS: Dulbecco's phosphate-buffered saline; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; PPARGC1B/PGC-1β: PPARG coactivator 1 beta; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced kinase 1; qPCR: quantitative polymerase chain reaction; RNA-seq: RNA sequencing; RP: rapamycin; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-16"},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142820265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rubicon regulates exosome secretion via the non-autophagic pathway.","authors":"Kyosuke Yanagawa, Tamotsu Yoshimori","doi":"10.1080/15548627.2024.2437653","DOIUrl":"https://doi.org/10.1080/15548627.2024.2437653","url":null,"abstract":"<p><p>Exosomes are small extracellular vesicles (EVs), which have the diameter of 50-150 nm and originate from intralumenal vesicles in multivesicular endosomes (MVBs). Exosomes secreted from donor cells are delivered to recipient cells for transferring of exosome cargos, such as proteins, lipids and nucleic acids. The cargo transfer by exosomes has a pivotal role in cell-to-cell communication for many cellular processes; however, the detailed mechanism remains largely elusive. In our recent study, we found that RUBCN/rubicon regulates exosome secretion through endosomal recruitment of WIPI2, which promotes ESCRT-dependent MVB formation. We further showed that this pathway is essential for age-dependent increasing of exosomes, which transfer the pro-senescent microRNAs, including <i>Mir26a</i> and <i>Mir486a</i>, and accelerate cellular senescence in the recipient cells. Our findings highlight RUBCN's key role in exosome secretion and its impact on cellular senescence, providing insights into its potential contributions to aging.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142820277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy-dependent hepatocyte secretion of DBI/ACBP induced by glucocorticoids determines the pathogenesis of cushing syndrome.","authors":"Hui Pan, Ai-Ling Tian, Fréderic Castinetti, Isabelle Martins, Oliver Kepp, Guido Kroemer","doi":"10.1080/15548627.2024.2437649","DOIUrl":"https://doi.org/10.1080/15548627.2024.2437649","url":null,"abstract":"<p><p>DBI/ACBP is a phylogenetically ancient hormone that stimulates appetite and lipo-anabolism. In response to starvation, DBI/ACBP is secreted through a noncanonical, macroautophagy/autophagy-dependent pathway. The physiological hunger reflex involves starvation-induced secretion of DBI/ACBP from multiple cell types. DBI/ACBP concentrations subsequently increase in extracellular fluids to stimulate food intake. Recently, we observed that glucocorticoids, which are endogenous stress hormones as well as anti-inflammatory drugs, upregulate DBI/ACBP expression at the transcriptional level and stimulate autophagy in hepatocytes, thereby causing a surge in circulating DBI/ACBP levels. Prolonged increase in glucocorticoid concentrations causes an extreme form of metabolic syndrome, dubbed \"Cushing syndrome\", which is characterized by clinical features including hyperphagia, hyperdipsia, dyslipidemia, hyperinsulinemia, insulin resistance, lipodystrophy, visceral adiposity, steatosis, sarcopenia and osteoporosis. Mice and patients with Cushing syndrome exhibit supraphysiological DBI/ACBP plasma levels. Of note, neutralization of extracellular DBI/ACBP protein with antibodies or mutation of the DBI/ACBP receptor (i.e. the GABRG2 subunit of GABR [gamma-aminobutyric acid type A receptor]) renders mice resistant to the induction of Cushing syndrome. Similarly, knockout of <i>Dbi/Acbp</i> in hepatocytes suppresses the corticotherapy-induced surge in plasma DBI/ACBP concentrations and prevents the manifestation of most of the characteristics of Cushing syndrome. We conclude that autophagy-mediated secretion of DBI/ACBP by hepatocytes constitutes a critical step of the pathomechanism of Cushing syndrome. It is tempting to speculate that stress-induced chronic elevations of endogenous glucocorticoids also compromise human health due to the protracted augmentation of circulating DBI/ACBP concentrations.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy modulates male fertility in arabidopsis.","authors":"Zhen Lu, He Yan, Hao Wang","doi":"10.1080/15548627.2024.2441305","DOIUrl":"https://doi.org/10.1080/15548627.2024.2441305","url":null,"abstract":"<p><p>Macroautophagy/autophagy is a highly conserved catabolic process in eukaryotes and plays pivotal roles in regulating male fertility and sexual reproduction. In metazoans, mutations in core ATG (autophagy related) proteins frequently result in severe defects in sperm formation and maturation, resulting in male sterility. In contrast, autophagy has traditionally been considered dispensable for reproduction in <i>Arabidopsis thaliana</i>, as most <i>atg</i> mutants can complete fertilization and produce viable progeny without apparent reproductive defects. We recently systematically re-assessed the role of autophagy in Arabidopsis male gametophyte development and fertility using <i>atg5</i> and <i>atg7</i> mutants, and the double mutant. These mutants exhibited partial defects in pollen germination, pollen tube growth and seed production compared to the wild type (WT). Furthermore, our findings reveal that autophagy is essential for modulating actin dynamic organization during sperm cell formation within pollen grains and for supporting pollen tube elongation. This is achieved through the selective degradation of actin depolymerizing factors ADF7 and PFN2/Profilin2. NBR1 is identified as a key receptor mediating this process. This study provides valuable insights into the evolutionary conservation and functional divergence of autophagy in modulating male fertility, highlighting distinctions between plant and mammalian systems.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP4 depletion-driven RAB7A ubiquitylation impairs autophagosome-lysosome fusion and aggravates periodontitis.","authors":"Sen Kang, Shuxin Liu, Xian Dong, Haoyu Li, Yuanyi Qian, Anna Dai, Wentao He, Xiaojun Li, Qianming Chen, Huiming Wang, Pei-Hui Ding","doi":"10.1080/15548627.2024.2429371","DOIUrl":"https://doi.org/10.1080/15548627.2024.2429371","url":null,"abstract":"<p><p>Periodontitis, a prevalent and chronic inflammatory disease, is intricately linked with macroautophagy/autophagy, which has a dual role in maintaining periodontal homeostasis. Despite its importance, the precise interplay between autophagy and periodontitis pathogenesis remains to be fully elucidated. In this study, our investigation revealed that the ubiquitination of RAB7A, mediated by reduced levels of the deubiquitinating enzyme USP4 (ubiquitin specific peptidase 4), disrupts normal lysosomal trafficking and autophagosome-lysosome fusion, thereby contributing significantly to periodontitis progression. Specifically, through genomic and histological analysis of clinical gingival samples, we observed a decreased RAB7A expression and impaired autophagic activity in periodontitis. This was further substantiated through experimental periodontitis mice, where RAB7A inactivation was shown to directly affect autophagy efficiency and drive periodontitis progression. Next, we explored the function of active RAB7A to promote lysosomal trafficking dynamics and autophagosome-lysosome fusion, which was inhibited by RAB7A ubiquitination in macrophages stimulated by <i>Porphyromonas gingivalis</i> (<i>P. g</i>.), one of the keystone pathogens of periodontitis. Last, by proteomics analysis, we revealed that the ubiquitination of RAB7A was mediated by USP4 and validated that upregulation of USP4 could attenuate periodontitis in vivo. In conclusion, these findings highlight the interaction between USP4 and RAB7A as a promising target for therapeutic intervention in managing periodontal diseases.<b>Abbreviation:</b> 3-MA: 3-methyladenine; Baf A1:bafilomycin A₁; BECN1: beclin 1, autophagy related; CEJ-ABC: cementoenamel junctionto alveolar bone crest; IL1B/IL-1β: interleukin 1 beta; KD:knockdown; LPS: lipopolysaccharide; MOI: multiplicity of infection;OE: overexpression; <i>P.g</i>.: <i>Porphyromonasgingivalis</i>; RILP: Rabinteracting lysosomal protein; ScRNA-seq: single-cell RNA sequencing; SQSTM1/p62: sequestosome 1; <i>S.s</i>.: <i>Streptococcus sanguinis</i>; USP4:ubiquitin specific peptidase 4.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-18"},"PeriodicalIF":0.0,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysosomal damage due to cholesterol accumulation triggers immunogenic cell death.","authors":"Karla Alvarez-Valadez, Allan Sauvat, Julien Diharce, Marion Leduc, Gautier Stoll, Lionel Guittat, Flavia Lambertucci, Juliette Paillet, Omar Motino, Lucille Ferret, Alexandra Muller, Sabrina Forveille, Maria Chiara Maiuri, Oliver Kepp, Alexandre G de Brevern, Harald Wodrich, Jonathan G Pol, Guido Kroemer, Mojgan Djavaheri-Mergny","doi":"10.1080/15548627.2024.2440842","DOIUrl":"https://doi.org/10.1080/15548627.2024.2440842","url":null,"abstract":"<p><p>Cholesterol serves as a vital lipid that regulates numerous physiological processes. Nonetheless, its role in regulating cell death processes remains incompletely understood. In this study, we investigated the role of cholesterol trafficking in immunogenic cell death. Through cell-based drug screening, we identified two antidepressants, sertraline and indatraline, as potent inducers of the nuclear translocation of TFEB (transcription factor EB). Activation of TFEB was mediated through the autophagy-independent lipidation of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3). Both compounds promoted cholesterol accumulation within lysosomes, resulting in lysosomal membrane permeabilization, disruption of autophagy and cell death that could be reversed by cholesterol depletion. Molecular docking analysis indicated that sertraline and indatraline have the potential to inhibit cholesterol binding to the lysosomal cholesterol transporters, NPC1 (NPC intracellular cholesterol transporter 1) and NPC2. This inhibitory effect might be further enhanced by the upregulation of NPC1 and NPC2 expression by TFEB. Both antidepressants also upregulated PLA2G15 (phospholipase A2 group XV), an enzyme that elevates lysosomal cholesterol. In cancer cells, sertraline and indatraline elicited immunogenic cell death, converting dying cells into prophylactic vaccines that were able to confer protection against tumor growth in mice. In a therapeutic setting, a single dose of each compound was sufficient to significantly reduce the outgrowth of established tumors in a T-cell-dependent manner. These results identify sertraline and indatraline as immunostimulatory agents for cancer treatment. More generally, this research shed light on novel therapeutic avenues harnessing lysosomal cholesterol transport to regulate immunogenic cell death.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Janus-like behavior of intrinsically disordered regions in reticulophagy.","authors":"Sergio Alejandro Poveda Cuevas, Kateryna Lohachova, Borna Markusic, Ivan Dikic, Gerhard Hummer, Ramachandra Bhaskara","doi":"10.1080/15548627.2024.2437652","DOIUrl":"https://doi.org/10.1080/15548627.2024.2437652","url":null,"abstract":"<p><p>Intrinsically disordered regions (IDRs) are crucial to homeostatic and organellar remodeling pathways. In reticulophagy/ER-phagy, long cytosolic IDR-containing receptors (e.g. RETREG1/FAM134B) house the LC3-interacting region (LIR) motif to recruit the phagophore. The precise functions of the IDR beyond engaging the autophagic machinery are unclear. Here, we comment on the role of the RETREG1-IDR based on our recent computer modeling and molecular dynamics (MD) simulations. Extensive analysis of the RETREG1-IDR indicates a continuum of conformations between expanded and compact structures, displaying a Janus-like feature. Using an adapted MARTINI model, we find that the IDR ensemble properties vary widely depending on the membrane anchor. IDRs alone are sufficient to promote and sense membrane curvature and can act as entropic tethers. When anchored to the RHD, they adopt compact collapsed conformations, acting as effector scaffolds that amplify RHD membrane remodeling properties, enhancing receptor-clustering and accelerating spontaneous budding. These findings expand the operational scope of IDRs within reticulophagy, offering fresh insights into a mechanistic understanding of membrane remodeling.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired chaperone-mediated autophagy leads to abnormal SORT1 (sortilin 1) turnover and CES1-dependent triglyceride hydrolysis.","authors":"You-Jin Choi, Yoon Ah Nam, Ji Ye Hyun, Jihyeon Yu, Yewon Mun, Sung Ho Yun, Wonseok Lee, Cheon Jun Park, Byung Woo Han, Byung-Hoon Lee","doi":"10.1080/15548627.2024.2435234","DOIUrl":"10.1080/15548627.2024.2435234","url":null,"abstract":"<p><p>SORT1 (sortilin 1), a member of the the Vps10 (vacuolar protein sorting 10) family, is involved in hepatic lipid metabolism by regulating very low-density lipoprotein (VLDL) secretion and facilitating the lysosomal degradation of CES1 (carboxylesterase 1), crucial for triglyceride (TG) breakdown in the liver. This study explores whether SORT1 is targeted for degradation by chaperone-mediated autophagy (CMA), a selective protein degradation pathway that directs proteins containing KFERQ-like motifs to lysosomes via LAMP2A (lysosomal-associated membrane protein 2A). Silencing LAMP2A or HSPA8/Hsc70 with siRNA increased cytosolic SORT1 protein levels. Leupeptin treatment induced lysosomal accumulation of SORT1, unaffected by si<i>LAMP2A</i> co-treatment, indicating CMA-dependent degradation. Human SORT1 contains five KFERQ-like motifs (₆₅₈VVTKQ₆₆₂, ₇₃₀VREVK₇₃₄, ₇₃₃VKDLK₇₃₇, ₇₃₄KDLKK₇₃₈, and ₇₃₅DLKKK₇₃₉), crucial for HSPA8 recognition; mutating any single amino acid within these motifs decreased HSPA8 binding. Furthermore, compromised CMA activity resulted in elevated SORT1-mediated degradation of CES1, contributing to increased lipid accumulation in hepatocytes. Consistent with <i>in vitro</i> findings, LAMP2A knockdown in mice exacerbated high-fructose diet-induced fatty liver, marked by increased SORT1 and decreased CES1 levels. Conversely, LAMP2A overexpression promoted SORT1 degradation and CES1D accumulation, counteracting fasting-induced CES1D suppression through CMA activation. Our findings reveal that SORT1 is a substrate of CMA, highlighting its crucial role in directing CES1 to lysosomes. Consequently, disrupting CMA-mediated SORT1 degradation significantly affects CES1-dependent TG hydrolysis, thereby affecting hepatic lipid homeostasis.<b>Abbreviations</b>: APOB: apolipoprotein B; CES1: carboxylesterase 1; CMA: chaperone-mediated autophagy; HSPA8/Hsc70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; LDL-C: low-density lipoprotein-cholesterol; PLIN: perilipin; SORT1: sortilin 1; TG: triglyceride; VLDL: very low-density lipoprotein; Vps10: vacuolar protein sorting 10.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-13"},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142752380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upregulation of ISG15 induced by MAPT/tau accumulation represses autophagic flux by inhibiting HDAC6 activity: a vicious cycle in alzheimer disease.","authors":"Qian Liu, Xin Wang, Zhi-Ting Fang, Jun-Ning Zhao, Xue-Xiang Rui, Bing-Ge Zhang, Ye He, Rui-Juan Liu, Jian Chen, Gao-Shang Chai, Gong-Ping Liu","doi":"10.1080/15548627.2024.2431472","DOIUrl":"https://doi.org/10.1080/15548627.2024.2431472","url":null,"abstract":"<p><p>Alzheimer disease (AD), a prevalent neurodegenerative condition in the elderly, is marked by a deficit in macroautophagy/autophagy, leading to intracellular MAPT/tau accumulation. While ISG15 (ISG15 ubiquitin like modifier) has been identified as a regulator of selective autophagy in ataxia telangiectasia (A-T), its role in AD remains unexplored. Our study reveals elevated ISG15 levels in the brains of patients with sporadic AD and AD models <i>in vivo</i> and <i>in vitro</i>. ISG15 overexpression in cells and the hippocampus inhibited HDAC6 (histone deacetylase 6) activity through C-terminal LRLRGG binding to HDAC6. Consequently, this increased CTTN (cortactin) acetylation, disrupted CTTN and F-actin recruitment to lysosomes, and impaired autophagosome (AP)-lysosome (LY) fusion. These disruptions led to MAPT/tau accumulation, synaptic damage, neuronal loss, and cognitive deficits. Conversely, ISG15 knockdown in our HsMAPT (human MAPT) pathology model restored HDAC6 activity, promoted AP-LY fusion, and improved cognitive function. This study identifies ISG15 as a key regulator of autophagic flux in AD, suggesting that targeting ISG15-mediated autophagy could offer therapeutic potential for AD.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preserving mitochondrial homeostasis protects against drug-induced liver injury via inducing OPTN (optineurin)-dependent Mitophagy.","authors":"Jiajia Wang, Yueping Qiu, Lijun Yang, Jincheng Wang, Jie He, Chengwu Tang, Zhaoxu Yang, Wenxiang Hong, Bo Yang, Qiaojun He, Qinjie Weng","doi":"10.1080/15548627.2024.2384348","DOIUrl":"10.1080/15548627.2024.2384348","url":null,"abstract":"<p><p>Disruption of mitochondrial function is observed in multiple drug-induced liver injuries (DILIs), a significant global health threat. However, how the mitochondrial dysfunction occurs and whether maintain mitochondrial homeostasis is beneficial for DILIs remains unclear. Here, we show that defective mitophagy by OPTN (optineurin) ablation causes disrupted mitochondrial homeostasis and aggravates hepatocytes necrosis in DILIs, while OPTN overexpression protects against DILI depending on its mitophagic function. Notably, mass spectrometry analysis identifies a new mitochondrial substrate, GCDH (glutaryl-CoA dehydrogenase), which can be selectively recruited by OPTN for mitophagic degradation, and a new cofactor, VCP (valosin containing protein) that interacts with OPTN to stabilize BECN1 during phagophore assembly, thus boosting OPTN-mediated mitophagy initiation to clear damaged mitochondria and preserve mitochondrial homeostasis in DILIs. Then, the accumulation of OPTN in different DILIs is further validated with a protective effect, and pyridoxine is screened and established to alleviate DILIs by inducing OPTN-mediated mitophagy. Collectively, our findings uncover a dual role of OPTN in mitophagy initiation and implicate the preservation of mitochondrial homeostasis via inducing OPTN-mediated mitophagy as a potential therapeutic approach for DILIs.<b>Abbreviation:</b> AILI: acetaminophen-induced liver injury; ALS: amyotrophic lateral sclerosis; APAP: acetaminophen; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DILI: drug-induced liver injury; FL: full length; GCDH: glutaryl-CoA dehydrogenase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GO: gene ontology; GSEA: gene set enrichment analysis; GPT/ALT: glutamic - pyruvic transaminase; INH: isoniazid; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MST: microscale thermophoresis; MT-CO2/COX-II: mitochondrially encoded cytochrome c oxidase II; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TSN: toosendanin; VCP: valosin containing protein, WIPI2: WD repeat domain, phosphoinositide interacting 2.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2677-2696"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}