Autophagy最新文献

{"title":"Endothelial F3-mediated autolysosome and lipid metabolism promote resistance to anti-VEGFA therapy in metastatic colorectal cancer.","authors":"Nan Huang, Junxi Ren, Xinyue Deng, Qize Bao, Genjie Huang, Shimeng Zhi, Yuedan Li, Juan Li, Binghui Hu, Dongqiang Zeng, Huiying Sun, Wei Zeng, Min Shi, Wangjun Liao, Jianhua Wu, Na Huang","doi":"10.1080/15548627.2025.2551720","DOIUrl":"https://doi.org/10.1080/15548627.2025.2551720","url":null,"abstract":"<p><p>Patients with metastatic colorectal cancer (mCRC) to the liver exhibit poor survival rates. Chemotherapy combined with anti-vascular therapy has emerged as the standard treatment, but resistance to anti-VEGFA therapy inevitably develops. The metabolic reprogramming of tumor vascular endothelial cells (TECs) plays a crucial, yet still poorly understood, role in the development of therapeutic resistance. We identified lipid-rich and fatty acid oxidation (FAO)-activated proliferating TECs in fatty colorectal cancer liver metastasis (CRLM) that mediate resistance to anti-VEGFA treatment. The TEC-specific F3 protein inhibited the macroautophagy/autophagy-lysosome pathway through the MAPK/JNK-MAPK/ERK-TP53/p53 signaling axis, thereby prevented CPT1A protein degradation and enhanced FAO. F3 was also involved in promoting lipid uptake and lipophagy. This process promoted cellular FAO under conditions of fatty acids and anti-VEGFA stimulation. Targeting FAO proved effective in overcoming resistance to anti-VEGFA treatment. Our findings elucidated the role of lipid metabolism in therapy-resistant TECs in fatty CRLM and provided a theoretical foundation for further research on anti-VEGFA therapy resistance. Moreover, we underscored the potential of combining FAO inhibitors to enhance the efficacy of anti-angiogenic therapy.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-20"},"PeriodicalIF":14.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145024841","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 dictates PHGDH-mediated serine metabolism in a timely manner to support oocyte development.","authors":"Hainan He, Qianqian Zhang, Zhengang Fan, Hongfei Duan, Yu Wang, Bingbing Luo, Qiao Li, Junjie Liu, Delong Li, Shengya Fang, Xia Zhang, Junling Wang, Yi-Liang Miao, Jilong Zhou","doi":"10.1080/15548627.2025.2552907","DOIUrl":"10.1080/15548627.2025.2552907","url":null,"abstract":"<p><p>The metabolic co-dependence of the oocyte and surrounding granulosa cells is crucial for oocyte developmental competence. Previous research has shown that serine-glycine and its key downstream metabolites are significantly involved in the process of oocyte maturation. However, the mechanism of serine metabolism and its influence on oocyte maturation remain unclear. In this study, we demonstrate that the serine metabolism enzyme PHGDH, which mediates <i>de novo</i> serine synthesis, is highly activated in granulosa cells and plays a crucial role in maintaining their metabolic and transcriptional homeostasis. By using our previously reported granulosa cell-oocyte co-culture system, we found that macroautophagy/autophagy regulates oocyte maturation by modulating PHGDH-mediated serine metabolism in a stage-specific manner, and this regulation is mediated by CALCOCO2/NDP52-dependent selective autophagy. Additional experiments indicated that S-adenosylmethionine (SAM) is a potential downstream product of serine metabolism, and that restoring SAM significantly rescues both granulosa cell homeostasis and oocyte quality. At the molecular level, we demonstrated that SAM regulates <i>Igf1</i> expression by altering the H3K4me3 modification level in its promoter region, highlighting a serine-SAM-H3K4me3<i>-Igf1</i> regulatory axis during oocyte maturation. Finally, we demonstrated that oocyte developmental capacity depends on <i>de novo</i> serine synthesis in granulosa cells during germinal vesicle breakdown (GVBD) stage rather than on the exogenous uptake of serine, and that disruption of serine synthesis significantly affects oocyte developmental capacity. Overall, our findings reveal how serine metabolism links granulosa cells and oocytes, provides new targets for predicting oocyte quality, and may help with strategies for early diagnosis or therapeutic intervention in improving reproductive outcomes.<b>Abbreviations</b> aa: amino acid; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; COCs: cumulus-oocyte complexes; CQ: chloroquine; DEG: differentially expressed gene; GV: germinal vesicle; GVBD: germinal vesicle breakdown; IGF1: insulin-like growth factor 1; MII: metaphase II stage of meiosis; OPTN: optineurin; Pb1: first polar body: PHGDH: 3-phosphoglycerate dehydrogenase; ROS: reactive oxygen species; SAM: s-adenosylmethionine; SQSTM1/p62: sequestosome 1; Ub: ubiquitin; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-20"},"PeriodicalIF":14.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982345","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":"A novel <i>C. elegans</i> model for MAPT/Tau spreading reveals genes critical for endolysosomal integrity and seeded MAPT/Tau aggregation.","authors":"Carl Alexander Sandhof, Nicole Martin, Jessica Tittelmeier, Annabelle Schlueter, Martina Pezzali, David C Schoendorf, Timo Lange, Peter Reinhardt, Janina S Ried, Siwen Liang, Gamze Uzunoglu, Laura Gasparini, Thomas R Jahn, Dagmar E Ehrnhoefer, Carmen Nussbaum-Krammer","doi":"10.1080/15548627.2025.2551676","DOIUrl":"10.1080/15548627.2025.2551676","url":null,"abstract":"<p><p>The spreading of MAPT/Tau pathology is closely associated with the progression of neurodegeneration and cognitive decline in Alzheimer disease and other tauopathies. A key event in this process is the rupture of endolysosomal vesicles following the intercellular transfer of MAPT/Tau aggregates, releasing the transferred MAPT/Tau species into the cytosol where they can promote the aggregation of endogenous MAPT/Tau. However, understanding of the cellular pathways involved in this process remains limited. In this study, we investigated cellular pathways that prevent endolysosomal vesicle rupture. We established a new <i>C. elegans</i> model of MAPT/Tau spreading by introducing an mCherry-labeled, disease-associated aggregation-prone fragment of human MAPT/Tau (F3ΔK281::mCh) into the six touch receptor neurons. F3ΔK281::mCh transgenic animals exhibited significant neurotoxicity and mechanosensory deficits due to the accumulation of this MAPT/Tau fragment. In addition, its intercellular transmission compromised the endolysosomal system in receiving hypodermal cells. Using this model, we conducted an unbiased genome-wide RNAi screen and identified 59 genes critical for maintaining endolysosomal integrity. GO-term analysis revealed an enrichment of genes related to the ESCRT complex, the ubiquitin-proteasome system, mRNA splicing, and fatty acid metabolism. Silencing of selected conserved genes exacerbated seeded MAPT/Tau aggregation in a human induced pluripotent stem cell (hiPSC)-derived cortical neuron model and triggered endolysosomal rupture in HEK293T cells, confirming the crucial role of endolysosomal damage in seeded MAPT/Tau aggregation. Overall, this study discovered novel cellular pathways that safeguard endolysosomal integrity. These findings may guide the development of therapeutics that improve endolysosomal integrity to halt the progression of MAPT/Tau pathology.<b>Abbreviations</b>: AD: Alzheimer disease; ALM: anterior lateral microtubule cell; AVM: anterior ventral microtubule cell; BWM: body wall muscle; <i>C. elegans</i>: <i>Caenorhabditis elegans</i>; DA: dopaminergic; hiPSC: human induced pluripotent stem cell; LGALS3: galectin 3; MAPT/Tau: microtubule associated protein tau; mCh: monomeric Cherry; PD: Parkinson disease; PLM: posterior lateral microtubule cell; PVM: posterior ventral microtubule cell; sfGFP: superfolder green flourescent protein; SNCA: synuclein alpha; nt-cntrl: non-targeting siRNA; rPHFs: recombinant paired helical filaments.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-19"},"PeriodicalIF":14.3,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982263","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":"Reconstitution of autophagic-like membrane tethering reveals that Atg11 can bind and cluster vesicles on cargo mimetics.","authors":"Devika Andhare, Sarah Katzenell, Sarah I Najera, Sylvie C Mauras, Katherine M Bauer, Michael J Ragusa","doi":"10.1080/15548627.2025.2551678","DOIUrl":"10.1080/15548627.2025.2551678","url":null,"abstract":"<p><p>Macroautophagy (hereafter, autophagy) is essential for the degradation of mitochondria from yeast to humans. Mitochondrial autophagy in yeast is initiated when the selective autophagy scaffolding protein Atg11 is recruited to mitochondria through its interaction with the selective autophagy receptor Atg32. This also results in the recruitment of small 30-nm vesicles that fuse to generate the initial phagophore membrane. We demonstrate that Atg11 can bind to autophagic-like membranes in vitro in a curvature-dependent manner in part via a predicted amphipathic helix. Deletion of the amphipathic helix from Atg11 results in a delay in the formation of mitophagy initiation sites in yeast. Furthermore, using a novel biochemical approach, we demonstrate that the interaction between Atg11 and Atg32 results in the tethering of autophagic-like vesicles in clusters to giant unilamellar vesicles containing a lipid composition designed to mimic the outer mitochondrial membrane. We also demonstrate that the N-terminal region of Atg11 is an important mediator of vesicle tethering to cargo mimetics and that clustering of autophagic-like vesicles requires the C-terminal region of Atg11. Taken together, our results reveal that Atg11 clusters into high-order oligomers, can tether autophagic-like membranes and due to its ability to oligomerize can cluster vesicles on the surface of cargo mimetics. This work provides new insight into the mechanisms of protein and membrane clustering by Atg11. Given the increasing importance of protein oligomerization and clustering in autophagy, these results have important implications in the initiation of mitochondrial autophagy.<b>Abbreviations</b> Atg11: autophagy related 11; Atg11-Cterm: C-terminal region of Atg11; Atg11-Nterm: N-terminal region of Atg11; Atg32: autophagy related 32; COV: coefficient of variance; DOPC: 1,2-dioleoyl-sn-glycero-3-phosphocholine; DOPE: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; DOPS: 1,2-dioleoyl-sn-glycero-3-phospho-L-serine; FRAP: fluorescence recovery after photobleaching; GLT: GUV and liposome tethering; GUV: giant unilamellar vesicle; MKO: multiple knockout; OMM: outer mitochondrial membrane; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PtdIns: phosphatidylinositol; PtdIns3P: phosphatidylinositol-3-phosphate; RhPE: rhodamine phosphatidylethanolamine; SAR: selective autophagy receptor; SEC: size-exclusion chromatography; SLB: supported lipid bilayers; SMrT: supported membrane templates; YPL: yeast polar lipids.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-20"},"PeriodicalIF":14.3,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12453139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982336","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}

{"title":"Impaired MAPT/tau-secretory lysosomes are linked to cognitive vulnerability in Alzheimer patients.","authors":"Preeti Sharma, Anuma Pallavi, Ananya Chatterjee, Vidya Mangala Prasad, Nikhil R Gandasi, Sivaprakasam R Saroja","doi":"10.1080/15548627.2025.2552905","DOIUrl":"https://doi.org/10.1080/15548627.2025.2552905","url":null,"abstract":"<p><p>MAPT/tau proteins propagate between brain regions in a prion-like manner, driving the onset and progression of dementia in Alzheimer disease (AD). However, the basis for variability in dementia progression among AD patients remains poorly understood. Here, we demonstrate that cognitively resilient AD patients, characterized by reduced MAPT/tau pathology, maintain lysosomal integrity, whereas cognitively vulnerable patients, exhibiting greater MAPT/tau burden, display lysosomal dysfunction. Lysosomes in cognitively vulnerable AD brains contain partially digested, seed-competent MAPT/tau species composed mainly of the amyloidogenic core with degraded peripheral regions. These pathogenic MAPT/tau forms are secreted via lysosomal exocytosis, facilitating MAPT/tau propagation and contributing to cognitive decline. Cognitively vulnerable female AD patients show increased lysosome-mediated MAPT/tau secretion relative to their male counterparts. Our findings suggest that lysosomal dysfunction, marked by altered protein expression, pH dysregulation, and MAPT/tau accumulation, underlies the heterogeneity in dementia severity. Targeting lysosomal exocytosis and the amyloidogenic core of MAPT/tau fibrils offer a promising therapeutic avenue to mitigate MAPT/tau pathology and promote cognitive resilience in AD and related dementias.<b>Abbreviation:</b> AD: Alzheimer disease, LAMP1; lysosomal associated membrane protein 1, NFT: neurofibrillary tangles; MAPT: microtubule associated protein tau; PHF: paired helical filaments; TIRF: total internal reflection fluorescence; TARDBP/TDP-43:TAR DNA binding protein.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-15"},"PeriodicalIF":14.3,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982316","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":"VAMP8 stabilization by DRAM1 enables autophagosome-lysosome fusion and promotes metastatic extravasation.","authors":"Rui Zhang, Vincenzo Torraca, Chaojun Yan, Hao Lyu, Shuai Xiao, Dong Guo, Qi Zhang, Cefan Zhou, Jingfeng Tang","doi":"10.1080/15548627.2025.2554794","DOIUrl":"10.1080/15548627.2025.2554794","url":null,"abstract":"<p><p>Autophagosome-lysosome fusion, essential for macroautophagy/autophagy completion, requires the STX17-SNAP29-VAMP8 SNARE complex. While VAMP8 is crucial, its regulatory mechanisms remain incompletely understood. Here, we identify DRAM1 (DNA damage regulated autophagy modulator 1) as a key interactor and stabilizer of VAMP8 on lysosomes. In this study, we demonstrated that DRAM1 directly binds VAMP8, and this interaction is enhanced during autophagy induction. Mechanistically, DRAM1 inhibits ubiquitin-mediated degradation of lysosomal VAMP8 by the E3 ligase STUB1/CHIP to enhance autolysosome formation. DRAM1 competitively binds VAMP8 within residues 66-100 aa, shielding lysines 68, 72, and 75 from STUB1-mediated ubiquitination. This stabilization promotes assembly of the STX17-SNAP29-VAMP8 complex, enhancing autophagosome-lysosome fusion. Functionally, DRAM1-mediated VAMP8 stabilization and autophagic flux promote the extravasation and metastasis of hepatocellular carcinoma (HCC) cells <i>in vitro</i> and <i>in vivo</i> (mouse and zebrafish models). Depletion of core autophagy genes (<i>ATG5</i> or <i>ATG7</i>) abolishes DRAM1's pro-metastatic effects. Our findings reveal a novel DRAM1-VAMP8 axis that regulates autophagic flux and identify DRAM1 as a potential therapeutic target for inhibiting autophagy-dependent HCC metastasis. Here, we summarize our findings and discuss their implications for our understanding of autophagy regulation.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":14.3,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981953","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":"UCHL1 alleviates nucleus pulposus cell senescence by promoting chaperone-mediated autophagy antagonizing autophagy-dependent ferroptosis through deubiquitination of HSPA8.","authors":"Zhouwei Wu, Shu Yang, Zhichen Jiang, Yuxuan Zhu, Haibo Liang, Yifeng Shi, Sunlong Li, Shuhao Zhang, Yining Xu, Chenglong Hong, Juntao Ying, Chenggui Wang, Xiangyang Wang","doi":"10.1080/15548627.2025.2544287","DOIUrl":"10.1080/15548627.2025.2544287","url":null,"abstract":"<p><p>Chaperone-mediated autophagy (CMA), a lysosome-dependent protein degradation pathway, plays a pivotal yet poorly understood role in cellular senescence-related degenerative diseases. Our study sheds light on a novel mechanism whereby UCHL1 plays a crucial role in mitigating nucleus pulposus cell (NPC) senescence and intervertebral disc degeneration (IVDD) by activating CMA to counteract autophagy-dependent ferroptosis. Through sequencing analysis of human samples, we identified UCHL1 as a potential factor influencing disc degeneration. Further research revealed that UCHL1 activates CMA by stabilizing HSPA8 through deubiquitination. HSPA8, in turn, recognizes and promotes the degradation of HPCAL1 via the CMA pathway by binding to its \"KFERQ\" motif, ultimately alleviating NPC senescence. Importantly, we demonstrated that engineered exosomes delivering <i>UCHL1</i>-overexpressing plasmids effectively alleviated NPC senescence and significantly mitigated the progression of IVDD. This finding underscores the significance of CMA-regulated ferroptosis in IVDD through UCHL1 modulation and as a promising target for improving chronic pain and IVDD progression.<b>Abbreviations:</b> AAV: adeno-associated virus; AB: Alcian Blue; ACSL4: acyl-CoA synthetase long chain family member 4; ALP: autophagy-lysosome pathway; Baf-A1: bafilomycin A1; CHX: cycloheximide; CMA: chaperone-mediated autophagy; Co-IP: co-immunoprecipitation; DUBs: deubiquitinating enzymes; eMI: endosomal microautophagy; Evs: extracellular vesicles; Exo: exosome; GPX4: glutathione peroxidase 4; H&E: hematoxylin and eosin; HsNPCs: Human NPCs; IF: immunofluorescence; IHC: immunohistochemistry; IP-MS: immunoprecipitation mass spectrometry; IVDD: intervertebral disc degeneration; IVDs: intervertebral discs; LBP: low back pain; LDP: lumbar disc prolapse; MRI: magnetic resonance imaging; N/L: NH4Cl and leupeptin; NP: nucleus pulposus; NPCs: nucleus pulposus cells; PCA: principal component analysis; qRT-PCR: quantitative real-time PCR; RnBMSCs: rat bone marrow mesenchymal stem cells; RnNPCs: rat NPCs; ROS: reactive oxygen species; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SASP: senescence-associated secretory phenotype; SD: Sprague-Dawley; SO: Safranin O-Fast Green; TBHP: tert-butyl hydroperoxide; UCHL1: ubiquitin C-terminal hydrolase L1; UPS: ubiquitin-proteasome system.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-25"},"PeriodicalIF":14.3,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982280","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":"R406 and its structural analogs reduce SNCA/α-synuclein levels via autophagic degradation.","authors":"Chao Zhong, Xiaoge Gao, Qi Chen, Bowen Guan, Wanli Wu, Zhiqiang Ma, Mengdan Tao, Xihuan Liu, Yu Ding, Yiyan Fei, Yan Liu, Boxun Lu, Zhaoyang Li","doi":"10.1080/15548627.2025.2483886","DOIUrl":"10.1080/15548627.2025.2483886","url":null,"abstract":"<p><p>The presence of neuronal Lewy bodies mainly composed of SNCA/α-synuclein aggregations is a pathological feature of Parkinson disease (PD), whereas reducing SNCA protein levels may slow the progression of this disease. We hypothesized that compounds enhancing SNCA's interaction with MAP1LC3/LC3 May increase its macroautophagic/autophagic degradation. Here, we conducted small molecule microarray (SMM)-based screening to identify such compounds and revealed that the compound R406 could decrease SNCA protein levels in an autophagy-dependent manner. We further validated the proposed mechanism, in which knockdown of essential gene <i>ATG5</i> for autophagy formation and using the autophagy inhibitor chloroquine (CQ) blocked the effect of R406. Additionally, R406 also reduced the levels of phosphorylated serine 129 of SNCA (p-S129-SNCA) in SNCA preformed fibrils (PFFs)-induced cellular models and rescued neuron degeneration. Importantly, we confirmed that R406 could alleviate PD-relevant disease phenotypes in human SNCA PFFs-induced cellular models and PD patient-derived organoid models. Taken together, we demonstrated the possibility of lowering SNCA levels by enhancing its autophagic degradation by compounds increasing SNCA-LC3 interactions.<b>Abbreviations</b>: ATTEC: autophagy-tethering compounds; BafA1: bafilomycin A₁; BiFC: bimolecular fluorescence complementation; CQ: chloroquine; hMOs: human midbrain organoids; iPSC: induced pluripotent stem cells; MBP: maltose-binding protein; mHTT: mutant huntingtin; OI-RD: oblique-incidence reflectivity difference; PFFs: preformed fibrils; p-S129-SNCA: phosphorylated serine 129 of SNCA; PD: Parkinson disease; ROS: reactive oxygen species; siRNA: small interfering RNA; SMM: small molecule microarray; SNCA: synuclein alpha; SYK: spleen associated tyrosine kinase.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1945-1961"},"PeriodicalIF":14.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143722983","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}

{"title":"ESCRT III-mediated lysosomal repair improve renal tubular cell injury in cisplatin-induced AKI.","authors":"Zhangyu Tian, Yiming Wu, Bin Yi, Ling Li, Yan Liu, Hao Zhang, Aimei Li","doi":"10.1080/15548627.2025.2483598","DOIUrl":"10.1080/15548627.2025.2483598","url":null,"abstract":"<p><p>The chemotherapeutic agent cisplatin is widely utilized for the treatment of various solid tumors. However, its clinical utility is limited by nephrotoxicity. Although numerous studies have demonstrated the potential of enhancing macroautophagy/autophagy in alleviating cisplatin-induced acute kidney injury (AKI), the dynamics of the autophagic process during renal tubular injury remain to be elucidated. In our investigation, we observed that cisplatin treatment leads to increased expression of LC3-II, GABARAPL1, SQSTM1/p62 and NBR1 in mouse renal tubular epithelial cells and BUMPT cells. Moreover, ultrastructurally, there is extensive accumulation of autophagic vacuoles in AKI mice. These findings imply that cisplatin-induced AKI results in impaired autophagic flow within renal tubular cells. Furthermore, LGALS3 (galectin 3) was found to be enriched in lysosomes after cisplatin treatment, revealing a close association between autophagy dysfunction and impaired lysosomal membrane integrity. Given the damaging contents of lysosomes, lysosomal membrane permeabilization must be rapidly resolved. Our findings showed that ESCRT III subunit CHMP4A-mediated lysosomal membrane repair significantly ameliorates autophagic defects and protects against lysosomal damage-induced cell death in a cisplatin-induced AKI model. In conclusion, our study indicates that ESCRT III-mediated lysosomal repair can relieve cisplatin-induced cell apoptosis and restore normal autophagy function in renal tubular epithelial cells. This mechanism plays a protective role against cisplatin-induced AKI.<b>Abbreviations:</b> AAV: adeno-associated virus; AKI: acute kidney injury; CQ: chloroquine; ESCRT: endosomal sorting complex required for transport; LMP: lysosomal membrane permeabilization; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PAS: periodic acid Schiff; PTECs: proximal renal tubule epithelial cells; TEM: transmission electron microscopy; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1927-1944"},"PeriodicalIF":14.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733605","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}

{"title":"SNX10 at the crossroad of endocytosis and piecemeal mitophagy.","authors":"Laura Trachsel-Moncho, Benan John Mathai, Chiara Veroni, Anne Simonsen","doi":"10.1080/15548627.2025.2499641","DOIUrl":"10.1080/15548627.2025.2499641","url":null,"abstract":"<p><p>Mitophagy targets damaged or dysfunctional mitochondria for lysosomal degradation. While canonical mitophagy pathways target the whole mitochondria for lysosomal degradation, it has become clear that selected mitochondrial components can be targeted for lysosomal degradation via other pathways, such as piecemeal mitophagy or mitochondria-derived vesicles. In a recent study, we identified the PX domain-containing endosomal protein SNX10 as a negative modulator of piecemeal mitophagy. Endosomal SNX10-positive vesicles dynamically interact with mitochondria and acquire selected mitochondrial proteins upon hypoxia. Zebrafish larvae lacking Snx10 show elevated Cox-IV degradation, increased levels of reactive oxygen species (ROS), and ROS-dependent neuronal death.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2077-2079"},"PeriodicalIF":14.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055061","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}