Autophagy最新文献

{"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":"https://doi.org/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}

{"title":"BNIP3-mediated mitophagy in macrophages regulates obesity-induced adipose tissue metaflammation.","authors":"Sangseob Kim, Cheoljun Choi, Yeonho Son, Junhyuck Lee, Sungug Joo, Yun-Hee Lee","doi":"10.1080/15548627.2025.2487035","DOIUrl":"10.1080/15548627.2025.2487035","url":null,"abstract":"<p><p>Adipose tissue macrophages (ATMs) are key cellular components that respond to nutritional excess, contributing to obesity-induced inflammation and insulin resistance. However, the mechanisms underlying macrophage polarization and recruitment in adipose tissue during obesity remain unclear. In this study, we investigated mitophagy-dependent metabolic reprogramming in ATMs and identified a crucial role of the mitophagy receptor BNIP3 in regulating macrophage polarization in response to obesity. Mitophagic flux in ATMs increased following 12 weeks of high-fat diet (HFD) feeding, with <i>Bnip3</i> levels upregulated in a HIF1A dependent manner, without affecting other mitophagy receptors. Macrophage-specific <i>bnip3</i> knockout reduced HFD-induced adipose tissue inflammation and improved glucose tolerance and insulin sensitivity. Mechanistically, hypoxic conditions <i>in vitro</i> induced HIF1A-BNIP3-mediated mitophagy and glycolytic shift in macrophages. Furthermore, HIF1A-BNIP3 signaling-enhanced lipopolysaccharide-induced pro-inflammatory activation in macrophages. These findings demonstrate that BNIP3-mediated mitophagy regulates the glycolytic shift and pro-inflammatory polarization in macrophages and suggest that BNIP3 could be a therapeutical target for obesity-related metabolic diseases.<b>Abbreviation:</b> 2-DG: 2-deoxyglucose; ACADM/MCAD: acyl-CoA dehydrogenase medium chain; ADGRE1/F4/80: adhesion G protein-coupled receptor E1; ATMs: adipose tissue macrophages; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CLS: crown-like structure; CoCl₂: cobalt(II) chloride; COX4/COXIV: cytochrome c oxidase subunit 4; ECAR: extracellular acidification rate; ECM: extraceullular matrix; gWAT: gonadal white adipose tissue; HFD: high-fat diet; HIF1A/HIF-1 α: hypoxia inducible factor 1 subunit alpha; IL1B/IL-1β: interleukin 1 beta; ITGAM/CD11B: integrin subunit alpha M; KO: knockout; LAMs: lipid-associated macrophages; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MRC1/CD206: mannose receptor C-type 1; mtDNA: mitochondrial DNA; NCD: normal chow diet; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PTPRC/CD45: protein tyrosine phosphatase receptor type C; SVFs: stromal vascular fractions; TEM: transmission electron microscopy; TMRM: tetramethylrhodamine methyl ester; TOMM20: Translocase of outer mitochondrial membrane 20; TREM2: triggering receptor expressed on myeloid cells 2; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2009-2027"},"PeriodicalIF":14.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805047","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":"ER tubular body: an ER-derived compartment for redirecting autophagy to secretory functions.","authors":"Min Seok Song, Hun Ju Sim, Shin Hye Noh, Vivek Malhotra, Min Goo Lee","doi":"10.1080/15548627.2025.2508935","DOIUrl":"10.1080/15548627.2025.2508935","url":null,"abstract":"<p><p>The secretion of proteins that do not follow the well-characterized endoplasmic reticulum (ER)-Golgi apparatus pathway, known as unconventional protein secretion (UCPS), is gradually revealing its complexities. Our study has identified an ER-based tubulovesicular network, termed ER tubular body (ER-TB), as a central compartment in this process. We demonstrate that ER-TBs are formed by two reticulophagy receptors, ATL3 and RTN3L, under conditions of cellular stress. In addition to their role in stress-induced secretion, the activation of UCPS via ER-TBs facilitates cell surface trafficking of trafficking-deficient transmembrane proteins such as ΔF508-CFTR. Furthermore, their involvement in ER remodeling and vesicle trafficking suggests a potential role in viral replication, particularly in the formation of membrane compartments utilized by positive-strand RNA viruses. By uncovering ER-TBs as key cellular structures in stress-induced UCPS and demonstrating their regulation by autophagy-related factors, our findings offer valuable insights into protein homeostasis, viral pathogenesis, and potential therapeutic strategies for diseases linked to trafficking defects.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2082-2084"},"PeriodicalIF":14.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103306","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":"Corrigendum.","authors":"","doi":"10.1080/15548627.2025.2519055","DOIUrl":"10.1080/15548627.2025.2519055","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"ii-iii"},"PeriodicalIF":14.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12427090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478230","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":"SMAD3 and PINK1 constitute a new positive feedback loop in regulation of mitophagy.","authors":"Mingzhu Tang, Guang Lu, Han-Ming Shen","doi":"10.1080/15548627.2025.2496364","DOIUrl":"10.1080/15548627.2025.2496364","url":null,"abstract":"<p><p>Mitophagy, selective degradation of dysfunctional mitochondria by the autophagy-lysosome pathway, is critical for maintaining cellular homeostasis. In recent years, significant progress has been made in understanding how PINK1 (PTEN-induced kinase 1)-mediated phosphorylation and the E3 ubiquitin (Ub) ligase (PRKN/parkin)-mediated ubiquitination form a positive feedforward loop in control of mitophagy. Nevertheless, a fundamental question remains: How is PINK1 transcriptionally modulated under mitochondrial stress to finely support mitophagy? Recently, we unveiled a novel mechanism in control of <i>PINK1</i> transcription by SMAD3 (SMAD family member 3), an essential component of the TGFB/TGFβ (transforming growth factor beta)-SMAD signaling pathway. Upon mitochondrial depolarization, SMAD3 is activated through PINK1-mediated phosphorylation of SMAD3 at serine 423/425 independent of canonical TGFB signaling. More importantly, the SMAD3-PINK1 regulatory axis appears to functionally provide a pro-survival mechanism against mitochondrial stress. Therefore, PINK1 and SMAD3 constitute a newly discovered positive feedforward loop to regulate mitophagy, highlighting the need for further exploring the crosstalk between TGFB-SMAD signaling and mitophagy.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2074-2076"},"PeriodicalIF":14.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060321","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}