Autophagy最新文献

{"title":"Evidence of an unprecedented cytoplasmic function of DDX11, the Warsaw breakage syndrome DNA helicase, in regulating autophagy.","authors":"Raffaella Bonavita, Antonello Prodomo, Giuseppe Cortone, Fulvia Vitale, Marcello Germoglio, Angeleen Fleming, Jesper A Balk, Job de Lange, Maurizio Renna, Francesca M Pisani","doi":"10.1080/15548627.2025.2507617","DOIUrl":"10.1080/15548627.2025.2507617","url":null,"abstract":"<p><p>DDX11 is a DNA helicase involved in critical cellular functions, including DNA replication/repair/recombination as well as sister chromatid cohesion establishment. Bi-allelic mutations of <i>DDX11</i> lead to Warsaw breakage syndrome (WABS), a rare genome instability disorder marked by significant prenatal and postnatal growth restriction, microcephaly, intellectual disability, and sensorineural hearing loss. The molecular mechanisms underlying WABS remain largely unclear. In this study, we uncover a novel role of DDX11 in regulating the macroautophagic/autophagic pathway. Specifically, we demonstrate that knockout of <i>DDX11</i> in RPE-1 cells hinders the progression of autophagy. DDX11 depletion significantly reduces the conversion of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3), suggesting a defect in autophagosome biogenesis. This is supported by imaging analysis with a LC3 reporter fused in tandem with the red and green fluorescent proteins (mRFP-GFP-LC3), which reveals fewer autophagosomes and autolysosomes in <i>DDX11</i>-knockout cells. Moreover, the defect in autophagosome biogenesis, observed in DDX11-depleted cells, is linked to an upstream impairment of the ATG16L1-precursor trafficking and maturation, a step critical to achieve the LC3 lipidation. Consistent with this, DDX11-lacking cells exhibit a diminished capacity to clear aggregates of a mutant HTT (huntingtin) N-terminal fragment fused to the green fluorescent protein (HTTQ74-GFP), an autophagy substrate. Finally, we demonstrate the occurrence of a functional interplay between DDX11 and SQSTM1, an autophagy cargo receptor protein, in supporting LC3 modification during autophagosome biogenesis. Our findings highlight a novel unprecedented function of DDX11 in the autophagy process with important implications for our understanding of WABS etiology.<b>Abbreviations</b>: <i>ATG</i> autophagy related; BAF A₁ bafilomycin A₁; CTRL control; DDX11 DEAD/H-box; helicase 11; HF1 healthy donor fibroblasts; HTT huntingtin; KO knockout; MAP1LC3/LC3; microtubule associated protein 1 light chain 3; PLA proximity ligation assay; RPE-1 retinal; pigment epithelial cell line 1; TUBA α-TUBULIN; UBA ubiquitin binding domain; WABS Warsaw breakage syndrome.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-16"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144844","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":"Limiting cap-dependent translation increases 20S proteasomal degradation and protects the proteomic integrity in autophagy-deficient skeletal muscle.","authors":"Han Dong, Yifan Lyu, Chien-Yung Huang, Shih-Yin Tsai","doi":"10.1080/15548627.2025.2457925","DOIUrl":"10.1080/15548627.2025.2457925","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Postmitotic skeletal muscle critically depends on tightly regulated protein degradation to maintain proteomic stability. Impaired macroautophagy/autophagy-lysosomal or ubiquitin-proteasomal protein degradation causes the accumulation of damaged proteins, ultimately accelerating muscle dysfunction with age. While &lt;i&gt;in vitro&lt;/i&gt; studies have demonstrated the complementary nature of these systems, their interplay at the organism levels remains poorly understood. Here, our study reveals novel insights into this complex relationship in autophagy-deficient skeletal muscle. We demonstrated that despite a compensatory increase in proteasome level in response to autophagy impairment, 26S proteasome activity was not proportionally enhanced in autophagy-deficient skeletal muscle. This functional deficit was partly attributed to reduced ATP levels to fuel the 26S proteasome. Remarkably, we found that activation of EIF4EBP1, a crucial inhibitor of cap-dependent translation, restored and even augmented proteasomal function through dual mechanisms. First, genetically activating EIF4EBP1 enhanced both ATP-dependent 26S proteasome and ATP-independent 20S proteasome activities, thereby expanding overall protein degradation capacity. Second, EIF4EBP1 activation caused muscle fiber transformation and increased mitochondrial biogenesis, thus replenishing ATP levels for 26S proteasome activation. Notably, the improved performance of the 20S proteasome in EIF4EBP1-activated skeletal muscle was attributed to an increased abundance of the immunoproteasome, a subtype specially adapted to function under oxidative stress conditions. This dual action of EIF4EBP1 activation preserved proteomic integrity in autophagy-deficient skeletal muscle. Our findings uncover a novel role of EIF4EBP1 in improving protein quality control, presenting a promising therapeutic strategy for autophagy-related muscular disorders and potentially other conditions characterized by proteostatic imbalance.&lt;b&gt;Abbreviations&lt;/b&gt;: 3-MA: 3-methyladenine; ACAC/ACC: acetyl-Coenzyme A carboxylase; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATP: adenosine triphosphate; ATP5F1A/ATP5A: ATP synthase F1 subunit alpha; CKM-Cre: creatine kinase, muscle-Cre; CMA: chaperone-mediated autophagy; CTSB: cathepsin B; CTSK: cathepsin K; CTSL: cathepsin L; CUL3: cullin 3; EDL: extensor digitorum longus; EIF4E: eukaryotic translation initiation factor 4E; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; EIF4F: eukaryotic translation initiation factor 4F complex; FBXO32/ATROGIN1/MAFbx: F-box protein 32; GFP: green fluorescent protein; IFNG/IFN-γ: interferon gamma; KEAP1: kelch-like ECH-associated protein 1; LAMP1: lysosomal-associated membrane protein 1; LAMP2: lysosomal-associated membrane protein 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; &lt;i&gt;Myl1/Mlc1f&lt;/i&gt;-Cre: myosin, light polypeptide 1 (promo","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1212-1227"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061560","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":"Scrambling stem cell development: VMP1 and TMEM41B regulate FZD2/FRIZZLED2 secretion during primitive endoderm specification.","authors":"Markus Holzner, Giulio Di Minin","doi":"10.1080/15548627.2025.2468483","DOIUrl":"10.1080/15548627.2025.2468483","url":null,"abstract":"<p><p>The endoplasmic reticulum (ER) is a central hub for lipid metabolism and protein secretion, crucial for maintaining cellular homeostasis and mediating environmental interactions. ER-resident proteins VMP1 and TMEM41B function as scramblases, regulating lipid membranes to support macroautophagy and lipid droplet metabolism. To explore their developmental roles, we generated <i>Vmp1</i> and <i>Tmem41b</i> mutations in mouse embryonic stem cells (ESCs). While these mutations did not affect ESC self-renewal or pluripotency, they impaired differentiation into the primitive endoderm lineage. Our findings reveal that this defect stems from VMP1 and TMEM41B's critical role in the maturation and stability of FZD2/FRIZZLED2, essential for WNT signaling. Thus, this study highlights their extensive role in protein trafficking, linking lipid metabolism to cell signaling and deepening our understanding of their diverse contributions to cellular and developmental processes.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1384-1386"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451316","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":"Correction.","authors":"","doi":"10.1080/15548627.2025.2486869","DOIUrl":"10.1080/15548627.2025.2486869","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"x-xiii"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782238","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":"Correction.","authors":"","doi":"10.1080/15548627.2023.2260140","DOIUrl":"10.1080/15548627.2023.2260140","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"vii"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41160364","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":"Heat-shock chaperone HSPB1 mitigates poly-glycine-induced neurodegeneration via restoration of autophagic flux.","authors":"Ning Ding, Yijie Song, Yuhang Zhang, Wei Yu, Xinnan Li, Wei Li, Lei Li","doi":"10.1080/15548627.2025.2466144","DOIUrl":"10.1080/15548627.2025.2466144","url":null,"abstract":"<p><p>The CGG repeat expansions in the 5'-UTR regions of certain genes have been implicated in various neurodegenerative and muscular disorders. However, the underlying pathogenic mechanisms are not well understood. In this study, we explore the role of the small molecular chaperone HSPB1 in counteracting neurodegeneration induced by poly-glycine (poly-G) aggregates. Employing a reporter system, we demonstrate that CGG repeat expansions within the 5'-UTR of the <i>GIPC1</i> gene produce poly-G proteins, by repeat-associated non-AUG (RAN) translation. Through proximity labeling and subsequent mass spectrometry analysis, we characterize the composition of poly-G insoluble aggregates and reveal that these aggregates sequester key macroautophagy/autophagy receptors, SQSTM1/p62 and TOLLIP. This sequestration disrupts MAP1LC3/LC3 recruitment and impairs autophagosome formation, thereby compromising the autophagic pathway. Importantly, we show that HSPB1 facilitates the dissociation of these receptors from poly-G aggregates and consequently restores autophagic function. Overexpressing HSPB1 alleviates poly-G-induced neurodegeneration in mouse models. Taken together, these findings highlight a mechanistic basis for the neuroprotective effects of HSPB1 and suggest its potential as a therapeutic target in treating poly-G-associated neurodegenerative diseases.<b>Abbreviations</b>: AD: Alzheimer disease; AIF1/Iba1: allograft inflammatory factor 1; Baf A₁: bafilomycin A₁; BFP: blue fluorescent protein; CQ: chloroquine; EIF2A/eIF-2α: eukaryotic translation initiation factor 2A; FRAP: fluorescence recovery after photobleaching; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary acidic protein; GFP: green fluorescent protein; HSPB1: heat shock protein family B (small) member 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; NOTCH2NLC: notch 2 N-terminal like C; PD: Parkinson disease; PFA: paraformaldehyde; poly-A: poly-alanine; poly-G: poly-glycine; poly-R: poly-arginine; RAN translation: repeat-associated non-AUG translation; RBFOX3/NeuN: RNA binding fox-1 homolog 3; STED: stimulated emission depletion; TARDBP/TDP-43: TAR DNA binding protein; TG: thapsigargin; TOLLIP: toll interacting protein.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1298-1315"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401012","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":"<i>Mycobacterium bovis</i> Mb3523c protein regulates host ferroptosis via chaperone-mediated autophagy.","authors":"Haoran Wang, Dingpu Liu, Xin Ge, Yuanzhi Wang, Xiangmei Zhou","doi":"10.1080/15548627.2025.2468139","DOIUrl":"10.1080/15548627.2025.2468139","url":null,"abstract":"<p><p>The occurrence of necrosis during <i>Mycobacterium bovis</i> (<i>M. bovis</i>) infection is regarded as harmful to the host because it promotes the spread of <i>M. bovis</i>. Ferroptosis is a controlled type of cell death that occurs when there is an excessive buildup of both free iron and harmful lipid peroxides. Here, we demonstrate that the mammalian cell entry (Mce) 4 family protein Mb3523c triggers ferroptosis to promote <i>M. bovis</i> pathogenicity and dissemination. Mechanistically, Mb3523c, through its Y237 and G241 site, interacts with host HSP90 protein to stabilize the LAMP2A on the lysosome to promote the chaperone-mediated autophagy (CMA) pathway. Then, GPX4 is delivered to lysosomes for destruction via the CMA pathway, eventually inducing ferroptosis to promote <i>M. bovis</i> transmission. In summary, our findings offer novel insights into the molecular mechanisms of pathogen-induced ferroptosis, demonstrating that targeting the GPX4-dependent ferroptosis through blocking the <i>M. bovis</i> Mb3523c-host HSP90 interface represents a potential therapeutic strategy for tuberculosis (TB).<b>Abbreviations</b>: CFU: colony-forming units; CMA: chaperone-mediated autophagy; Co-IP: co-immunoprecipitation; Fer-1: ferrostatin-1; GPX4: glutathione peroxidase 4; HSP90: heat shock protein 90; LDH: lactate dehydrogenase; Mce: mammalian cell entry; MOI: multiplicity of infection; Nec-1: necrostatin-1; PI: propidium iodide; RCD: regulated cell death.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1335-1352"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451313","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":"Nonreceptor tyrosine kinase ABL1 regulates lysosomal acidification by phosphorylating the ATP6V1B2 subunit of the vacuolar-type H⁺-ATPase.","authors":"Caiwei Song, Qincai Dong, Yi Yao, Yan Cui, Chunmei Zhang, Lijun Lin, Lin Zhu, Yong Hu, Hainan Liu, Yanwen Jin, Ping Li, Xuan Liu, Cheng Cao","doi":"10.1080/15548627.2024.2448913","DOIUrl":"10.1080/15548627.2024.2448913","url":null,"abstract":"<p><p>The vacuolar-type H⁺-ATPase (V-ATPase) is a proton pump responsible for controlling the intracellular and extracellular pH of cells. Its activity and assembly are tightly controlled by multiple pathways, of which phosphorylation-mediated regulation is poorly understood. In this report, we show that in response to starvation stimuli, the nonreceptor tyrosine kinase ABL1 directly interacts with ATP6V1B2, a subunit of the V₁ domain of the V-ATPase, and phosphorylates ATP6V1B2 at Y68. Y68 phosphorylation in ATP6V1B2 facilitates the recruitment of the ATP6V1D subunit into the V₁ subcomplex of V-ATPase, therefore potentiating the assembly of the V₁ subcomplex with the membrane-embedded V₀ subcomplex to form the integrated functional V-ATPase. ABL1 inhibition or depletion impairs V-ATPase assembly and lysosomal acidification, resulting in an increased lysosomal pH, a decreased lysosomal hydrolase activity, and consequently, the suppressed degradation of lumenal cargo during macroautophagy/autophagy. Consistently, the efficient removal of damaged mitochondrial residues during mitophagy is also impeded by ABL1 deficiency. Our findings suggest that ABL1 is a crucial autophagy regulator that maintains the adequate lysosomal acidification required for both physiological conditions and stress responses.<b>Abbreviation</b>: ANOVA: analysis of variance; Baf A1: bafilomycin A1; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CRK: CRK proto-oncogene, adaptor protein; CTSD: cathepsin D; DMSO: dimethylsulfoxide; EBSS: Earle's balanced salt solution; FITC: fluorescein isothiocyanate; GFP: green fluorescent protein; GST: glutathione S-transferase; LAMP2: lysosomal associated membrane protein 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; PD: Parkinson disease; PLA: proximity ligation assay; RFP: red fluorescent protein; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1192-1211"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932467","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":"ESRRA (estrogen related receptor, alpha) induces ribosomal protein RPLP1-mediated adaptive hepatic translation during prolonged starvation.","authors":"Madhulika Tripathi, Karine Gauthier, Reddemma Sandireddy, Jin Zhou, Priyanka Gupta, Suganya Sakthivel, Nah Jiemin, Kabilesh Arul, Keziah Tikno, Sung-Hee Park, Yajun Wu, Lijin Wang, Boon-Huat Bay, Lena Ho, Vincent Giguere, Sujoy Ghosh, Donald P McDonnell, Paul M Yen, Brijesh K Singh","doi":"10.1080/15548627.2025.2465183","DOIUrl":"10.1080/15548627.2025.2465183","url":null,"abstract":"<p><p>Protein translation is an energy-intensive ribosome-driven process that is reduced during nutrient scarcity to conserve cellular resources. During prolonged starvation, cells selectively translate specific proteins to enhance their survival (adaptive translation); however, this process is poorly understood. Accordingly, we analyzed protein translation and mRNA transcription by multiple methods <i>in vitro</i> and <i>in vivo</i> to investigate adaptive hepatic translation during starvation. While acute starvation suppressed protein translation in general, proteomic analysis showed that prolonged starvation selectively induced translation of lysosome and autolysosome proteins. Significantly, the expression of the orphan nuclear receptor, ESRRA (estrogen related receptor, alpha) increased during prolonged starvation and served as a master regulator of this adaptive translation by transcriptionally stimulating <i>Rplp1</i> (ribosomal protein lateral stalk subunit P1) gene expression. Overexpression or siRNA knockdown of <i>Esrra in vitro</i> or <i>in vivo</i> led to parallel changes in <i>Rplp1</i> gene expression, lysosome and macroautophagy/autophagy protein translation, and autophagy activity. Remarkably, we have found that ESRRA had dual functions by not only regulating transcription but also controlling adaptive translation via the ESRRA-RPLP1-lysosome-autophagy pathway during prolonged starvation.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1283-1297"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400995","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":"Phosphorylation of BCL2L13 by PRKAA2/AMPKα2 activates mitophagy in pressure-overloaded heart.","authors":"Tomokazu Murakawa, Kinya Otsu","doi":"10.1080/15548627.2025.2465408","DOIUrl":"10.1080/15548627.2025.2465408","url":null,"abstract":"<p><p>In heart failure patients, the accumulation of damaged mitochondria is frequently observed in cardiomyocytes. Damaged mitochondria are degraded through mitophagy, a form of mitochondria-specific autophagy. Previously, we identified BCL2L13 as a mitophagy receptor and demonstrated its ability to induce mitophagy and mitochondrial fission in mammalian cells and the necessity of phosphorylation at Ser272 for its activation. However, the <i>in vivo</i> role of BCL2L13 remains unclear. In this study, we investigated the cardiac function of BCL2L13 using <i>bcl2l13</i> knockout mice and knock-in mice expressing a non-phosphorylatable BCL2L13^S272A mutant. In the hearts of these genetically modified mice, pressure overload leads to suppressed mitochondrial fission and mitophagy, resulting in reduced ATP production. Additionally, we analyzed <i>bcl2l13</i> and <i>prkn/parkin</i> double-knockout mice but found no additive effects of <i>prkn</i> deletion. Furthermore, we identified PRKAA2/AMPKα2 as the kinase responsible for phosphorylating BCL2L13 at Ser272. These findings highlight the critical role of BCL2L13 and its phosphorylation in activating mitophagy as part of the cardiac stress response and suggest that targeting BCL2L13 phosphorylation could serve as a potential therapeutic strategy for heart failure.<b>Abbreviation</b>: BCL2L13, BCL2 like 13; ATG, autophagy related; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 beta; KO, knockout; TAC, transverse aortic constriction; LVFS, left ventricular fractional shortening; ROS, reactive oxygen species; DKO, double knockout; siRNA, small interfering RNA; PRKAA2/AMPKα2, protein kinase, AMP-activated alpha 2 catalytic subunit; CCCP, carbonyl cyanide 3-chlorophenylhydrazone.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1382-1383"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495024","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}