Cell metabolismPub Date : 2025-03-04DOI: 10.1016/j.cmet.2025.02.001
Allyson Evans
{"title":"Decoding the complex systems of obesity","authors":"Allyson Evans","doi":"10.1016/j.cmet.2025.02.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.02.001","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Main text</h2>We present this special focus issue on March 4th, coinciding with <span><span>World Obesity Day 2025</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>, to show our solidarity with the World Obesity Federation and advocate for increased awareness, prevention, and treatment of obesity. We embrace this year’s World Obesity Day theme, \"Changing Systems,\" which challenges us to broaden our perspective from viewing obesity as solely an individual issue and recognize the wider systemic factors that contribute to the rapidly escalating rates of obesity worldwide.</section></section>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"35 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-03-04DOI: 10.1016/j.cmet.2025.02.006
Jonas Petersen, Valdemar Brimnes Ingemann Johansen, Christoffer Clemmensen
{"title":"SnapShot: Brain-targeting anti-obesity medications","authors":"Jonas Petersen, Valdemar Brimnes Ingemann Johansen, Christoffer Clemmensen","doi":"10.1016/j.cmet.2025.02.006","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.02.006","url":null,"abstract":"Advances in the understanding of homeostatic regulation of body weight and the neurobiology of appetite, combined with innovations in medicinal chemistry, have paved the way for safe and effective weight loss medications. Long-acting GLP-1 receptor agonists have revolutionized obesity treatment, and, together with emerging GLP-1-based multi-agonists and combination therapies, offer significant potential to combat cardiometabolic diseases and a range of other chronic health challenges. To view this SnapShot, open or download the PDF.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"16 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-03-03DOI: 10.1016/j.cmet.2025.01.022
Daniel Hansen, Jasmin E.R. Jensen, Christian A.T. Andersen, Peter R. Jakobsgaard, Jesper Havelund, Line Lauritsen, Samuel Mandacaru, Majken Siersbaek, Oliver L. Shackleton, Hiroshi Inoue, Jonathan R. Brewer, Robert F. Schwabe, Blagoy Blagoev, Nils J. Færgeman, Marko Salmi, Kim Ravnskjaer
{"title":"Hepatic stellate cells regulate liver fatty acid utilization via plasmalemma vesicle-associated protein","authors":"Daniel Hansen, Jasmin E.R. Jensen, Christian A.T. Andersen, Peter R. Jakobsgaard, Jesper Havelund, Line Lauritsen, Samuel Mandacaru, Majken Siersbaek, Oliver L. Shackleton, Hiroshi Inoue, Jonathan R. Brewer, Robert F. Schwabe, Blagoy Blagoev, Nils J. Færgeman, Marko Salmi, Kim Ravnskjaer","doi":"10.1016/j.cmet.2025.01.022","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.022","url":null,"abstract":"The liver is essential for normal fatty acid utilization during fasting. Circulating fatty acids are taken up by hepatocytes and esterified as triacylglycerols for either oxidative metabolization and ketogenesis or export. Whereas the regulation of fatty acid oxidation in hepatocytes is well understood, the uptake and retention of non-esterified fatty acids by hepatocytes is not. Here, we show that murine hepatic stellate cells (HSCs) and their abundantly expressed plasmalemma vesicle-associated protein (PLVAP) control hepatic substrate preference for fasting energy metabolism. HSC-specific ablation of PLVAP in mice elevated hepatic insulin signaling and improved glucose tolerance. Fasted HSC PLVAP knockout mice showed suppressed hepatic fatty acid esterification into di- and triacylglycerols, shifting fasting metabolism from fatty acid oxidation to reliance on carbohydrates. By super-resolution microscopy, we localized HSC PLVAP to caveolae residing along the sinusoidal lumen, supporting a role for HSCs and PLVAP-diaphragmed caveolae in normal fasting metabolism of the liver.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"84 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-03-03DOI: 10.1016/j.cmet.2025.01.019
Zhou-Li Cheng, Shuyuan Zhang, Zhenning Wang, Aixia Song, Chao Gao, Jun-Bin Song, Pu Wang, Lei Zhang, Yue Zhou, Wenyan Shan, Chen Zhang, Jinye Zhang, Yiping Sun, Yanhui Xu, Fei Lan, Ming Zhong, Liang-Dong Lyu, Guanghua Huang, Fei Xavier Chen, Gang Li, Dan Ye
{"title":"Pathogen-derived glyoxylate inhibits Tet2 DNA dioxygenase to facilitate bacterial persister formation","authors":"Zhou-Li Cheng, Shuyuan Zhang, Zhenning Wang, Aixia Song, Chao Gao, Jun-Bin Song, Pu Wang, Lei Zhang, Yue Zhou, Wenyan Shan, Chen Zhang, Jinye Zhang, Yiping Sun, Yanhui Xu, Fei Lan, Ming Zhong, Liang-Dong Lyu, Guanghua Huang, Fei Xavier Chen, Gang Li, Dan Ye","doi":"10.1016/j.cmet.2025.01.019","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.019","url":null,"abstract":"Pathogenic bacterial persistence enables survival during antibiotic treatment, leading to treatment failure and recurrent infections, yet its underlying mechanisms remain unclear. Here, we reveal that glyoxylate, a metabolite originally evolved for alternative carbon utilization, functions as a signaling molecule to reprogram the host transcriptome and promote persister formation. Glyoxylate inhibits the DNA dioxygenase TET2, suppressing pro-inflammatory gene expression and attenuating host immune defense. Notably, stimulating TET2 activity with vitamin C or blocking glyoxylate production by <em>Salmonella</em> reduces bacterial antibiotic resistance and improves infection treatment outcomes. Beyond its metabolic role, glyoxylate emerges as a regulator of host-pathogen interactions, while TET2 plays a critical role in preventing bacterial persistence. Our findings suggest that targeting glyoxylate production or enhancing TET2 activity offers promising therapeutic strategies to combat bacterial persistence and enhance the efficacy of antibiotic treatments.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"37 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-03-03DOI: 10.1016/j.cmet.2025.01.021
Klaudia Borbényi-Galambos, Katalin Erdélyi, Tamás Ditrói, Eszter Petra Jurányi, Noémi Szántó, Réka Szatmári, Ágnes Czikora, Edward E. Schmidt, Dorottya Garai, Mihály Cserepes, Gabriella Liszkay, Erika Tóth, József Tóvári, Péter Nagy
{"title":"Realigned transsulfuration drives BRAF-V600E-targeted therapy resistance in melanoma","authors":"Klaudia Borbényi-Galambos, Katalin Erdélyi, Tamás Ditrói, Eszter Petra Jurányi, Noémi Szántó, Réka Szatmári, Ágnes Czikora, Edward E. Schmidt, Dorottya Garai, Mihály Cserepes, Gabriella Liszkay, Erika Tóth, József Tóvári, Péter Nagy","doi":"10.1016/j.cmet.2025.01.021","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.021","url":null,"abstract":"BRAF V600E-inhibition effectively treats melanoma, but acquired resistance rapidly develops. Protein expression profiles, mitochondrial energetics, metabolomics and fluxomics data in cell line, xenograft, and patient-derived xenograft systems revealed that concerted reprogramming of metabolic pathways (including glutaminolysis, glycolysis, TCA cycle, electron transport chain [ETC], and transsulfuration), along with an immediate cytoprotective response to drug-induced oxidative stress, underpins drug-tolerant persister cancer cell survival. Realignment of cysteine (Cys) metabolism, in particular an immediate upregulation of cystathionine-γ-lyase (CSE), was vital in persister cells. The oxidative cellular environment, drug-induced elevated cystine uptake and oxidative Cys catabolism, increased intracellular cystine/Cys ratios, thereby favoring cystine as a CSE substrate. This produces persulfides and hydrogen sulfide to protect protein thiols and support elevated energy demand in persister cells. Combining BRAF V600E inhibitors with CSE inhibitors effectively diminished proliferative relapse in culture models and increased progression-free survival of xenografted mice. This, together with induced CSE expression in patient samples under BRAF-V600E-inhibition, reveals an approach to increase BRAF-V600E-targeted therapeutic efficacy.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"34 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-02-27DOI: 10.1016/j.cmet.2025.01.018
Qionghua Cui, Shijin Li, Xidan Liu, Jie Liu, Wenxin Chen, Ye Sheng, Peng Xie, Li Jin, Fanxin Zeng, Fengxiang Lv, Xinli Hu, Rui-Ping Xiao
{"title":"MIF-ACKR3 causes irreversible fat loss by impairing adipogenesis in cancer cachexia","authors":"Qionghua Cui, Shijin Li, Xidan Liu, Jie Liu, Wenxin Chen, Ye Sheng, Peng Xie, Li Jin, Fanxin Zeng, Fengxiang Lv, Xinli Hu, Rui-Ping Xiao","doi":"10.1016/j.cmet.2025.01.018","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.018","url":null,"abstract":"Both exercise and cancer can cause adipose tissue shrinkage. However, only cancer-associated weight loss, namely cachexia, is characterized by profound adipose inflammation and fibrosis. Here, we identified tumor-secreted macrophage migration inhibitory factor (MIF) as a major driver that skews the differentiation of adipose stem and progenitor cells (ASPCs) toward a pro-inflammatory and pro-fibrogenic direction, with reduced adipogenic capacity in cancer cachexia. By contrast, circulating MIF is moderately reduced after exercise. Mechanistically, atypical chemokine receptor 3 (ACKR3) in ASPCs serves as the predominant MIF receptor mediating its pathological effects. Inhibition of MIF by gene ablation in tumor cells or pharmacological blockade, as well as ASPC-specific <em>Ackr3</em> deficiency, markedly alleviates tumor-induced cachexia. These findings unveil MIF-ACKR3 signaling as a critical link between tumors and cachectic manifestations, providing a promising therapeutic target for cancer cachexia.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"35 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-02-26DOI: 10.1016/j.cmet.2025.01.016
Jie Jiang, Yuqing Gao, Jiang Wang, Yan Huang, Rong Yang, Yongxin Zhang, Yuandi Ma, Yingquan Wen, Gongkai Luo, Shurui Zhang, Yutang Cao, Minjun Yu, Qinxue Wang, Shulei Hu, Kanglong Wang, Xiaozhen Guo, Frank J. Gonzalez, Yameng Liu, Hong Liu, Qing Xie, Cen Xie
{"title":"Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism","authors":"Jie Jiang, Yuqing Gao, Jiang Wang, Yan Huang, Rong Yang, Yongxin Zhang, Yuandi Ma, Yingquan Wen, Gongkai Luo, Shurui Zhang, Yutang Cao, Minjun Yu, Qinxue Wang, Shulei Hu, Kanglong Wang, Xiaozhen Guo, Frank J. Gonzalez, Yameng Liu, Hong Liu, Qing Xie, Cen Xie","doi":"10.1016/j.cmet.2025.01.016","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.016","url":null,"abstract":"Metabolic-dysfunction-associated steatohepatitis (MASH) remains a major health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific <em>Smpd3</em> gene disruption or pharmacological inhibition of SMPD3 alleviates MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. Although healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses sirtuin 1 (SIRT1), triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes disease progression by enhancing caveolae-dependent lipid uptake and extracellular vesicle secretion from steatotic hepatocytes to exacerbate inflammation and fibrosis. Consequently, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid metabolism and holds great promise for developing novel MASH therapies.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"24 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"EHBP1 suppresses liver fibrosis in metabolic dysfunction-associated steatohepatitis","authors":"Fanglin Ma, Miriam Longo, Marica Meroni, Dipankar Bhattacharya, Erika Paolini, Shama Mughal, Syed Hussain, Sumit Kumar Anand, Neha Gupta, Yiwei Zhu, Amaia Navarro-Corcuera, Kenneth Li, Satya Prakash, Bruno Cogliati, Shuang Wang, Xin Huang, Xiaobo Wang, Arif Yurdagul, Oren Rom, Liheng Wang, Bishuang Cai","doi":"10.1016/j.cmet.2025.01.020","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.020","url":null,"abstract":"Excess cholesterol accumulation contributes to fibrogenesis in metabolic dysfunction-associated steatohepatitis (MASH), but how hepatic cholesterol metabolism becomes dysregulated in MASH is not completely understood. We show that human fibrotic MASH livers have decreased EH-domain-binding protein 1 (EHBP1), a genome-wide association study (GWAS) locus associated with low-density lipoprotein (LDL) cholesterol, and that EHBP1 loss- and gain-of-function increase and decrease MASH fibrosis in mice, respectively. Mechanistic studies reveal that EHBP1 promotes sortilin-mediated PCSK9 secretion, leading to LDL receptor (LDLR) degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector. At a cellular level, EHBP1 deficiency affects the intracellular localization of retromer, a protein complex required for sortilin stabilization. Our therapeutic approach to stabilizing retromer is effective in mitigating MASH fibrosis. Moreover, we show that the tumor necrosis factor alpha (TNF-α)/peroxisome proliferator-activated receptor alpha (PPARα) pathway suppresses EHBP1 in MASH. These data not only provide mechanistic insights into the role of EHBP1 in cholesterol metabolism and MASH fibrosis but also elucidate an interplay between inflammation and EHBP1-mediated cholesterol metabolism.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"27 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"AKR1D1 suppresses liver cancer progression by promoting bile acid metabolism-mediated NK cell cytotoxicity","authors":"Haoran Wei, Caixia Suo, Xuemei Gu, Shengqi Shen, Kashuai Lin, Chuxu Zhu, Kai Yan, Zhenhua Bian, Liang Chen, Tong Zhang, Ronghui Yan, Zhiyi Yang, Yingxuan Yu, Zhikun Li, Rui Liu, Junming He, Qiwei He, Xiuying Zhong, Weidong Jia, Chun-Ming Wong, Ping Gao","doi":"10.1016/j.cmet.2025.01.011","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.011","url":null,"abstract":"Bile acid metabolism and antitumor immunity are both disrupted during liver cancer progression. However, the complex regulatory relationship between them remains largely unclear. Here, we find that loss of aldo-keto reductase 1D1 (AKR1D1) promotes the accumulation of isolithocholic acid (iso-LCA) through gut microbiome dysregulation, thereby impairing the cytotoxic function of natural killer (NK) cells and leading to the accelerated development of hepatocellular carcinoma (HCC). Mechanistically, AKR1D1 deficiency leads to an increased proportion of <em>Bacteroidetes ovatus</em> (<em>B. ovatus</em>), which breaks down chenodeoxycholic acid (CDCA) into iso-LCA. Moreover, accumulated iso-LCA impairs the antitumor activity of hepatic NK cells in a phosphorylated-CREB1 (p-CREB1)-dependent manner. The potassium-sparing diuretic spironolactone treatment significantly enhances the inhibitory effect of anti-PD1 antibody on HCC progression by targeting iso-LCA-mediated tumor immune escape. Taken together, our results uncover a previously unappreciated link between AKR1D1 and HCC and suggest that targeting iso-LCA produced by <em>B. ovatus</em> might be a promising strategy to activate NK cell cytotoxicity to treat HCC.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"28 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-02-24DOI: 10.1016/j.cmet.2025.01.017
Giovanni Rigoni, Enrique Calvo, Christina Glytsou, Marta Carro-Alvarellos, Masafumi Noguchi, Martina Semenzato, Charlotte Quirin, Federico Caicci, Natascia Meneghetti, Mattia Sturlese, Takaya Ishihara, Stefano Moro, Chiara Rampazzo, Naotada Ishihara, Fabrizio Bezzo, Leonardo Salviati, Jesùs Vazquez, Gabriele Sales, Chiara Romualdi, Jose Antonio Enriquez, Maria Eugenia Soriano
{"title":"MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling","authors":"Giovanni Rigoni, Enrique Calvo, Christina Glytsou, Marta Carro-Alvarellos, Masafumi Noguchi, Martina Semenzato, Charlotte Quirin, Federico Caicci, Natascia Meneghetti, Mattia Sturlese, Takaya Ishihara, Stefano Moro, Chiara Rampazzo, Naotada Ishihara, Fabrizio Bezzo, Leonardo Salviati, Jesùs Vazquez, Gabriele Sales, Chiara Romualdi, Jose Antonio Enriquez, Maria Eugenia Soriano","doi":"10.1016/j.cmet.2025.01.017","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.017","url":null,"abstract":"Mitochondrial proteins assemble dynamically in high molecular weight complexes essential for their functions. We generated and validated two searchable compendia of these mitochondrial complexes. Following identification by mass spectrometry of proteins in complexes separated using blue-native gel electrophoresis from unperturbed, cristae-remodeled, and outer membrane-permeabilized mitochondria, we created MARIGOLD, a mitochondrial apoptotic remodeling complexome database of 627 proteins. MARIGOLD elucidates how dynamically proteins distribute in complexes upon mitochondrial membrane remodeling. From MARIGOLD, we developed MitoCIAO, a mitochondrial complexes interactome tool that, by statistical correlation, calculates the likelihood of protein cooccurrence in complexes. MitoCIAO correctly predicted biologically validated interactions among components of the mitochondrial cristae organization system (MICOS) and optic atrophy 1 (OPA1) complexes. We used MitoCIAO to functionalize two ATPase family AAA domain-containing 3A (ATAD3A) complexes: one with OPA1 that regulates mitochondrial ultrastructure and the second containing ribosomal proteins that is essential for mitoribosome stability. These compendia reveal the dynamic nature of mitochondrial complexes and enable their functionalization.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"8 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}