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Misregulation of mitochondrial 6mA promotes the propagation of mutant mtDNA and causes aging in C. elegans 线粒体 6mA 的调控失误会促进突变 mtDNA 的传播并导致秀丽隐杆线虫的衰老
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-08-21 DOI: 10.1016/j.cmet.2024.07.020
Anne Hahn, Grace Ching Ching Hung, Arnaud Ahier, Chuan-Yang Dai, Ina Kirmes, Brian M. Forde, Daniel Campbell, Rachel Shin Yie Lee, Josiah Sucic, Tessa Onraet, Steven Zuryn
{"title":"Misregulation of mitochondrial 6mA promotes the propagation of mutant mtDNA and causes aging in C. elegans","authors":"Anne Hahn, Grace Ching Ching Hung, Arnaud Ahier, Chuan-Yang Dai, Ina Kirmes, Brian M. Forde, Daniel Campbell, Rachel Shin Yie Lee, Josiah Sucic, Tessa Onraet, Steven Zuryn","doi":"10.1016/j.cmet.2024.07.020","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.07.020","url":null,"abstract":"<p>In virtually all eukaryotes, the mitochondrial DNA (mtDNA) encodes proteins necessary for oxidative phosphorylation (OXPHOS) and RNAs required for their synthesis. The mechanisms of regulation of mtDNA copy number and expression are not completely understood but crucially ensure the correct stoichiometric assembly of OXPHOS complexes from nuclear- and mtDNA-encoded subunits. Here, we detect adenosine N6-methylation (6mA) on the mtDNA of diverse animal and plant species. This modification is regulated in <em>C. elegans</em> by the DNA methyltransferase DAMT-1 and demethylase ALKB-1. Misregulation of mtDNA 6mA through targeted modulation of these activities inappropriately alters mtDNA copy number and transcript levels, impairing OXPHOS function, elevating oxidative stress, and shortening lifespan. Compounding these defects, mtDNA 6mA hypomethylation promotes the cross-generational propagation of a deleterious mtDNA. Together, these results reveal that mtDNA 6mA is highly conserved among eukaryotes and regulates lifespan by influencing mtDNA copy number, expression, and heritable mutation levels <em>in vivo</em>.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"14 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142023088","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}
引用次数: 0
Amelioration of nonalcoholic fatty liver disease by inhibiting the deubiquitylating enzyme RPN11 通过抑制去泛素化酶 RPN11 改善非酒精性脂肪肝的病情
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-08-14 DOI: 10.1016/j.cmet.2024.07.014
{"title":"Amelioration of nonalcoholic fatty liver disease by inhibiting the deubiquitylating enzyme RPN11","authors":"","doi":"10.1016/j.cmet.2024.07.014","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.07.014","url":null,"abstract":"Nonalcoholic fatty liver disease (NAFLD), including its more severe manifestation nonalcoholic steatohepatitis (NASH), is a global public health chall…","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"8 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981035","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}
引用次数: 0
Integrative clinical and preclinical studies identify FerroTerminator1 as a potent therapeutic drug for MASH 临床和临床前综合研究发现 FerroTerminator1 是治疗 MASH 的有效药物
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-08-13 DOI: 10.1016/j.cmet.2024.07.013
{"title":"Integrative clinical and preclinical studies identify FerroTerminator1 as a potent therapeutic drug for MASH","authors":"","doi":"10.1016/j.cmet.2024.07.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.07.013","url":null,"abstract":"<p>The complex etiological factors associated with metabolic dysfunction-associated fatty liver disease (MAFLD), including perturbed iron homeostasis, and the unclear nature by which they contribute to disease progression have resulted in a limited number of effective therapeutic interventions. Here, we report that patients with metabolic dysfunction-associated steatohepatitis (MASH), a pathological subtype of MAFLD, exhibit excess hepatic iron and that it has a strong positive correlation with disease progression. FerroTerminator1 (FOT1) effectively reverses liver injury across multiple MASH models without notable toxic side effects compared with clinically approved iron chelators. Mechanistically, our multi-omics analyses reveal that FOT1 concurrently inhibits hepatic iron accumulation and c-Myc-Acsl4-triggered ferroptosis in various MASH models. Furthermore, MAFLD cohort studies suggest that serum ferritin levels might serve as a predictive biomarker for FOT1-based therapy in MASH. These findings provide compelling evidence to support FOT1 as a promising novel therapeutic option for all stages of MAFLD and for future clinical trials.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"13 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974204","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}
引用次数: 0
Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism 肝细胞精氨酸酶 2 对三羧酸循环的分级调节将尿素循环与氧化代谢联系起来
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-08-07 DOI: 10.1016/j.cmet.2024.07.007
{"title":"Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism","authors":"","doi":"10.1016/j.cmet.2024.07.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.07.007","url":null,"abstract":"<p>Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (<em>Arg2</em><sup>LKO</sup>) and revealed a mild compensated urea cycle defect. Stable isotope tracing and respirometry revealed hepatocyte urea and TCA cycle flux defects, impaired mitochondrial oxidative metabolism, and glutamine anaplerosis despite normal energy and glucose homeostasis during early adulthood. Yet during middle adulthood, chow- and diet-induced obese <em>Arg2</em><sup>LKO</sup> mice develop exaggerated glucose and lipid derangements, which are reversible by replacing the TCA cycle oxidative substrate nicotinamide adenine dinucleotide. Moreover, serum-based hallmarks of urea, TCA cycle, and mitochondrial derangements predict incident fibroinflammatory liver disease in 106,606 patients nearly a decade in advance. The data reveal hierarchical urea-TCA cycle control via ARG2 to drive oxidative metabolism. Moreover, perturbations in this circuit may causally link urea cycle compromise to fibroinflammatory liver disease.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"99 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141899959","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}
引用次数: 0
Nourishing the mind: Fasting for brain health 滋养心灵断食促进大脑健康
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-08-06 DOI: 10.1016/j.cmet.2024.06.005
{"title":"Nourishing the mind: Fasting for brain health","authors":"","doi":"10.1016/j.cmet.2024.06.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.06.005","url":null,"abstract":"<p>Aging and obesity are intertwined in a vicious circle that leads to declining general and brain-specific functions. Kapogiannis and colleagues demonstrate that implementing just 8 weeks of two distinct low-calorie regimes can enhance cognition and biochemical markers of aging in older people with obesity.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"293 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895780","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}
引用次数: 0
Intermittent clearance of p21-highly-expressing cells extends lifespan and confers sustained benefits to health and physical function 间歇性清除 p21 高表达细胞可延长寿命，并为健康和身体机能带来持续益处
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-08-06 DOI: 10.1016/j.cmet.2024.07.006
{"title":"Intermittent clearance of p21-highly-expressing cells extends lifespan and confers sustained benefits to health and physical function","authors":"","doi":"10.1016/j.cmet.2024.07.006","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.07.006","url":null,"abstract":"<p>A key challenge in aging research is extending lifespan in tandem with slowing down functional decline so that life with good health (healthspan) can be extended. Here, we show that monthly clearance, starting from 20 months, of a small number of cells that highly express <em>p21</em><sup>Cip1</sup> (<em>p21</em><sup>high</sup>) improves cardiac and metabolic function and extends both median and maximum lifespans in mice. Importantly, by assessing the health and physical function of these mice monthly until death, we show that clearance of <em>p21</em><sup>high</sup> cells improves physical function at all remaining stages of life, suggesting healthspan extension. Mechanistically, <em>p21</em><sup>high</sup> cells encompass several cell types with a relatively conserved proinflammatory signature. Clearance of <em>p21</em><sup>high</sup> cells reduces inflammation and alleviates age-related transcriptomic signatures of various tissues. These findings demonstrate the feasibility of healthspan extension in mice and indicate <em>p21</em><sup>high</sup> cells as a therapeutic target for healthy aging.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"42 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895789","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}
引用次数: 0
SLC25A48 controls mitochondrial choline import and metabolism SLC25A48 控制线粒体胆碱的输入和代谢
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-08-06 DOI: 10.1016/j.cmet.2024.07.010
{"title":"SLC25A48 controls mitochondrial choline import and metabolism","authors":"","doi":"10.1016/j.cmet.2024.07.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.07.010","url":null,"abstract":"<p>Choline is an essential nutrient for the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism with a critical step being its import into mitochondria. However, the underlying mechanisms and biological significance remain poorly understood. Here, we report that SLC25A48, a previously uncharacterized mitochondrial inner-membrane carrier protein, controls mitochondrial choline transport and the synthesis of choline-derived methyl donors. We found that SLC25A48 was required for brown fat thermogenesis, mitochondrial respiration, and mitochondrial membrane integrity. Choline uptake into the mitochondrial matrix via SLC25A48 facilitated the synthesis of betaine and purine nucleotides, whereas loss of SLC25A48 resulted in increased production of mitochondrial reactive oxygen species and imbalanced mitochondrial lipids. Notably, human cells carrying a single nucleotide polymorphism on the <em>SLC25A48</em> gene and cancer cells lacking SLC25A48 exhibited decreased mitochondrial choline import, increased oxidative stress, and impaired cell proliferation. Together, this study demonstrates that SLC25A48 regulates mitochondrial choline catabolism, bioenergetics, and cell survival.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"39 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895779","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}
引用次数: 0
Dopaminylation of endothelial TPI1 suppresses ferroptotic angiocrine signals to promote lung regeneration over fibrosis 内皮 TPI1 的多巴胺化抑制铁质血管内分泌信号，促进肺纤维化后的肺再生
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-08-06 DOI: 10.1016/j.cmet.2024.07.008
{"title":"Dopaminylation of endothelial TPI1 suppresses ferroptotic angiocrine signals to promote lung regeneration over fibrosis","authors":"","doi":"10.1016/j.cmet.2024.07.008","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.07.008","url":null,"abstract":"<p>Lungs can undergo facultative regeneration, but handicapped regeneration often leads to fibrosis. How microenvironmental cues coordinate lung regeneration via modulating cell death remains unknown. Here, we reveal that the neurotransmitter dopamine modifies the endothelial niche to suppress ferroptosis, promoting lung regeneration over fibrosis. A chemoproteomic approach shows that dopamine blocks ferroptosis in endothelial cells (ECs) via dopaminylating triosephosphate isomerase 1 (TPI1). Suppressing TPI1 dopaminylation in ECs triggers ferroptotic angiocrine signaling to aberrantly activate fibroblasts, leading to a transition from lung regeneration to fibrosis. Mechanistically, dopaminylation of glutamine (Q) 65 residue in TPI1 directionally enhances TPI1’s activity to convert dihydroxyacetone phosphate (DHAP) to glyceraldehyde 3-phosphate (GAP), directing ether phospholipid synthesis to glucose metabolism in regenerating lung ECs. This metabolic shift attenuates lipid peroxidation and blocks ferroptosis. Restoring TPI1 Q65 dopaminylation in an injured endothelial niche overturns ferroptosis to normalize pro-regenerative angiocrine function and alleviate lung fibrosis. Overall, dopaminylation of TPI1 balances lipid/glucose metabolism and suppresses pro-fibrotic ferroptosis in regenerating lungs.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"126 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895783","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}
引用次数: 0
A pattern emerges in chromatin aging: AP-1 steals the show 染色质老化出现了一种模式：AP-1抢尽风头
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-08-06 DOI: 10.1016/j.cmet.2024.07.015
{"title":"A pattern emerges in chromatin aging: AP-1 steals the show","authors":"","doi":"10.1016/j.cmet.2024.07.015","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.07.015","url":null,"abstract":"<p>During aging, transcriptional programs of cell identity are partially eroded, reducing cellular fitness and resilience. Patrick et al.<span><span><sup>1</sup></span></span> unveil a general mechanism for this process that consists of the progressive loss of transcription factor AP-1 from cell identity enhancers and its relocation by competition to stress-response elements.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"4 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895858","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}
引用次数: 0
Understanding the metabolism of infants using whole-body metabolic models 利用全身代谢模型了解婴儿的新陈代谢
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-08-06 DOI: 10.1016/j.cmet.2024.07.001
{"title":"Understanding the metabolism of infants using whole-body metabolic models","authors":"","doi":"10.1016/j.cmet.2024.07.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.07.001","url":null,"abstract":"<p>A whole-body model is a computational representation of sex-specific and organ-resolved whole-body metabolism. In this issue of <em>Cell Metabolism</em>, Zaunseder et al. report whole-body models of infants that represent metabolic, physiological, energetic, and nutritional features, accurately simulating the growth of infants and providing foundations for personalized medicine for infants.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"42 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895761","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}
引用次数: 0
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