Molecular Metabolism最新文献

{"title":"Peroxisomes and PPARs: Emerging role as master regulators of cancer metabolism","authors":"Anggi Muhtar Pratama ,&nbsp;Mansi Sharma ,&nbsp;Srivatsava Naidu ,&nbsp;Heike Bömmel ,&nbsp;Samudyata C. Prabhuswamimath ,&nbsp;Thati Madhusudhan ,&nbsp;Hevi Wihadmadyatami ,&nbsp;Akash Bachhuka ,&nbsp;Srikanth Karnati","doi":"10.1016/j.molmet.2024.102044","DOIUrl":"10.1016/j.molmet.2024.102044","url":null,"abstract":"<div><div>Cancer is a disease characterized by the acquisition of a multitude of unique traits. It has long been understood that cancer cells divert significantly from normal cell metabolism. The most obvious of metabolic changes is that cancer cells strongly rely on glucose conversion by aerobic glycolysis. In addition, they also regularly develop mechanisms to use lipids and fatty acids for their energy needs. Peroxisomes lie central to these adaptive changes of lipid metabolism.</div><div>Peroxisomes are metabolic organelles that take part in over 50 enzymatic reactions crucial for cellular functioning. Thus, they are essential for an effective and comprehensive use of lipids’ energy supplied to cells. Cancer cells display a substantial increase in the biogenesis of peroxisomes and an increased expression of proteins necessary for the enzymatic functions provided by peroxisomes. Moreover, the enzymatic conversion of FAs in peroxisomes is a significant source of reactive oxygen and nitrogen species (ROS/RNS) that strongly impact cancer malignancy. Important regulators in peroxisomal FA oxidation and ROS/RNS generation are the transcription factors of the peroxisome proliferator-activated receptor (PPAR) family. This review describes the metabolic changes in tumorigenesis and cancer progression influenced by peroxisomes. We will highlight the ambivalent role that peroxisomes and PPARs play in the different stages of tumor development and summarize our current understanding of how to capitalize on the comprehension of peroxisomal biology for cancer treatment.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102044"},"PeriodicalIF":7.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mammalian D-Cysteine controls insulin secretion in the pancreas","authors":"Robin Roychaudhuri ,&nbsp;Timothy West ,&nbsp;Soumyaroop Bhattacharya ,&nbsp;Harry G. Saavedra ,&nbsp;Hangnoh Lee ,&nbsp;Lauren Albacarys ,&nbsp;Moataz M. Gadalla ,&nbsp;Mario Amzel ,&nbsp;Peixin Yang ,&nbsp;Solomon H. Snyder","doi":"10.1016/j.molmet.2024.102043","DOIUrl":"10.1016/j.molmet.2024.102043","url":null,"abstract":"<div><h3>Background</h3><div>D-amino acids are being recognized as important molecules in mammals with function. This is a first identification of endogenous D-cysteine in mammalian pancreas.</div></div><div><h3>Methods</h3><div>Using a novel stereospecific bioluminescent assay, chiral chromatography, enzyme kinetics and a transgenic mouse model we identify endogenous D-cysteine. We elucidate its function in two mice models of type 1 diabetes (STZ and NOD), and in tests of Glucose Stimulated Insulin Secretion in isolated mouse and human islets and INS-1 832/13 cell line.</div></div><div><h3>Results and Discussion</h3><div>D-cysteine is synthesized by serine racemase (SR) and SR^−/− mice produce 6–10 fold higher levels of insulin in the pancreas and plasma including higher glycogen and ketone bodies in the liver. The excess insulin is stored as amyloid in secretory vesicles and exosomes. In glucose stimulated insulin secretion in mouse and human islets, equimolar amount of D-cysteine showed higher inhibition of insulin secretion compared to D-serine, another closely related stereoisomer synthesized by SR. In mouse models of diabetes (Streptozotocin (STZ) and Non Obese Diabetes (NOD) and human pancreas, the diabetic state showed increased expression of D-cysteine compared to D-serine followed by increased expression of SR. SR^−/− mice show decreased cAMP in the pancreas, lower DNA methyltransferase enzymatic and promoter activities followed by reduced phosphorylation of CREB (S133), resulting in decreased methylation of the <em>Ins1</em> promoter. D-cysteine is efficiently metabolized by D-amino acid oxidase and transported by ASCT2 and Asc1. Dietary supplementation with methyl donors restored the high insulin levels and low DNMT enzymatic activity in SR^−/− mice.</div></div><div><h3>Conclusions</h3><div>Our data show that endogenous D-cysteine in the mammalian pancreas is a regulator of insulin secretion.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102043"},"PeriodicalIF":7.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatic retinol dehydrogenase 11 dampens stress associated with the maintenance of cellular cholesterol levels","authors":"Michael F. Keating ,&nbsp;Christine Yang ,&nbsp;Yingying Liu ,&nbsp;Eleanor AM. Gould ,&nbsp;Mitchell T. Hallam ,&nbsp;Darren C. Henstridge ,&nbsp;Natalie A. Mellett ,&nbsp;Peter J. Meikle ,&nbsp;Kevin I. Watt ,&nbsp;Paul Gregorevic ,&nbsp;Anna C. Calkin ,&nbsp;Brian G. Drew","doi":"10.1016/j.molmet.2024.102041","DOIUrl":"10.1016/j.molmet.2024.102041","url":null,"abstract":"<div><h3>Objective</h3><div>Dysregulation of hepatic cholesterol metabolism can contribute to elevated circulating cholesterol levels, which is a significant risk factor for cardiovascular disease. Cholesterol homeostasis in mammalian cells is tightly regulated by an integrated network of transcriptional and post-transcriptional signalling pathways. Whilst prior studies have identified many of the central regulators of these pathways, the extended supporting networks remain to be fully elucidated.</div></div><div><h3>Methods</h3><div>Here, we leveraged an integrated discovery platform, combining multi-omics data from 107 strains of mice to investigate these supporting networks. We identified retinol dehydrogenase 11 (RDH11; also known as SCALD) as a novel protein associated with cholesterol metabolism. Prior studies have suggested that RDH11 may be regulated by alterations in cellular cholesterol status, but its specific roles in this pathway are mostly unknown.</div></div><div><h3>Results</h3><div>Here, we show that mice fed a Western diet (high fat, high cholesterol) exhibited a significant reduction in hepatic <em>Rdh11</em> mRNA expression. Conversely, mice treated with a statin (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitor) exhibited a 2-fold increase in hepatic <em>Rdh11</em> mRNA expression. Studies in human and mouse hepatocytes demonstrated that <em>RDH11</em> expression was regulated by altered cellular cholesterol conditions in a manner consistent with SREBP2 target genes <em>HMGCR</em> and <em>LDLR</em>. Modulation of RDH11 <em>in vitro</em> and <em>in vivo</em> demonstrated modulation of pathways associated with cholesterol metabolism, inflammation and cellular stress. Finally, RDH11 silencing in mouse liver was associated with a reduction in hepatic cardiolipin abundance and a concomitant reduction in the abundance of proteins of the mitochondrial electron transport chain.</div></div><div><h3>Conclusion</h3><div>Taken together, these findings suggest that RDH11 likely plays a role in protecting cells against the cellular toxicity that can arise as a by-product of endogenous cellular cholesterol synthesis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102041"},"PeriodicalIF":7.0,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The metabolic sensor AMPK: Twelve enzymes in one","authors":"William J. Smiles ,&nbsp;Ashley J. Ovens ,&nbsp;Jonathan S. Oakhill ,&nbsp;Barbara Kofler","doi":"10.1016/j.molmet.2024.102042","DOIUrl":"10.1016/j.molmet.2024.102042","url":null,"abstract":"<div><h3>Background</h3><div>AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of energy metabolism. AMPK is sensitive to acute perturbations to cellular energy status and leverages fundamental bioenergetic pathways to maintain cellular homeostasis. AMPK is a heterotrimer comprised of αβγ-subunits that in humans are encoded by seven individual genes (isoforms α1, α2, β1, β2, γ1, γ2 and γ3), permitting formation of at least 12 different complexes with personalised biochemical fingerprints and tissue expression patterns. While the canonical activation mechanisms of AMPK are well-defined, delineation of subtle, as well as substantial, differences in the regulation of heterogenous AMPK complexes remain poorly defined.</div></div><div><h3>Scope of review</h3><div>Here, taking advantage of multidisciplinary findings, we dissect the many aspects of isoform-specific AMPK function and links to health and disease. These include, but are not limited to, allosteric activation by adenine nucleotides and small molecules, co-translational myristoylation and post-translational modifications (particularly phosphorylation), governance of subcellular localisation, and control of transcriptional networks. Finally, we delve into current debate over whether AMPK can form novel protein complexes (e.g., dimers lacking the α-subunit), altogether highlighting opportunities for future and impactful research.</div></div><div><h3>Major conclusions</h3><div>Baseline activity of α1-AMPK is higher than its α2 counterpart and is more sensitive to synergistic allosteric activation by metabolites and small molecules. α2 complexes however, show a greater response to energy stress (i.e., AMP production) and appear to be better substrates for LKB1 and mTORC1 upstream. These differences may explain to some extent why in certain cancers α1 is a tumour promoter and α2 a suppressor. β1-AMPK activity is toggled by a ‘myristoyl-switch’ mechanism that likely precedes a series of signalling events culminating in phosphorylation by ULK1 and sensitisation to small molecules or endogenous ligands like fatty acids. β2-AMPK, not entirely beholden to this myristoyl-switch, has a greater propensity to infiltrate the nucleus, which we suspect contributes to its oncogenicity in some cancers. Last, the unique N-terminal extensions of the γ2 and γ3 isoforms are major regulatory domains of AMPK. mTORC1 may directly phosphorylate this region in γ2, although whether this is inhibitory, especially in disease states, is unclear. Conversely, γ3 complexes might be preferentially regulated by mTORC1 in response to physical exercise.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102042"},"PeriodicalIF":7.0,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel long non-coding RNA connects obesity to impaired adipocyte function","authors":"Aina Lluch ,&nbsp;Jèssica Latorre ,&nbsp;Núria Oliveras-Cañellas ,&nbsp;Ana Fernández-Sánchez ,&nbsp;José M. Moreno-Navarrete ,&nbsp;Anna Castells-Nobau ,&nbsp;Ferran Comas ,&nbsp;Maria Buxò ,&nbsp;José I. Rodríguez-Hermosa ,&nbsp;María Ballester ,&nbsp;Isabel Espadas ,&nbsp;Alejandro Martín-Montalvo ,&nbsp;Birong Zhang ,&nbsp;You Zhou ,&nbsp;Ralph Burkhardt ,&nbsp;Marcus Höring ,&nbsp;Gerhard Liebisch ,&nbsp;Ainara Castellanos-Rubio ,&nbsp;Izortze Santin ,&nbsp;Asha Kar ,&nbsp;Francisco J. Ortega","doi":"10.1016/j.molmet.2024.102040","DOIUrl":"10.1016/j.molmet.2024.102040","url":null,"abstract":"<div><h3>Background</h3><div>Long non-coding RNAs (lncRNAs) can perform tasks of key relevance in fat cells, contributing, when defective, to the burden of obesity and its sequelae. Here, scrutiny of adipose tissue transcriptomes before and after bariatric surgery (GSE53378) granted identification of 496 lncRNAs linked to the obese phenotype. Only expression of linc-GALNTL6-4 displayed an average recovery over 2-fold and FDR-adjusted p-value &lt;0.0001 after weight loss. The aim of the present study was to investigate the impact on adipocyte function and potential clinical value of impaired adipose linc-GALNTL6-4 in obese subjects.</div></div><div><h3>Methods</h3><div>We employed transcriptomic analysis of public dataset GSE199063, and cross validations in two large transversal cohorts to report evidence of a previously unknown association of adipose linc-GALNTL6-4 with obesity. We then performed functional analyses in human adipocyte cultures, genome-wide transcriptomics, and untargeted lipidomics in cell models of loss and gain of function to explore the molecular implications of its associations with obesity and weight loss.</div></div><div><h3>Results</h3><div>The expression of linc-GALNTL6-4 in human adipose tissue is adipocyte-specific and co-segregates with obesity, being normalized upon weight loss. This co-segregation is demonstrated in two longitudinal weight loss studies and two cross-sectional samples. While compromised expression of linc-GALNTL6-4 in obese subjects is primarily due to the inflammatory component in the context of obesity, adipogenesis requires the transcriptional upregulation of linc-GALNTL6-4, the expression of which reaches an apex in terminally differentiated adipocytes. Functionally, we demonstrated that the knockdown of linc-GALNTL6-4 impairs adipogenesis, induces alterations in the lipidome, and leads to the downregulation of genes related to cell cycle, while propelling in adipocytes inflammation, impaired fatty acid metabolism, and altered gene expression patterns, including that of apolipoprotein C1 (APOC1). Conversely, the genetic gain of linc-GALNTL6-4 ameliorated differentiation and adipocyte phenotype, putatively by constraining APOC1, also contributing to the metabolism of triglycerides in adipose.</div></div><div><h3>Conclusions</h3><div>Current data unveil the unforeseen connection of adipocyte-specific linc-GALNTL6-4 as a modulator of lipid homeostasis challenged by excessive body weight and meta-inflammation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102040"},"PeriodicalIF":7.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-10a regulates cell death and inflammation in adipose tissue of male mice with diet-induced obesity","authors":"Sumin Lee ,&nbsp;Yoon Keun Cho ,&nbsp;Heeseong Kim ,&nbsp;Cheoljun Choi,&nbsp;Sangseob Kim,&nbsp;Yun-Hee Lee","doi":"10.1016/j.molmet.2024.102039","DOIUrl":"10.1016/j.molmet.2024.102039","url":null,"abstract":"<div><h3>Objective</h3><div>Adipose tissue remodeling plays a critical role in obesity-induced metabolic dysfunction, but the underlying molecular mechanisms remain incompletely understood. This study investigates the role of <em>miR-10a-5p</em> in adipose tissue inflammation and metabolic dysfunction induced by a high-fat diet (HFD).</div></div><div><h3>Methods</h3><div>Male <em>miR-10a</em> knockout (KO) mice were fed a HFD to induce obesity for up to 16 weeks. RNA sequencing (RNA-seq) analysis was performed to profile mRNA expression and assess the effects of <em>miR-10a-5p</em> KO in gonadal white adipose tissue (gWAT). Additional analyses included immunoblotting, qPCR, histological examination, and validation of the <em>miR-10a-5p</em> target sequence using a dual-luciferase reporter assay.</div></div><div><h3>Results</h3><div><em>miR-10a-5p</em> was highly expressed in gWAT but decreased after 8 weeks of HFD feeding. Over the 16-week HFD period, <em>miR-10a</em> KO mice exhibited greater weight gain and reduced energy expenditure compared to wild-type (WT) controls. gWAT of <em>miR-10a</em> KO mice on a HFD showed an increased population of proinflammatory macrophages, elevated inflammation, and increased cell death, characterized by upregulated apoptosis and necrosis markers. This was also associated with increased triglyceride accumulation in liver. Mechanistically, the proapoptotic gene <em>Bcl2l11</em> was identified as a direct target of <em>miR-10a-5p</em>. Loss of <em>miR-10a-5p</em> led to BIM-mediated adipocyte death and inflammation, contributing to mitochondrial metabolic dysregulation, increased fibrosis marker expression, and the onset of inflammation in adipose tissue.</div></div><div><h3>Conclusions</h3><div>This study demonstrates the significant role of <em>miR-10a-5p</em> and its downstream target BIM in regulating adipocyte death during diet-induced obesity. This signaling pathway presents a potential therapeutic target for modulating obesity-induced inflammation and cell death in adipose tissue.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102039"},"PeriodicalIF":7.0,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying targetable metabolic dependencies across colorectal cancer progression","authors":"Danny N. Legge ,&nbsp;Tracey J. Collard ,&nbsp;Ewelina Stanko ,&nbsp;Ashley J. Hoskin ,&nbsp;Amy K. Holt ,&nbsp;Caroline J. Bull ,&nbsp;Madhu Kollareddy ,&nbsp;Jake Bellamy ,&nbsp;Sarah Groves ,&nbsp;Eric H. Ma ,&nbsp;Emma Hazelwood ,&nbsp;David Qualtrough ,&nbsp;Borko Amulic ,&nbsp;Karim Malik ,&nbsp;Ann C. Williams ,&nbsp;Nicholas Jones ,&nbsp;Emma E. Vincent","doi":"10.1016/j.molmet.2024.102037","DOIUrl":"10.1016/j.molmet.2024.102037","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system – comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102037"},"PeriodicalIF":7.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “The BBSome regulates mitochondria dynamics and function molecular metabolism” [Mol Metabol 67 (2023) 101654]","authors":"Deng-Fu Guo ,&nbsp;Ronald A. Merrill ,&nbsp;Lan Qian ,&nbsp;Ying Hsu ,&nbsp;Qihong Zhang ,&nbsp;Zhihong Lin ,&nbsp;Daniel R. Thedens ,&nbsp;Yuriy M. Usachev ,&nbsp;Isabella Grumbach ,&nbsp;Val C. Sheffield ,&nbsp;Stefan Strack ,&nbsp;Kamal Rahmouni","doi":"10.1016/j.molmet.2024.102038","DOIUrl":"10.1016/j.molmet.2024.102038","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102038"},"PeriodicalIF":7.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production","authors":"Allison C. Sharrow ,&nbsp;Emily Megill ,&nbsp;Amanda J. Chen ,&nbsp;Afifa Farooqi ,&nbsp;Naveen Kumar Tangudu ,&nbsp;Apoorva Uboveja ,&nbsp;Stacy McGonigal ,&nbsp;Nadine Hempel ,&nbsp;Nathaniel W. Snyder ,&nbsp;Ronald J. Buckanovich ,&nbsp;Katherine M. Aird","doi":"10.1016/j.molmet.2024.102031","DOIUrl":"10.1016/j.molmet.2024.102031","url":null,"abstract":"<div><div>Quiescence is a reversible cell cycle exit traditionally thought to be associated with a metabolically inactive state. Recent work in muscle cells indicates that metabolic reprogramming is associated with quiescence. Whether metabolic changes occur in cancer to drive quiescence is unclear. Using a multi-omics approach, we found that the metabolic enzyme ACSS2, which converts acetate into acetyl-CoA, is both highly upregulated in quiescent ovarian cancer cells and required for their survival. Indeed, quiescent ovarian cancer cells have increased levels of acetate-derived acetyl-CoA, confirming increased ACSS2 activity in these cells. Furthermore, either inducing ACSS2 expression or supplementing cells with acetate was sufficient to induce a reversible quiescent cell cycle exit. RNA-Seq of acetate treated cells confirmed negative enrichment in multiple cell cycle pathways as well as enrichment of genes in a published G0 gene signature. Finally, analysis of patient data showed that ACSS2 expression is upregulated in tumor cells from ascites, which are thought to be more quiescent, compared to matched primary tumors. Additionally, high <em>ACSS2</em> expression is associated with platinum resistance and worse outcomes. Together, this study points to a previously unrecognized ACSS2-mediated metabolic reprogramming that drives quiescence in ovarian cancer. As chemotherapies to treat ovarian cancer, such as platinum, have increased efficacy in highly proliferative cells, our data give rise to the intriguing question that metabolically-driven quiescence may affect therapeutic response.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102031"},"PeriodicalIF":7.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linking metabolism and histone acetylation dynamics by integrated metabolic flux analysis of Acetyl-CoA and histone acetylation sites","authors":"Anna-Sophia Egger ,&nbsp;Eva Rauch ,&nbsp;Suraj Sharma ,&nbsp;Tobias Kipura ,&nbsp;Madlen Hotze ,&nbsp;Thomas Mair ,&nbsp;Alina Hohenegg ,&nbsp;Philipp Kobler ,&nbsp;Ines Heiland ,&nbsp;Marcel Kwiatkowski","doi":"10.1016/j.molmet.2024.102032","DOIUrl":"10.1016/j.molmet.2024.102032","url":null,"abstract":"<div><h3>Objectives</h3><div>Histone acetylation is an important epigenetic modification that regulates various biological processes and cell homeostasis. Acetyl-CoA, a hub molecule of metabolism, is the substrate for histone acetylation, thus linking metabolism with epigenetic regulation. However, still relatively little is known about the dynamics of histone acetylation and its dependence on metabolic processes, due to the lack of integrated methods that can capture site-specific histone acetylation and deacetylation reactions together with the dynamics of acetyl-CoA synthesis.</div></div><div><h3>Methods</h3><div>In this study, we present a novel proteo-metabo-flux approach that combines mass spectrometry-based metabolic flux analysis of acetyl-CoA and histone acetylation with computational modelling. We developed a mathematical model to describe metabolic label incorporation into acetyl-CoA and histone acetylation based on experimentally measured relative abundances.</div></div><div><h3>Results</h3><div>We demonstrate that our approach is able to determine acetyl-CoA synthesis dynamics and site-specific histone acetylation and deacetylation reaction rate constants, and that consideration of the metabolically labelled acetyl-CoA fraction is essential for accurate determination of histone acetylation dynamics. Furthermore, we show that without correction, changes in metabolic fluxes would be misinterpreted as changes in histone acetylation dynamics, whereas our proteo-metabo-flux approach allows to distinguish between the two processes.</div></div><div><h3>Conclusions</h3><div>Our proteo-metabo-flux approach expands the repertoire of metabolic flux analysis and cross-omics and represents a valuable approach to study the regulatory interplay between metabolism and epigenetic regulation by histone acetylation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102032"},"PeriodicalIF":7.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}