bims-mimead 2025-05-04 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–05–04
twelve papers selected by
Rachel M. Handy, University of Guelph

NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
Precision nutrition for cardiometabolic diseases.
GIPR-Ab/GLP-1 peptide-antibody conjugate requires brain GIPR and GLP-1R for additive weight loss in obese mice.
Resveratrol Prevents Weight Gain, Counteracts Visceral Adipose Tissue Dysfunction, and Improves Hypothalamic Leptin Sensitivity in Diet-Induced Obese Rats.
The NLRP3 inhibitor NT-0796 enhances and sustains GLP-1R agonist-mediated weight loss in a murine diet-induced obesity model.
Global and tissue-specific transcriptomic dysregulation in human aging: Pathways and predictive biomarkers.
Effects of Children's microbiota on adipose and intestinal development in sex-matched mice persist into adulthood following a single fecal microbiota transplantation.
Weight loss in MASLD restores the balance of liver fatty acid sources.
Cgref1 is a CREB-H-regulated hepatokine that promotes hepatic de novo lipogenesis by mediating epididymal fat insulin resistance.
Loss of Ovarian Function Prevents Exercise-Induced Activation of Hepatic Mitophagic Flux.
Adipocyte-specific deletion of Dbc1 does not recapitulate healthy obesity phenotype but suggests regulation of inflammation signaling.
Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.

Cell Metab. 2025 Apr 24. pii: S1550-4131(25)00212-8. [Epub ahead of print]

NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.

Sabina Chubanava, Iuliia Karavaeva, Amy M Ehrlich, Roger M Justicia, Astrid L Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N Rodrigues, Jesper F Havelund, Farina L Schlabs, Steen Larsen, Caio Y Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Zachary Gerhart-Hines, Thomas Moritz, Juleen R Zierath, Kei Sakamoto, Thomas E Jensen, Nils J Færgeman, Gareth G Lavery, Atul S Deshmukh, Jonas T Treebak.

  Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD+ abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.

Keywords:  NAD metabolism; NAD(+) biosynthesis; NAMPT; aging; epigenetic clock; exercise; mitochondrial supercomplexes; nicotinamide; reactive oxygen species; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2025.04.002
Nat Med. 2025 Apr 30.

Precision nutrition for cardiometabolic diseases.

Marta Guasch-Ferré, Clemens Wittenbecher, Marie Palmnäs, Orly Ben-Yacov, Ellen E Blaak, Christina C Dahm, Tove Fall, Berit L Heitmann, Tine R Licht, Marie Löf, Ruth Loos, Chirag J Patel, Carmelo Quarta, Leanne M Redman, Eran Segal, Nicola Segata, Michael Snyder, Qi Sun, Deirdre K Tobias, Frank B Hu, Paul W Franks, Rikard Landberg, Jennifer L Sargent, Jordi Merino.

Precision nutrition is a vibrant and rapidly evolving field of scientific research and innovation with the potential to deliver health, societal and economic benefits by improving healthcare delivery and policies. Advances in deep phenotyping technologies, digital tools and artificial intelligence have made possible early proof-of-concept research that expands the understanding of within- and between-person variability in responses to diet. These studies illustrate the promise of precision nutrition to complement the traditional 'one size fits all' dietary guidelines, which, while considering broad life-stage and disease-specific nutritional requirements, often lack the granularity to account fully for individual variations in nutritional needs and dietary responses. Despite these developments, however, considerable challenges remain before precision nutrition can be implemented on a broader scale. This Review examines the current state of precision nutrition research, with a focus on its application to reducing the incidence and burden of cardiometabolic diseases. We critically examine the evidence base, explore the potential benefits and discuss the challenges and opportunities ahead.

DOI: https://doi.org/10.1038/s41591-025-03669-9
Nat Metab. 2025 Apr 29.

GIPR-Ab/GLP-1 peptide-antibody conjugate requires brain GIPR and GLP-1R for additive weight loss in obese mice.

Clarissa M Liu, Elizabeth A Killion, Rola Hammoud, Shu-Chen Lu, Renee Komorowski, Tongyu Liu, Matt Kanke, Veena A Thomas, Kevin Cook, Glenn N Sivits, Aerielle B Ben, Larissa I Atangan, Rajaa Hussien, Amy Tang, Artem Shkumatov, Chi-Ming Li, Daniel J Drucker, Murielle M Véniant.

Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide 1 receptor (GLP-1R) are expressed in the central nervous system (CNS) and regulate food intake. Here, we demonstrate that a peptide-antibody conjugate that blocks GIPR while simultaneously activating GLP-1R (GIPR-Ab/GLP-1) requires both CNS GIPR and CNS GLP-1R for maximal weight loss in obese, primarily male, mice. Moreover, dulaglutide produces greater weight loss in CNS GIPR knockout (KO) mice, and the weight loss achieved with dulaglutide + GIPR-Ab is attenuated in CNS GIPR KO mice. Wild-type mice treated with GIPR-Ab/GLP-1 and CNS GIPR KO mice exhibit similar changes in gene expression related to tissue remodelling, lipid metabolism and inflammation in white adipose tissue and liver. Moreover, GIPR-Ab/GLP-1 is detected in circumventricular organs in the brain and activates c-FOS in downstream neural substrates involved in appetite regulation. Hence, both CNS GIPR and GLP-1R signalling are required for the full weight loss effect of a GIPR-Ab/GLP-1 peptide-antibody conjugate.

DOI: https://doi.org/10.1038/s42255-025-01295-w
Mol Nutr Food Res. 2025 Apr 27. e70075

Resveratrol Prevents Weight Gain, Counteracts Visceral Adipose Tissue Dysfunction, and Improves Hypothalamic Leptin Sensitivity in Diet-Induced Obese Rats.

Maria Ibars-Serra, Aïda Pascual-Serrano, Andrea Ardid-Ruiz, Núria Doladé, Sonia Aguilar-González, Julieta Cirasino, Begoña Muguerza, Manuel Suárez, Jaap Keijer, Anna Arola-Arnal, Gerard Aragonès.

  In obesity, increased adipocyte size is associated with metabolic complications, while elevated adipocyte numbers are considered a protective mechanism against metabolic disturbances. Adipose tissue dysfunction leads to decreased leptin sensitivity and disrupted energy balance regulation. Resveratrol (RSV), a bioactive compound known for potential health benefits, including obesity-related disorder prevention, has unclear modulatory effects on adipocyte dysfunction and leptin signaling in established obesity. This study investigated the impact of RSV on adiposity and hypothalamic leptin sensitivity in obesity. Rats were fed a cafeteria diet for 9 weeks and subsequently supplemented with different doses of RSV for 22 days. The 200 mg/kg RSV dose reduced leptin concentrations, body weight gain, and body fat mass in obese animals, while mitigating adipocyte hypertrophy and promoting adipocyte hyperplasia in the retroperitoneal fat depot. RSV also improved hypothalamic leptin sensitivity, shedding light on the molecular mechanisms underlying the benefits of RSV consumption for obesity-related disorders.

Keywords:  WAT; cafeteria; hypothalamus; liver; obesity; polyphenols

DOI:  https://doi.org/10.1002/mnfr.70075
Obesity (Silver Spring). 2025 Apr 30.

The NLRP3 inhibitor NT-0796 enhances and sustains GLP-1R agonist-mediated weight loss in a murine diet-induced obesity model.

Peter Thornton, Valérie Reader, Zsofia Digby, John Doedens, Nicola Lindsay, Nicholas Clarke, Alan P Watt.

OBJECTIVE: In order to investigate whether a central nervous system penetrant anti-inflammatory could augment or sustain obesity treatment with semaglutide (Wegovy), a glucagon-like peptide-1 receptor (GLP-1R) agonist, we tested two hypotheses in models of diet-induced obesity (DIO): 1) a centrally penetrant NLPR3 inhibitor, NT-0796, drives enhanced weight loss when combined with low-dose semaglutide, compared to monotherapy; and 2) NT-0796 monotherapy sustains weight loss induced by semaglutide.
METHODS: Mice fed a standard high-fat or a polyunsaturated fatty acid diet served as models of DIO and were dosed with low-dose semaglutide, NT-0796, or combinations. Body weight, food intake, peripheral inflammatory markers, and hypothalamic glial fibrillary acidic protein expression were assessed.
RESULTS: Combined dosing of NT-0796 with semaglutide drove greater weight loss than either monotherapy alone, and this effect was enhanced in mice consuming the polyunsaturated fatty acid diet. In addition, NT-0796 sharply limited weight regain following cessation of semaglutide therapy and normalized markers of both peripheral inflammation and hypothalamic astrogliosis to a far greater extent than either semaglutide or calorie restriction.
CONCLUSIONS: Alleviation of obesity-associated inflammation via NLRP3 inhibition 1) constitutes an effective weight-loss strategy as monotherapy in mice with DIO, 2) augments the weight-loss efficacy of a subtherapeutic dose of semaglutide, and 3) blocks recovery of lost weight following cessation of semaglutide.

DOI: https://doi.org/10.1002/oby.24305
Geroscience. 2025 Apr 28.

Global and tissue-specific transcriptomic dysregulation in human aging: Pathways and predictive biomarkers.

Muhammad Arif, Andrea Lehoczki, György Haskó, Falk W Lohoff, Zoltan Ungvari, Pal Pacher.

  Aging is a universal biological process that impacts all tissues, leading to functional decline and increased susceptibility to age-related diseases, particularly cardiometabolic disorders. While aging is characterized by hallmarks such as mitochondrial dysfunction, chronic inflammation, and dysregulated metabolism, the molecular mechanisms driving these processes remain incompletely understood, particularly in a tissue-specific context. To address this gap, we conducted a comprehensive transcriptomic analysis across 40 human tissues using data from the Genotype-Tissue Expression (GTEx) project, comparing individuals younger than 40 years with those older than 65 years. We identified over 17,000 differentially expressed genes (DEGs) across tissues, with distinct patterns of up- and down-regulation. Enrichment analyses revealed that up-regulated DEGs were associated with inflammation, immune responses, and apoptosis, while down-regulated DEGs were linked to mitochondrial function, oxidative phosphorylation, and metabolic processes. Using gene co-expression network (GCN) analyses, we identified 1,099 genes as dysregulated nodes (DNs) shared across tissues, reflecting global aging-associated transcriptional shifts. Integrating machine learning approaches, we pinpointed key aging biomarkers, including GDF15 and EDA2R, which demonstrated strong predictive power for aging and were particularly relevant in cardiometabolic tissues such as the heart, liver, skeletal muscle, and adipose tissue. These genes were also validated in plasma proteomics studies and exhibited significant correlations with clinical cardiometabolic health indicators. This study provides a multi-tissue, integrative perspective on aging, uncovering both systemic and tissue-specific molecular signatures. Our findings advance understanding of the molecular underpinnings of aging and identify novel biomarkers that may serve as therapeutic targets for promoting healthy aging and mitigating age-related diseases.

Keywords:  Aging biomarkers; Cardiometabolic health; Gene co-expression networks; Inflammation; Machine learning; Mitochondrial dysfunction; Transcriptomics

DOI:  https://doi.org/10.1007/s11357-025-01672-z
Mol Metab. 2025 Apr 25. pii: S2212-8778(25)00064-X. [Epub ahead of print] 102157

Effects of Children's microbiota on adipose and intestinal development in sex-matched mice persist into adulthood following a single fecal microbiota transplantation.

Federica La Rosa, Maria Angela Guzzardi, Mercedes Pardo-Tendero, Monica Barone, Chiara Ruocco, Gabriele Conti, Daniele Panetta, Daria Riabitch, Silvia Bernardi, Assuero Giorgetti, Daniela Campani, Daniel Monleon, Enzo Nisoli, Patrizia Brigidi, Patricia Iozzo.

   BACKGROUND: The global prevalence of obesity and type 2 diabetes, particularly among children, is rising, yet the long-term impacts of early-life fecal microbiota transplantation (FMT) on metabolic health remain poorly understood.
OBJECTIVES: To investigate how early-life FMT from children to young, sex-matched mice influences metabolic outcomes and adipose tissue function in later, adult life.
METHODS: Germ-free mice were colonized with fecal microbiota from either lean children or children with obesity. The impacts on brown adipose tissue (BAT), white adipose tissue (WAT), glucose metabolism, and gut health were analyzed in male and female mice. Microbial communities and metabolite profiles were characterized using sequencing and metabolomics.
RESULTS: Male mice receiving FMT from obese donors exhibited marked BAT whitening and impaired amino acid and glucose metabolism. In contrast, female recipients developed hyperglycemia, accompanied by gut barrier dysfunction and WAT impairment. Distinct microbial and metabolite profiles were associated with these phenotypes: Collinsella and trimethylamine in females; and Paraprevotella, Collinsella, Lachnospiraceae NK4A136, Bacteroides, Coprobacillus, and multiple metabolites in males. These phenotypic effects persisted despite changes in host environment and diet.
CONCLUSIONS: Early-life FMT induced long-lasting effects on the metabolic landscape, profoundly affecting adipose tissue function and systemic glucose homeostasis in adulthood. Donor dietary habits correlated with the fecal microbial profiles observed in recipient mice. These findings highlight the critical need for identifying and leveraging beneficial exposures during early development to combat obesity and diabetes.

Keywords:  Adipose tissue; Gut microbiota; Intestinal permeability; Metabolomics; Obesity; Positron emission tomography; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.molmet.2025.102157
J Clin Invest. 2025 May 01. pii: e174233. [Epub ahead of print]135(9):

Weight loss in MASLD restores the balance of liver fatty acid sources.

Jennifer E Lambert, Maria A Ramos-Roman, Maressa J Valdez, Jeffrey D Browning, Thomas Rogers, Elizabeth J Parks.

  BACKGROUNDLipogenesis contributes substantially to the pathological accumulation of intrahepatic triacylglycerol (IHTG) in metabolic dysfunction-associated steatotic liver disease (MASLD). Since hepatic lipogenesis is highly sensitive to energy intake, we hypothesized that mechanisms of MASLD regression induced by weight loss would be driven by a marked reduction in the lipogenic pathway.METHODSOverweight adults with high liver fat (HighLF; n = 9; IHTG ≥ 5.6% measured by 1H-magnetic resonance spectroscopy) or low (normal) liver fat (LowLF; n = 6; IHTG < 5.6%) received dietary counseling for 6 months and underwent comprehensive metabolic phenotyping during inpatient studies that captured fasting and fed states. Multiple stable isotopes were used to assess the contribution of lipogenesis, free fatty acids (FFAs), and dietary fat to IHTG.RESULTSBody weight loss (-10% ± 2%) reduced IHTG in individuals with MASLD (19.4% ± 3.6% to 4.5% ± 2.1%, P < 0.001). Insulin sensitivity improved significantly (46%, P < 0.01), while fasting FFA flux from adipose tissue was not different. VLDL-triacylglycerol (VLDL-TG) concentrations fell by 38% (P = 0.02) because of a 67% reduction in contribution from lipogenesis (P = 0.02), whereas the absolute contributions from FFAs and dietary fat to VLDL-TG were not different. Reduced lipogenesis was significantly associated with loss of IHTG.CONCLUSIONThese data underscore the primary role of lipogenesis in MASLD pathology and highlight the importance of controlling this pathway through treatment strategies.TRIAL REGISTRATIONClinicalTrials.gov (NCT01371396).FUNDINGNational Institutes of Health (NIH) grant RL1DK081187; Task Force for Obesity Research at Southwestern (TORS) NIH UL1DE019584; and Clinical and Translational Science Award NIH/National Center for Advancing Translational Sciences UL1-RR024982.

Keywords:  Clinical practice; Hepatology; Metabolism; Obesity

DOI:  https://doi.org/10.1172/JCI174233
Int J Biol Sci. 2025 ;21(6): 2568-2588

Cgref1 is a CREB-H-regulated hepatokine that promotes hepatic de novo lipogenesis by mediating epididymal fat insulin resistance.

Pearl Chan, Pak-Hin Hinson Cheung, Xiao-Zhuo Kang, Yun Cheng, Chi-Ming Wong, Dong-Yan Jin, Chi-Ping Chan.

  Rationale: Type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease (MASLD) are interrelated metabolic disorders that pose significant health concerns. Hepatokines and other regulatory factors implicated in these diseases are incompletely understood. Here, we report on a new hepatokine named cell growth regulator with EF-hand domain 1 (Cgref1) that modulates lipid metabolism to aggravate these conditions. Methods: Cgref1 was identified by microarray analysis of downregulated genes in liver of Creb3l3 -/- mice. Cgref1 -/- mice were subjected to transcriptomic, metabolomic and lipidomic analyses as well as metabolic assays. Gain-of-function and loss-of-function assays were performed in primary hepatocytes and cultured human and mouse cells. Results: Cgref1 expression is induced by hepatic transcription factor CREB-H. Secreted Cgref1 primarily targets epididymal white adipose tissue (eWAT), where insulin signalling and glucose uptake are suppressed. Cgref1-/- mice showed lower tendencies of developing obesity, hyperglycaemia and dyslipidaemia, associated with compromised hepatic de novo lipogenesis. Thus, Cgref1 poses an advantage to maintain the normal functioning of vital organs by preserving glucose from being absorbed into eWAT. However, in circumstances where Cgref1 expression becomes excessive, eWAT develops insulin resistance, which in turn promotes hepatic glucose production, lipogenesis and MASLD development. Conclusion: As a hepatokine that affects blood glucose levels and lipogenesis, Cgref1 is a potential target in the intervention of metabolic disorders.

Keywords:  CREB-H transcription factor; Cgref1; diabetes; hepatokine; metabolic dysfunction-associated steatotic liver disease (MASLD); metabolic syndrome

DOI:  https://doi.org/10.7150/ijbs.97008
Am J Physiol Endocrinol Metab. 2025 Apr 28.

Loss of Ovarian Function Prevents Exercise-Induced Activation of Hepatic Mitophagic Flux.

Edziu Franczak, Benjamin A Kugler, Sebastian F Salathe, Julie Allen, Mihaela E Sardiu, Colin S McCoin, Andrea L Hevener, E Matthew Morris, John P Thyfault.

  Exercise effectively treats metabolic dysfunction-associated steatotic liver disease (MASLD) by enhancing hepatic mitochondria energy metabolism. However, the efficiency of exercise in treating MASLD in post-menopausal women may be reduced. Previously, we showed acute treadmill exercise activates hepatic mitophagy, the selective degradation of low-functioning mitochondria. Mitophagic flux is differentially regulated in female mice compared to males, possibly by estrogen. Here, we tested if loss of ovarian function via ovariectomy (OVX), which reduces estrogen, drives MASLD and compromised hepatic mitochondrial energetics, would blunt activation of hepatic mitophagy induced by exercise. Following OVX, 12-15-week-old female mice were placed on a low-fat diet (LFD) or high-fat diet (HFD) for 4 weeks to induce MASLD, after which half of the mice performed a single acute bout of treadmill exercise to exhaustion or remained sedentary. Two hours post-exercise, isolated hepatic mitochondria were examined via western blotting and proteomics for accumulation of known mitophagy proteins. After exercise, reduced basal mitophagic flux in LFD-fed OVX was restored to levels found in Sham mice. However, exercise possessed blunted capacity to promote mitochondrial recruitment of DRP1 (regulator of fission) and accumulation mitophagy-associated proteins (E3-ubiquitin ligase, ubiquitin, autophagy adaptor proteins, and autophagosome cargo receptors) in OVX versus sham mice on HFD. Mitochondrial H2O2 production, which putatively activates mitophagy, was elevated following exercise in all conditions except OVX+HFD. In summary, OVX reduces mitophagic flux, blunting the stimulatory effects of exercise on these factors. The impaired regulation of mitophagy following cessation of ovarian function likely contributes to the pathogenesis of MASLD post-menopause.

Keywords:  Female; Liver; Mitophagy; Proteomics; Steatosis

DOI:  https://doi.org/10.1152/ajpendo.00107.2025
PLoS One. 2025 ;20(5): e0322732

Adipocyte-specific deletion of Dbc1 does not recapitulate healthy obesity phenotype but suggests regulation of inflammation signaling.

Leonardo Santos, Rafael Sebastián Fort, Geraldine Schlapp, Karina Cal, Valentina Perez-Torrado, Maria Noel Meikle, Ana Paula Mulet, Camila Espasandín, Camila Chiesa, José R Sotelo-Silveira, Jose M Verdes, Paola Contreras, Aldo J Calliari, Martina Crispo, Jose L Badano, Carlos Escande.

The protein Deleted in Breast Cancer 1 (Dbc1) is an important regulator of various transcription factors and epigenetic modulators, significantly influencing metabolism, obesity, and aging-related processes. Knockout mice lacking Dbc1 exhibit severe obesity but remain protected from liver steatosis, insulin resistance, and atherosclerosis. We hypothesized that this phenotype of "healthy obesity" results from adipose tissue expansion, which prevents free fatty acid spillover and subsequent metabolic damage to peripheral tissues. To further investigate the putative role of Dbc1 in adipose cells during obesity and its effects on metabolic dysregulation, we generated conditional Dbc1 knockout (KO) mice by backcrossing with AdipoQ-CRE transgenic mice to selectively abrogate Dbc1 expression in all mature adipocytes (Dbc1LoxP/LoxP;CRE). These mice demonstrated effective deletion of Dbc1 in mature adipocytes across various fat depots. We assessed the impact of Dbc1 deletion on metabolic regulation in male and female mice fed standard chow and high-fat diets. Our findings revealed that Dbc1 knockout in mature adipocytes did not influence weight gain, glucose tolerance, or other metabolic dysregulation markers, irrespective of sex. However, Dbc1 KO adipocytes exhibited an mRNA expression profile indicative of heightened inflammation during obesity. These results suggest that the protective phenotype observed in whole-body Dbc1 KO obese mice is not attributable to Dbc1's function within mature adipocytes but likely involves other cell types in adipose tissue. Moreover, the specific deletion of Dbc1 in mature adipocytes unveils a novel role of Dbc1 in inflammation signaling during obesity.

DOI: https://doi.org/10.1371/journal.pone.0322732
Nat Commun. 2025 Apr 29. 16(1): 4029

Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.

Mateus Prates Mori, Oswaldo A Lozoya, Ashley M Brooks, Carl D Bortner, Cristina A Nadalutti, Birgitta Ryback, Brittany P Rickard, Marta Overchuk, Imran Rizvi, Tatiana Rogasevskaia, Kai Ting Huang, Prottoy Hasan, György Hajnóczky, Janine H Santos.

Maintenance of the mitochondrial inner membrane potential (ΔΨm) is critical for many aspects of mitochondrial function. While ΔΨm loss and its consequences are well studied, little is known about the effects of mitochondrial hyperpolarization. In this study, we used cells deleted of ATP5IF1 (IF1), a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of increased resting ΔΨm. We found that the nuclear DNA hypermethylates when the ΔΨm is chronically high, regulating the transcription of mitochondrial, carbohydrate and lipid genes. These effects can be reversed by decreasing the ΔΨm and recapitulated in wild-type (WT) cells exposed to environmental chemicals that cause hyperpolarization. Surprisingly, phospholipid changes, but not redox or metabolic alterations, linked the ΔΨm to the epigenome. Sorted hyperpolarized WT and ovarian cancer cells naturally depleted of IF1 also showed phospholipid remodeling, indicating this as an adaptation to mitochondrial hyperpolarization. These data provide a new framework for how mitochondria can impact epigenetics and cellular biology to influence health outcomes, including through chemical exposures and in disease states.

DOI: https://doi.org/10.1038/s41467-025-59427-5