bims-mimead 2025-02-23 papers

Issue of 2025–02–23
eight papers selected by
Rachel M. Handy, University of Guelph

Cell Rep. 2025 Feb 18. pii: S2211-1247(25)00089-0. [Epub ahead of print]44(2): 115318

Overfeeding induces adipose tissue release of distinct mitochondria.

Joshua H Goodman, Chloé Berland, Rajesh K Soni, Anthony W Ferrante.

Overfeeding animals beyond what they eat ad libitum causes rapid adipose tissue expansion, leading to an unusual form of obesity characterized by low immune cell accumulation in fat and sustained anorexia. To investigate how overfeeding affects adipose tissue, we studied the protein secretome of fat from equally obese overfed and ad libitum-fed mice. Fat from overfed animals secretes lower amounts of immune regulatory proteins. Unexpectedly, fat from overfed mice releases larger amounts of mitochondrial proteins. Microscopy identified mitochondria in the conditioned medium of cultured fat that were found not within extracellular vesicles but rather as free extracellular organelles. The protein profile of released mitochondria was distinct from the mitochondrial protein profile of the whole fat, suggesting that the metabolic stress of overfeeding leads to the release of a mitochondrial subset favoring de novo lipogenesis. These findings add to growing evidence that cells alter their energy profiles through the release of mitochondria.

Keywords: CP: Metabolism; adipose tissue; mitochondria; obesity; overfeeding

DOI: https://doi.org/10.1016/j.celrep.2025.115318

Redox Biol. 2025 Feb 14. pii: S2213-2317(25)00054-0. [Epub ahead of print]81 103541

Multi-tissue metabolomics reveal mtDNA- and diet-specific metabolite profiles in a mouse model of cardiometabolic disease.

Abhishek Shastry, Mia S Wilkinson, Dalia M Miller, Michelle Kuriakose, Jennifer L M H Veeneman, Matthew Ryan Smith, Charles C T Hindmarch, Kimberly J Dunham-Snary.

RATIONALE: Excess consumption of sugar- and fat-rich foods has heightened the prevalence of cardiometabolic disease, which remains a driver of cardiovascular disease- and type II diabetes-related mortality globally. Skeletal muscle insulin resistance is an early feature of cardiometabolic disease and is a precursor to diabetes. Insulin resistance risk varies with self-reported race, whereby African-Americans have a greater risk of diabetes development relative to their White counterparts. Self-reported race is strongly associated with mitochondrial DNA (mtDNA) haplogroups, and previous reports have noted marked differences in bioenergetic and metabolic parameters in cells belonging to distinct mtDNA haplogroups, but the mechanism of these associations remains unknown. Additionally, distinguishing nuclear DNA (nDNA) and mtDNA contributions to cardiometabolic disease remains challenging in humans. The Mitochondrial-Nuclear eXchange (MNX) mouse model enables in vivo preclinical investigation of the role of mtDNA in cardiometabolic disease development, and has been implemented in studies of insulin resistance, fatty liver disease, and obesity in previous reports.
METHODS: Six-week-old male C57nDNA:C57mtDNA and C3HnDNA:C3HmtDNA wild-type mice, and C57nDNA:C3HmtDNA and C3HnDNA:C57mtDNA MNX mice, were fed sucrose-matched high-fat (45% kcal fat) or control diet (10% kcal fat) until 12 weeks of age (n = 5/group). Mice were weighed weekly and total body fat was collected at euthanasia. Gastrocnemius skeletal muscle and plasma metabolomes were characterized using untargeted dual-chromatography mass spectrometry; both hydrophilic interaction liquid chromatography (HILIC) and C18 columns were used, in positive- and negative-ion modes, respectively.
RESULTS: Comparative analyses between nDNA-matched wild-type and MNX strains demonstrated significantly increased body fat percentage in mice possessing C57mtDNA regardless of nDNA background. High-fat diet in mice possessing C57mtDNA was associated with differential abundance of phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, and glucose. Conversely, high-fat diet in mice possessing C3HmtDNA was associated with differential abundance of phosphatidylcholines, cardiolipins, and alanine. Glycerophospholipid metabolism and beta-alanine signaling pathways were enriched in skeletal muscle and plasma, indicating mtDNA-directed priming of mitochondria towards oxidative stress and increased fatty acid oxidation in C57nDNA:C57mtDNA wild-type and C3HnDNA:C57mtDNA MNX mice, relative to their nDNA-matched counterparts. In mtDNA-matched mice, C57mtDNA was associated with metabolite co-expression related to the pentose phosphate pathway and sugar-related metabolism; C3HmtDNA was associated with branched chain amino acid metabolite co-expression.
CONCLUSIONS: These results reveal novel nDNA-mtDNA interactions that drive significant changes in metabolite levels. Alterations to key metabolites involved in mitochondrial bioenergetic dysfunction and electron transport chain activity are implicated in elevated beta-oxidation during high-fat diet feeding; abnormally elevated rates of beta-oxidation may be a key driver of insulin resistance. The results reported here support the hypothesis that mtDNA influences cardiometabolic disease-susceptibility by modulating mitochondrial function and metabolic pathways.

Keywords: Cardiometabolic disease; Disease susceptibility; Metabolomics; Mitochondrial genetics; Mitochondrial-nuclear eXchange; Plasma; Skeletal muscle

DOI: https://doi.org/10.1016/j.redox.2025.103541

Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00024-5. [Epub ahead of print]

Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.

Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here, we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From these data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.

Keywords: MPST; ergothioneine; exercise; mitochondria

DOI: https://doi.org/10.1016/j.cmet.2025.01.024

bioRxiv. 2025 Feb 08. pii: 2025.02.05.636729. [Epub ahead of print]

Human differentiated adipocytes can serve as surrogate mature adipocytes for adipocyte-derived extracellular vesicle analysis.

Bradley L Butsch, Mangesh Dattu Hade, Paola Loreto Palacio, Kim Truc Nguyen, Dharti Shantaram, Sabrena Noria, Stacy A Brethauer, Bradley J Needleman, Willa Hsueh, Eduardo Reátegui, Setty M Magaña.

Obesity is a growing global health concern, contributing to diseases such as cancer, autoimmune disorders, and neurodegenerative conditions. Adipose tissue dysfunction, characterized by abnormal adipokine secretion and chronic inflammation, plays a key role in these conditions. Adipose-derived extracellular vesicles (ADEVs) have emerged as critical mediators in obesity-related diseases. However, the study of mature adipocyte-derived EVs (mAdipo-EVs) is limited due to the short lifespan of mature adipocytes in culture, low EV yields, and the low abundance of these EV subpopulations in the circulation. Additionally, most studies rely on rodent models, which have differences in adipose tissue biology compared to humans. To overcome these challenges, we developed a standardized approach for differentiating human preadipocytes (preAdipos) into mature differentiated adipocytes (difAdipos), which produce high-yield, human adipocyte EVs (Adipo-EVs). Using visceral adipose tissue from bariatric surgical patients, we isolated the stromal vascular fraction (SVF) and differentiated preAdipos into difAdipos. Brightfield microscopy revealed that difAdipos exhibited morphological characteristics comparable to mature adipocytes (mAdipos) directly isolated from visceral adipose tissue, confirming their structural similarity. Additionally, qPCR analysis demonstrated decreased preadipocyte markers and increased mature adipocyte markers, further validating successful differentiation. Functionally, difAdipos exhibited lipolytic activity comparable to mAdipos, supporting their functional resemblance to native adipocytes. We then isolated preAdipo-EVs and difAdipo-EVs using tangential flow filtration and characterized them using bulk and single EV analysis. DifAdipo-EVs displayed classical EV and adipocyte-specific markers, with significant differences in biomarker expression compared to preAdipo-EVs. These findings demonstrate that difAdipos serve as a reliable surrogate for mature adipocytes, offering a consistent and scalable source of adipocyte-derived EVs for studying obesity and its associated disorders.

DOI: https://doi.org/10.1101/2025.02.05.636729

bioRxiv. 2025 Feb 02. pii: 2025.01.31.635994. [Epub ahead of print]

Dnmt3b deficiency in adipocyte progenitor cells ameliorates obesity in female mice.

Yifei Huang, Sean Yu, Qiang Cao, Jia Jing, Weiqing Tang, Bingzhong Xue, Hang Shi.

Obesity arises from chronic energy imbalance where energy intake exceeds energy expenditure. Emerging evidence supports a key role of DNA methylation in the regulation of adipose tissue development and metabolism. We recently discovered a key role of DNA methylation, catalyzed by DNA methyltransferase 1 or 3a (Dnmt1 or 3a), in the regulation of adipocyte differentiation and metabolism. Here, we aimed to investigate the role of adipocyte progenitor cell Dnmt3b, an enzyme mediating de novo DNA methylation, in energy metabolism and obesity. We generated a genetic model with Dnmt3b knockout in adipocyte progenitor cells (PD3bKO) by crossing Dnmt3b -floxed mice with platelet-derived growth factor receptor alpha (Pdgfrα)-Cre mice. Dnmt3b gene deletion in adipocyte progenitors enhanced thermogenic gene expression in brown adipose tissue, increased overall energy expenditure, and mitigated high-fat diet (HFD)-induced obesity in female mice. PD3bKO mice also displayed a lower respiratory exchange ratio (RER), indicative of a metabolic shift favoring fat utilization as an energy source. Furthermore, female PD3bKO mice exhibited improved insulin sensitivity alongside their lean phenotype. In contrast, male PD3bKO mice showed no changes in body weight but demonstrated decreased insulin sensitivity, revealing a sexually dimorphic metabolic response to Dnmt3b deletion in adipocyte progenitor cells. These findings underscore the critical role of Dnmt3b in regulating energy homeostasis, body weight, and metabolic health, with significant implications for understanding sex-specific mechanisms of obesity and metabolism.

DOI: https://doi.org/10.1101/2025.01.31.635994

bioRxiv. 2025 Feb 08. pii: 2025.02.03.635951. [Epub ahead of print]

A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.

Anna S Monzel, Jack Devine, Darshana Kapri, Jose Antonio Enriquez, Caroline Trumpff, Martin Picard.

Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions 1-3 . All mitochondria share general features, but not all mitochondria are created equal 4 .Here we develop a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes - or mitotypes . By distilling hundreds of validated mitochondrial genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0 5 ) the simple mitotyping pipeline allows investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomics or proteomics data across a variety of natural and experimental contexts. We show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, contrasting anabolic (liver) and catabolic (brain) tissues. In cultured primary human fibroblasts exhibiting robust time-dependent and treatment-induced metabolic plasticity 6-8 , we demonstrate how the mitotype of a given cell type recalibrates i) over time in parallel with hallmarks of aging, and ii) in response to genetic, pharmacological, and metabolic perturbations. Investigators can now use MitotypeExplorer.org and the associated code to visualize, quantify and interpret the multivariate space of mitochondrial biology.

DOI: https://doi.org/10.1101/2025.02.03.635951

Pharmacol Ther. 2025 Feb 18. pii: S0163-7258(25)00034-8. [Epub ahead of print] 108822

G protein-coupled estrogen receptor biased signaling in health and disease.

Aisha Bushi, Yixuan Ma, Joseph Adu-Amankwaah, Rong Wang, Fen Cui, Rui Xiao, Jinming Zhao, Jinxiang Yuan, Rubin Tan.

G protein-coupled estrogen receptor (GPER) is now recognized for its pivotal role in cellular signaling, influencing diverse physiological processes and disease states. Unlike classical estrogen receptors, GPER exhibits biased signaling, wherein ligand binding triggers selective pathways over others, significantly impacting cellular responses. This review explores the nuanced mechanisms of biased signaling mediated by GPER, underscoring its relevance in cardiovascular health, neurological function, immune modulation, and oncogenic processes. Despite its critical implications, biased signaling through GPER remains underexplored compared to traditional signaling paradigms. We explore recent progress in understanding GPER signaling specificity and its potential therapeutic implications across various diseases. Future research directions aim to uncover the molecular basis of biased signaling, develop selective ligands, and translate these insights into personalized therapeutic approaches. Exploiting the therapeutic potential of GPER biased signaling represents a promising frontier in precision medicine, offering innovative strategies to address unmet medical needs.

Keywords: Biased signaling; Cellular pathways; GPER; Precision medicine; Therapeutic implications

DOI: https://doi.org/10.1016/j.pharmthera.2025.108822

Cytokine. 2025 Feb 14. pii: S1043-4666(25)00016-X. [Epub ahead of print]188 156869

Interleukin-4 ameliorates macrophage lipid stress through promoting cholesterol efflux and lipid homeostasis.

Kuo-Ting Ho, Fang-Yeh Chu, Yi-Kai Lin, Ho-Hsun Chin, Shun-Chun Yang, Ching-Ping Yang, Yih-Hsin Chang.

Over-nutrition and lipid metabolic abnormalities are correlated with obesity and type 2 diabetes mellitus (T2DM). Individuals with long-term hyperglycemia and dyslipidemia are susceptible to life-threatening complications such as atherosclerosis. Excess amounts of modified low density lipoprotein (mLDL) attract circulating monocytes to resident at arterial wall and differentiate into pro-inflammatory M1 macrophages. M1 cells uptake mLDL through scavenger receptors-mediated endocytosis, leading to increased lipids influx, cholesterol accumulation and foam cell formation. Besides, macrophages are attracted and infiltrated into the hypertrophic adipose tissue to mediate microenvironmental lipid metabolism. Our previous studies demonstrate that anti-inflammatory interleukin-4 (IL-4) regulates lipid metabolism by inhibiting lipid accumulation and promoting lipolysis of mature adipocytes. The effects of IL-4-polarized M2 macrophages on 3T3-L1 adipogenesis and macrophage-adipocyte interaction were explored in the present study. Our results showed lipid deposits and lipid droplets (LDs)-anchored perilipin of adipocytes cultured in IL-4-polarized M2-conditioned medium (M2-CM) were decreased, while adipogenesis-driving transcription factors and critical lipid metabolic enzymes remained unaffected. It indicates that M2-secreted mediators down-regulate lipid deposits and LDs formation in late adipogenic phase rather than interfering early programming phase and lipid synthesis machinery. In addition, IL-4 reduced intracellular lipid loads by up-regulating cholesterol efflux ATP-binding cassette transporter A1 (ABCA1) and ABCG1 despite cholesterol influx CD36 was also elevated. Accordingly, IL-4 shows beneficial effects to prevent atherosclerosis via promoting catabolism of the internalized lipids and cholesterol efflux, thus efficiently reduces lipid overload and foam cell formation. These findings illustrate novel roles and protective function of IL-4 to reduce the risk of atherosclerosis incidence by efficiently promoting macrophage cholesterol efflux and lipid homeostasis.

Keywords: Adipocyte; Atherosclerosis; Interleukin-4; Lipid homeostasis; Macrophage; Metabolism

DOI: https://doi.org/10.1016/j.cyto.2025.156869