bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2025–01–26
eight papers selected by
Henver Brunetta, Karolinska Institutet



  1. Lancet Diabetes Endocrinol. 2025 Jan 20. pii: S2213-8587(24)00304-8. [Epub ahead of print]
    STEP-HFpEF Trials Committees and Investigators
       BACKGROUND: About half of patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF) have type 2 diabetes. In the STEP-HFpEF DM trial of adults with obesity-related HFpEF and type 2 diabetes, subcutaneous once weekly semaglutide 2·4 mg conferred improvements in heart failure-related symptoms and physical limitations, bodyweight, and other heart failure outcomes. We aimed to determine whether these effects of semaglutide differ according to baseline HbA1c.
    METHODS: STEP-HFpEF DM, a double-blind, randomised, placebo-controlled trial conducted at 108 clinical research sites across 16 countries in Asia, Europe, and North and South America, included individuals aged 18 years or older with documented HFpEF (left ventricular ejection fraction ≥45%), type 2 diabetes, and obesity (BMI ≥30 kg/m2). Participants were randomly assigned (1:1), with a block size of four within each stratum using an interactive web response system, stratified by baseline BMI (<35 kg/m2vs ≥35 kg/m2), to receive either semaglutide 2·4 mg or placebo subcutaneously. The effects of semaglutide versus placebo on the efficacy endpoints were evaluated by HbA1c categories at baseline: low (<6·5%; <48 mmol/mol), medium (6·5% to <7·5%; 48 mmol/mol to <58 mmol/mol), and high (≥7·5%; ≥58 mmol/mol). The dual primary endpoints were change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and bodyweight percentage from baseline to 52 weeks and were assessed in all randomly assigned participants by intention to treat. Hypoglycaemia events were also analysed to assess safety in all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04916470.
    FINDINGS: Between June 27, 2021 and Sept 2, 2022, 616 participants were enrolled and randomly assigned (mean age 68·4 years [SD 8·9]; 273 [44%] were female, 343 [56%] were male, and 519 [84%] were White). The low baseline HbA1c group included 227 participants (112 assigned to semaglutide and 115 to placebo), the medium baseline HbA1c group included 226 participants (124 assigned to semaglutide and 102 to placebo), and the high baseline HbA1c group included 163 participants (74 assigned to semaglutide and 89 to placebo). The median duration of follow-up in the overall trial was 401 days (IQR 400-405). The change in KCCQ-CSS from baseline to 52 weeks was 12·4 points (95% CI 8·8 to 16·0) with semaglutide versus 5·7 points (2·1 to 9·2) with placebo (mean difference 6·7 points [1·6 to 11·8]) in the low baseline HbA1c group, 14·5 points (11·0 to 17·9) versus 8·5 points (4·8 to 12·2; 6·0 points [0·9 to 11·1]) in the medium baseline HbA1c group, and 14·5 points (10·0 to 19·0) versus 4·8 points (0·7 to 8·9; 9·6 points [3·5 to 15·7]) in the high baseline HbA1c group (pinteraction=0·64; ptrend=0·46). The change in bodyweight percentage from baseline to 52 weeks was -10·8 (95% CI -12·1 to -9·5) with semaglutide versus -3·3% (-4·6 to -2·0) with placebo (mean difference -7·5% [-9·4 to -5·6]) in the low baseline HbA1c group, -9·6% (-10·8 to -8·3) versus -3·3% (-4·7 to -1·9; -6·3 [-8·2 to -4·4]) in the medium baseline HbA1c group, and -8·6% (-10·2 to -7·0) versus -3·6% (-5·2 to -2·1; -5·0 [-7·2 to -2·7]) in the high baseline HbA1c group (pinteraction=0·22; ptrend=0·083). Hypoglycaemia events occurred in 30 (10%) of 310 participants (70 events; 22·9 events per 100 person-years) in the semaglutide group compared with 21 (7%) of 306 participants in the placebo group (90 events; 29·5 events per 100 person-years).
    INTERPRETATION: Semaglutide 2·4 mg improved heart failure-related symptoms and physical limitations, and reduced bodyweight in patients with obesity-related HFpEF and type 2 diabetes, all independently of baseline HbA1c, and resulted in lower rates of hypoglycaemia than placebo, despite a well controlled baseline HbA1c and broad use of concomitant glucose-lowering medications.
    FUNDING: Novo Nordisk.
    DOI:  https://doi.org/10.1016/S2213-8587(24)00304-8
  2. J Clin Endocrinol Metab. 2025 Jan 21. pii: dgaf038. [Epub ahead of print]
       OBJECTIVE: Obesity and insulin resistance in men are linked to decreased testosterone and increased estradiol (E2) levels. Aromatase (ARO) converts testosterone into E2, and this occurs mainly in adipose tissue in men. E2 acts through estrogen receptors ESR1 and ESR2, and they potentially affect development of type 2 diabetes (T2D). This study explored alterations in ARO, ESR1 and ESR2 in men with obesity or T2D.
    METHODS: Subcutaneous adipose tissue (SAT) from men with or without obesity or T2D was analyzed for ARO, ESR1, and ESR2 gene and protein expression. Data were compared across groups and correlated with markers of obesity, glycaemia, insulin resistance, and sex hormones. Moreover, SAT was incubated with E2 or testosterone for ex vivo glucose uptake measurements.
    RESULTS: Aromatase ARO levels were higher in SAT from men with obesity compared to non-obese men, and gene expression correlated positively with adiposity, hyperglycaemia and insulin resistance. No association was found between ARO and circulating E2. Men with obesity had lower levels of ESR1 and ESR1:ESR2 ratio, but not ESR2. ESR1 gene expression in SAT correlated negatively with adiposity and insulin resistance markers as well as with ARO expression, and tended to be lower in men with T2D. E2 reduced insulin-stimulated glucose uptake, while testosterone increased basal glucose uptake in adipocytes.
    CONCLUSION: Elevated ARO in SAT was found in obese men, and this was linked to insulin resistance and glycaemia, supporting that local estrogen production contributes to metabolic dysregulation. ESR1 was reduced in men with T2D and was linked to adiposity and insulin resistance. Taken together, high ARO and low ESR1 expression in SAT in obese men may contribute to insulin resistance and T2D development.
    Keywords:  T2D; adipose tissue; aromatase; estradiol; estrogen receptors; obesity
    DOI:  https://doi.org/10.1210/clinem/dgaf038
  3. Mol Cell Endocrinol. 2025 Jan 18. pii: S0303-7207(25)00014-0. [Epub ahead of print]598 112463
      Mitochondria play a central role in nutrient metabolism, besides being responsible for the production of adenosine triphosphate (ATP), the main source of cellular energy. However, the ATP production process is associated with the generation of reactive oxygen species (ROS), which excessive accumulation can cause mitochondrial dysfunction. This dysfunction, in turn, causes the accumulation of fatty acids in the adipose tissue, triggering a local inflammatory process that can evolve into systemic inflammation. In women with obesity, an increase in lipid levels in the placental environment is observed. The high presence of fatty acids compromises the structural integrity and mitochondrial membrane, culminating in the release of ROS. This process damages the DNA of placental cells and causes an inflammatory state, affecting metabolic efficiency. This vicious cycle is characterized by defects in mitochondrial ATP production, which can lead to lipid accumulation and inflammation. In pregnant women with obesity, these mitochondrial changes play a determining role in pregnancy outcomes. Hence, the objective of this study was to search the literature to review the impact of mitochondrial dysfunction in the maternal obesity.
    Keywords:  Gestation; Mitochondria; Obesity; Oxidative stress
    DOI:  https://doi.org/10.1016/j.mce.2025.112463
  4. Front Endocrinol (Lausanne). 2024 ;15 1488175
      The prevalence of obesity is increasing at an alarming rate in industrialized countries. Obesity is a systemic disease that causes not only macroscopic alterations, but also mitochondrial dysfunction. Laparoscopic sleeve gastrectomy (LSG) poses a potential therapeutic option for patients with severe obesity. In order to ascertain the efficacy of bariatric interventions, it is important to assess not only weight loss, but also changes in body composition. Additionally, the aim of this study was to investigate the association between weight loss and cellular oxygen metabolism, a surrogate for mitochondrial function. We used bioimpedance analysis (BIA) to assess changes in weight and body composition in patients up to one year after LSG. To evaluate mitochondrial oxygen metabolism, we used the Cellular Oxygen Metabolism Monitor (COMET) to non-invasively measure the mitochondrial oxygen tension (mitoPO2), mitochondrial oxygen consumption (mitoVO2) and mitochondrial oxygen delivery (mitoDO2). We compared the values obtained in patients with obesity with those of age- and sex-matched healthy controls and investigated changes up to one year after LSG. 48 patients (46.5 years [35.5-55.3]; 38/48 female (79.2%); BMI 46.7 [42.5-51.0]) completed the study. They showed a significant weight loss and a decrease in relative fat mass after six months. We found no differences in mitochondrial oxygen metabolism between obese patients and healthy controls. MitoPO2, mitoVO2 and mitoDO2 did not change up to one year after surgery. It is noteworthy that patients who exhibited higher mitoPO2, mitoVO2, and mitoDO2 values prior to surgery demonstrated superior weight loss outcomes one year after LSG. This was the first study to investigate the non-invasively measured mitochondrial oxygen metabolism in the long-term course after bariatric surgery. Further studies in larger cohorts are needed to confirm these findings.
    Clinical trial registration: https://www.bfarm.de/DE/Das-BfArM/Aufgaben/Deutsches-Register-Klinischer-Studien/_node.html, identifier DRKS00015891.
    Keywords:  COMET; bioimpedance analysis; mitochondrial dysfunction; mitochondrial oxygen metabolism; obesity; sleeve gastrectomy
    DOI:  https://doi.org/10.3389/fendo.2024.1488175
  5. Free Radic Biol Med. 2025 Jan 15. pii: S0891-5849(25)00028-0. [Epub ahead of print]229 58-67
      Manganese superoxide dismutase (MnSOD/SOD2) is an essential mitochondrial enzyme that detoxifies superoxide radicals generated during oxidative respiration. MnSOD/SOD2 lysine 68 acetylation (K68-Ac) is an important post-translational modification (PTM) that regulates enzymatic activity, responding to nutrient status or oxidative stress, and elevated levels have been associated with human illness. To determine the in vivo role of MnSOD-K68 in the heart, we used a whole-body non-acetylation mimic mutant (MnSODK68R) knock-in mouse. These mice exhibited several cardiovascular phenotypes, including lower blood pressure, decreased ejection fraction, and importantly, dilated cardiomyopathy, as evidenced by echocardiography at four months of age. In addition, both mouse embryo fibroblasts (MEFs) and cardiovascular tissue from MnSODK68R/K68R mice exhibited an increase in cellular senescence. Finally, MnSODK68R/K68R mouse hearts also showed an increase in lipid peroxidation. We conclude that constitutively active MnSOD detoxification activity, lacking the normal switch between non-acetylated and acetylated forms, dysregulates mitochondrial physiology during development, leading to dilated cardiomyopathy.
    Keywords:  Acetylation; Cardiomyopathy; Cell senescence; Echocardiography; Manganese superoxide dismutase; Mitochondria; MnSOD; SIRT3; SOD2; Sirtuin
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.028
  6. J Biol Chem. 2025 Jan 17. pii: S0021-9258(25)00053-5. [Epub ahead of print] 108206
      It has been well established that adenosine plays a key role in the control of inflammation through G protein coupled receptors and recently shown that it can regulate thermogenesis. Here we investigated the specific requirements of the adenosine A2A receptor (A2AR) in mature adipocytes for thermogenic functionality and metabolic homeostasis. We generated fat tissue specific adenosine A2A receptor knock-out mice to assess the influence of signaling through this receptor on brown and beige fat functionality, obesity, insulin sensitivity, inflammation and liver function. Fat specific A2AR knock-out and wild type littermate mice were compared for potential differences in cold tolerance and energy metabolism. In addition, we measured glucose metabolism, AT inflammation and liver phenotypes in mice of the two genotypes after exposure to a diet rich in fat. Our results provide novel evidence indicating that loss of the adenosine A2A receptor specifically in adipocytes is associated with cold intolerance and decreased oxygen consumption. Furthermore, mice with fat specific ablation of the A2AR exposed to a diet rich in fat showed increased propensity to obesity, decreased insulin sensitivity, elevated adipose tissue inflammation and hepato-steatosis and -steatitis. Overall, our data provide novel evidence that A2AR in mature adipocytes safeguards metabolic homeostasis, suggesting the possibility of targeting this receptor selectively in fat for the treatment of metabolic disease.
    Keywords:  UCP1; adenosine A2A receptor; brown and beige adipose tissue; insulin resistance; obesity
    DOI:  https://doi.org/10.1016/j.jbc.2025.108206
  7. Sci Adv. 2025 Jan 24. 11(4): eadq7307
      The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals. We have found that Suppressor of site IIIQo Electron Leak 1.2 (S3QEL 1.2), a specific inhibitor of reactive oxygen species (ROS) production from mitochondrial complex III, and myxothiazol, a complex III inhibitor, decrease IL-10 in lipopolysaccharide (LPS)-activated macrophages. IL-10 down-regulation is likely to be mediated by suppression of c-Fos, which is a subunit of activator protein 1 (AP1), a transcription factor required for IL-10 gene expression. S3QEL 1.2 impairs IL-10 production in vivo after LPS challenge and promotes the survival of mice bearing B16F10 melanoma by lowering tumor growth. Our data identify a link between complex III-dependent ROS generation and IL-10 production in macrophages, the targeting of which could have potential in boosting antitumor immunity.
    DOI:  https://doi.org/10.1126/sciadv.adq7307
  8. Proc Natl Acad Sci U S A. 2025 Jan 28. 122(4): e2408896122
      Nutritional status is a determining factor for growth during development and homeostatic maintenance in adulthood. In the context of muscle, growth hormone (GH) coordinates growth with nutritional status; however, the detailed mechanisms remain to be fully elucidated. Here, we show that the transcriptional repressor B cell lymphoma 6 (BCL6) maintains muscle mass by sustaining GH action. Muscle-specific genetic deletion of BCL6 at either perinatal or adult stages profoundly reduces muscle mass and compromises muscle strength. Conversely, muscle-directed viral overexpression of BCL6 significantly reverses the loss of muscle mass and strength. Mechanistically, we show that BCL6 transcriptionally represses the suppressor of cytokine signaling 2 to sustain the anabolic actions of GH in muscle. Additionally, we find that GH itself transcriptionally inhibits BCL6 through the Janus kinase and signal transducer and activator of transcription 5 (JAK/STAT5) pathway. Supporting the physiologic relevance of this feedback regulation, we show the coordinated suppression of muscle Bcl6 expression with the induction of GH in the fasted state. These findings reveal the complexity of the feedback controls modulating GH signaling and identify BCL6 as a key homeostatic regulator coordinating muscle mass with nutrient availability. Moreover, these studies open avenues for targeted therapeutic strategies to combat muscle-wasting conditions.
    Keywords:  BCL6; SOCS2; growth hormone; muscle mass; transcriptional repression
    DOI:  https://doi.org/10.1073/pnas.2408896122