bims-mimcad 2025-03-02 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2025–03–02
nine papers selected by
Henver Brunetta, Karolinska Institutet

Deep Learning Derived Adipocyte Size Reveals Adipocyte Hypertrophy is under Genetic Control.
Enhanced Fatty Acid Oxidation via SCD1 Downregulation Fuels Cardiac Reprogramming.
Predictability of genetic risk score for insulin resistance is influenced by both BMI and race.
Metabolic flexibility and reverse remodelling of the failing human heart.
Adipocyte Septin-7 attenuates obesogenic adipogenesis and promotes lipolysis to prevent obesity.
MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.
Identification of a novel transcript of mouse Sdha.
Leptin enhances the intracellular thyroid hormone activation in skeletal muscle to boost energy balance.
A systems-level, semi-quantitative landscape of metabolic flux in C. elegans.

medRxiv. 2025 Feb 12. pii: 2025.02.11.25322053. [Epub ahead of print]

Deep Learning Derived Adipocyte Size Reveals Adipocyte Hypertrophy is under Genetic Control.

Emil Jørsboe, Phil Kubitz, Julius Honecker, Andrea Flaccus, Dagmar Mvondo, Matthias Raggi, Torben Hansen, Hans Hauner, Matthias Blüher, Philip D Charles, Cecilia M Lindgren, Christoffer Nellåker, Melina Claussnitzer.

Fat distribution and macro structure of white adipose tissue are important factors in predicting obesity-associated diseases, but cellular microstructure of white adipose tissue has been less explored. To investigate the relationship between adipocyte size and obesity-related traits, and their underlying disease-driving genetic associations, we performed the largest study of automatic adipocyte phenotyping linking histological measurements and genetics to date. We introduce deep learning based methods for scalable and accurate semantic segmentation of subcutaneous and visceral adipose tissue histology samples (N=2,667) across 5 independent cohorts, including data from 9,000 whole slide images, with over 27 million adipocytes. Estimates of mean size of adipocytes were validated against Glastonbury et al. 2020. We show that adipocyte hypertrophy correlates with an adverse metabolic profile with increased levels of leptin, fasting plasma glucose, glycated hemoglobin and triglycerides, and decreased levels of adiponectin and HDL cholesterol. We performed the largest GWAS (N Subcutaneous = 2066, N Visceral = 1878) and subsequent meta-analysis of mean adipocyte area, and find two genome-wide significant loci (rs73184721, rs200047724) associated with increased 95%-quantile adipocyte size in respectively visceral and subcutaneous adipose tissue. Stratifying by sex, in females we find two genome-wide significant loci, with one variant (rs140503338) associated with increased mean adipocyte size in subcutaneous adipose tissue, and the other (rs11656704) is associated with decreased 95%-quantile adipocyte size in visceral adipose tissue.

DOI: https://doi.org/10.1101/2025.02.11.25322053
Mol Ther. 2025 Feb 24. pii: S1525-0016(25)00123-6. [Epub ahead of print]

Enhanced Fatty Acid Oxidation via SCD1 Downregulation Fuels Cardiac Reprogramming.

Zhenhua Jia, Lilin Xiang, Zhangyi Yu, Lenan Wang, Junyan Fang, Mengxin Liu, Xin Wu, Zhibing Lu, Li Wang.

Direct cardiac reprogramming has emerged as a promising therapeutic strategy to remuscularize injured myocardium. This approach converts non-contractile fibroblasts to induced cardiomyocytes (iCMs) that spontaneously contract, yet the intrinsic metabolic requirements driving cardiac reprogramming are not fully understood. Using single-cell metabolic flux estimation and flux balance analysis, we characterized the metabolic heterogeneity of iCMs and identified fatty acid oxidation (FAO) as a critical factor in iCM conversion. Both pharmacological and genetic inhibition of FAO impairs iCM generation. We further identified Stearoyl-CoA desaturase 1 (SCD1) as a metabolic switch that suppresses iCM reprogramming. Mechanistically, Scd1 knockdown activates PGC1α and PPARβ signaling, enhancing FAO-related gene expression and mitochondrial biogenesis, thereby improving reprogramming efficacy. Pharmacological manipulations targeting SCD1, PGC1α and PPARβ signaling axis further improved iCM generation and mitochondrial function. Our findings collectively highlight FAO as a key determinant of iCM fate and offer new therapeutic avenues for advancing reprogramming strategies.

DOI: https://doi.org/10.1016/j.ymthe.2025.02.034
Obesity (Silver Spring). 2025 Feb 24.

Predictability of genetic risk score for insulin resistance is influenced by both BMI and race.

Marian L Yurchishin, Lauren A Fowler, Amy M Goss, William T Garvey, Barbara A Gower.

OBJECTIVE: The study objective was to determine whether associations between a genetic risk score (GRS) for insulin resistance (IR) and measures of insulin sensitivity differ by race and/or BMI status in African American (AA) and European American (EA) adults without diabetes.
METHODS: Fifty-three AA and 54 EA participants were classified into "high" or "low" BMI groups using the sample median (25.9 kg/m2) as the cut point. The GRS was derived from 52 previously identified genetic variants. Skeletal muscle insulin sensitivity was measured with the hyperinsulinemic-euglycemic clamp. The homeostasis model assessment of insulin resistance (HOMA-IR) and the Matsuda index of insulin sensitivity were calculated from oral glucose tolerance test values to determine hepatic and whole-body insulin sensitivity, respectively. Linear regression models, stratified by race, assessed interactions between BMI status and GRS on measures of insulin sensitivity.
RESULTS: In EA participants, associations of GRS with HOMA-IR and the Matsuda index differed by BMI status, where the GRS was associated with IR in the high-BMI group only. In AA participants, associations from the clamp differed by BMI status, but an association was observed only in the low-BMI group.
CONCLUSIONS: These results highlight the heterogeneity of IR and support the hypothesis that the relationship between genetic predisposition for IR and obesity is race- and tissue-specific.

DOI: https://doi.org/10.1002/oby.24238
Eur Heart J. 2025 Feb 25. pii: ehaf033. [Epub ahead of print]

Metabolic flexibility and reverse remodelling of the failing human heart.

Peregrine G Green, William D Watson, Benjamin M Bussmann, Giovanni Luigi De Maria, Stefan Neubauer, Andrew J M Lewis, Oliver J Rider, Neil Herring.

   BACKGROUND AND AIMS: Cardiac resynchronization therapy (CRT) produces long-term reverse remodelling which requires greater adenosine triphosphate delivery to the contractile machinery. Whilst the heart retains some metabolic flexibility in non-ischaemic cardiomyopathy, whether this correlates with reverse remodelling is unknown. This study investigated whether CRT acutely changes cardiac substrate uptake, and whether this translates to favourable reverse remodelling.
METHODS: The effect of CRT on cardiac substrate uptake was assessed via direct coronary flow and arteriovenous measurements, with metabolomic/lipidomic analysis on infusions of insulin/glucose and intralipid. Cardiac function was assessed with left ventricular pressure-volume loops during implantation, and cardiac magnetic resonance before and 6 months following CRT, with and without biventricular pacing.
RESULTS: Regardless of substrate infusion, CRT acutely improved stroke work without increasing O2 uptake on both insulin/glucose (by 34%, P = .05) and intralipid (by 36%, P = .03). This was followed by increased fatty acid (FA) uptake on insulin/glucose (R = 0.89, P = .03) and increased β-hydroxybutyrate uptake (R = 0.81, P = .05) during intralipid infusion. After 6 months, there was a 48% (P < .001) reduction in left ventricular end diastolic volume, beyond that achievable by acutely shortening or lengthening QRS duration. Reverse remodelling significantly correlated with increased FA uptake with CRT on insulin/glucose (R = 0.71, P = .05) driven by long and medium chain uptake, and increased ketone uptake with CRT on intralipid (R = 0.79, P = .05).
CONCLUSIONS: CRT acutely alters the metabolic phenotype of non-ischaemic cardiomyopathy towards a more physiological picture of FA uptake which correlates with reverse remodelling. Retained metabolic flexibility may therefore be critical for subsequent reverse remodelling.

Keywords:  Metabolism; Non-ischaemic cardiomyopathy; Resynchronization; Reverse remodelling

DOI:  https://doi.org/10.1093/eurheartj/ehaf033
Mol Metab. 2025 Feb 25. pii: S2212-8778(25)00021-3. [Epub ahead of print] 102114

Adipocyte Septin-7 attenuates obesogenic adipogenesis and promotes lipolysis to prevent obesity.

Liran Xu, Chao Yang, Kaidan Pang, Ying Zhang, Yu He, Siyu Liu, Huijing Tian, Zehua Shao, Siyu Wang, Xingqian Liu, Ting Li, Yapeng Cao, Luqin Yan, Jinjin Liu, Yanan Wang, Yongxin Li, Wei Zhao, Youhua Wang, Yang Yan, Shengpeng Wang.

   OBJECTIVE: The white adipose tissue (WAT) expansion plays a significant role in the development of obesity. Cytoskeletal remodeling directly impacts adipogenic program, however, the precise mechanism remains poorly understood. Here, we identified a crucial role of Septin-7 (SEPT7), a cytoskeleton component, in the regulation of diet-induced processes of adipogenesis, lipogenesis, and lipolysis in WAT.
METHODS: A high-fat diet (HFD)-induced obesity model was constructed using mice with inducible adipocyte-specific SEPT7 deficiency. The impact of SEPT7 on adipocyte morphology, cell number and metabolism capacity were evaluated with immunofluorescence, isoproterenol induced lipolysis assay, glucose tolerance test and insulin tolerance test. Adipocyte mTmG reporter line was established to trace in vivo adipogenesis. The preadipocyte 3T3-L1 cell was induced for exploring role of SEPT7 in adipocyte differentiation. qRT-PCR and Western-blot were used to investigate the expression of PPARγ, C/EBPα, and HSL in 3T3-L1 cell with siRNA-mediated SEPT7 knockdown.
RESULTS: SEPT7 expression was greatly induced in obesogenic human and murine adipocytes. Mice lacking SEPT7 in mature white adipocytes demonstrated defective differentiation of preadipocyte into mature adipocytes when fed HFD resulting in larger adipocytes, increased WAT inflammation and reduced lipolysis, which leading to increased WAT mass, liver fat accumulation and impaired glucose tolerance. Mechanistically, we identified SEPT7 restrains store-operated Ca2+ entry (SOCE) and regulates adipocyte adipogenesis and lipolysis by targeting PPARγ, C/EBPα and HSL.
CONCLUSION: We demonstrated that SEPT7 negatively regulates adipogenesis while promotes lipolysis and its repression drives WAT expansion and impaired metabolic health.

Keywords:  Septin-7; adipocyte; adipogenensis; obesity

DOI:  https://doi.org/10.1016/j.molmet.2025.102114
Cell Metab. 2025 Feb 20. pii: S1550-4131(25)00017-8. [Epub ahead of print]

MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.

Giovanni Rigoni, Enrique Calvo, Christina Glytsou, Marta Carro-Alvarellos, Masafumi Noguchi, Martina Semenzato, Charlotte Quirin, Federico Caicci, Natascia Meneghetti, Mattia Sturlese, Takaya Ishihara, Stefano Moro, Chiara Rampazzo, Naotada Ishihara, Fabrizio Bezzo, Leonardo Salviati, Jesùs Vazquez, Gabriele Sales, Chiara Romualdi, Jose Antonio Enriquez, Luca Scorrano, Maria Eugenia Soriano.

  Mitochondrial proteins assemble dynamically in high molecular weight complexes essential for their functions. We generated and validated two searchable compendia of these mitochondrial complexes. Following identification by mass spectrometry of proteins in complexes separated using blue-native gel electrophoresis from unperturbed, cristae-remodeled, and outer membrane-permeabilized mitochondria, we created MARIGOLD, a mitochondrial apoptotic remodeling complexome database of 627 proteins. MARIGOLD elucidates how dynamically proteins distribute in complexes upon mitochondrial membrane remodeling. From MARIGOLD, we developed MitoCIAO, a mitochondrial complexes interactome tool that, by statistical correlation, calculates the likelihood of protein cooccurrence in complexes. MitoCIAO correctly predicted biologically validated interactions among components of the mitochondrial cristae organization system (MICOS) and optic atrophy 1 (OPA1) complexes. We used MitoCIAO to functionalize two ATPase family AAA domain-containing 3A (ATAD3A) complexes: one with OPA1 that regulates mitochondrial ultrastructure and the second containing ribosomal proteins that is essential for mitoribosome stability. These compendia reveal the dynamic nature of mitochondrial complexes and enable their functionalization.

Keywords:  ATAD3A; OPA1; cristae remodeling; interactome; mitochondria; mitochondrial complexes; mitoribosome stability

DOI:  https://doi.org/10.1016/j.cmet.2025.01.017
BMC Res Notes. 2025 Feb 25. 18(1): 83

Identification of a novel transcript of mouse Sdha.

María J Esteban-Amo, Amaia Telleria, Dino Gobelli, Pablo Serrano-Lorenzo, Juan J Tellería, María T Pérez-García, Piotr Kozlowski, Miguel Á de la Fuente, María Simarro.

   OBJECTIVE: This study aimed to identify novel isoforms of mouse succinate dehydrogenase complex flavoprotein subunit A (Sdha) arising from internal exon skipping, analogous to the process observed in human ortholog SDHA.
RESULTS: We identified a novel isoform, designated Δ3-10, which lacked the final 104 nucleotides of exon 3 and all of exons 4 through 10, yet did not alter the reading frame. The Δ3-10 Sdha cDNA was cloned into expression vectors, and overexpression resulted in a protein localized to the mitochondria. However, the endogenous Δ3-10 Sdha protein was not detected with the available antibodies.

Keywords:  Isoforms; Mitochondria; Mouse; Sdha

DOI:  https://doi.org/10.1186/s13104-025-07149-8
Cell Metab. 2025 Feb 14. pii: S1550-4131(25)00025-7. [Epub ahead of print]

Leptin enhances the intracellular thyroid hormone activation in skeletal muscle to boost energy balance.

Caterina Miro, Annunziata Gaetana Cicatiello, Annarita Nappi, Serena Sagliocchi, Lucia Acampora, Federica Restolfer, Ornella Cuomo, Giulia de Alteris, Gabriella Pugliese, Sepehr Torabinejad, Rosa Maritato, Melania Murolo, Emery Di Cicco, Nunzio Velotti, Marianna Capuano, Evelina La Civita, Daniela Terracciano, Roberto Ciampaglia, Mariano Stornaiuolo, Mario Musella, Giovanni Aprea, Giuseppe Pignataro, Silvia Savastano, Monica Dentice.

  Thyroid hormones (THs) are key modulators of energy metabolism and cross-talk with other endocrine and metabolic factors. Notably, leptin can increase hypothalamic control of TH synthesis as an adaptive metabolic response regulating body weight. In this study, we found that the TH signal is heightened in overweight humans and is lost with obesity. In mice, systemic and intracerebroventricular leptin injection induces the expression of type 2 deiodinase (D2), the TH-activating enzyme, in skeletal muscle. Mechanistically, leptin enhances the transcription of D2 by a STAT3- and α-melanocyte-stimulating hormone (α-MSH)/cyclic AMP (cAMP)-dependent regulation. Notably, mice lacking D2 or with a mutation in the TH receptor do not exhibit the metabolic effects of leptin, such as increased insulin sensitivity and oxygen consumption, indicating that leptin's peripheral metabolic effects in skeletal muscle are mediated by TH. These findings underscore the critical role of leptin in integrating the TH-induced metabolic activation, while also contributing to appetite suppression in response to perceived fat stores.

Keywords:  deiodinases; energy homeostasis; glucose uptake; leptin; melanocortin; obesity; skeletal muscle; thyroid hormone

DOI:  https://doi.org/10.1016/j.cmet.2025.01.025
Nature. 2025 Feb 26.

A systems-level, semi-quantitative landscape of metabolic flux in C. elegans.

Hefei Zhang, Xuhang Li, L Tenzin Tseyang, Gabrielle E Giese, Hui Wang, Bo Yao, Jingyan Zhang, Rachel L Neve, Elizabeth A Shank, Jessica B Spinelli, L Safak Yilmaz, Albertha J M Walhout.

Metabolic flux, or the rate of metabolic reactions, is one of the most fundamental metrics describing the status of metabolism in living organisms. However, measuring fluxes across the entire metabolic network remains nearly impossible, especially in multicellular organisms. Computational methods based on flux balance analysis have been used with genome-scale metabolic network models to predict network-level flux wiring1-6. However, such approaches have limited power because of the lack of experimental constraints. Here, we introduce a strategy that infers whole-animal metabolic flux wiring from transcriptional phenotypes in the nematode Caenorhabditis elegans. Using a large-scale Worm Perturb-Seq (WPS) dataset for roughly 900 metabolic genes7, we show that the transcriptional response to metabolic gene perturbations can be integrated with the metabolic network model to infer a highly constrained, semi-quantitative flux distribution. We discover several features of adult C. elegans metabolism, including cyclic flux through the pentose phosphate pathway, lack of de novo purine synthesis flux and the primary use of amino acids and bacterial RNA as a tricarboxylic acid cycle carbon source, all of which we validate by stable isotope tracing. Our strategy for inferring metabolic wiring based on transcriptional phenotypes should be applicable to a variety of systems, including human cells.

DOI: https://doi.org/10.1038/s41586-025-08635-6