Structural and functional characterization of the cardiac mitochondria-associated reticular membranes in the ob/ob mouse model
Type 2 diabetes (T2D) and obesity strongly lead to diabetic cardiomyopathy (DCM). The involvement of mitochondria-associated reticular membranes (MAMs), a signaling hub in the cardiomyocyte, starts to be demonstrated in T2D-related metabolic disorders. We recently discovered a cardiac MAM Ca<sup>2+</sup> uncoupling in a high-fat high-sucrose diet (HFHSD)-induced mouse model of DCM. To better determine the role of MAMs in the progression of DCM, we here aimed to characterize the proteomic composition and function of the cardiac MAMs of another obesogenic T2D mouse model, the leptin-deficient <i>ob/ob</i> mouse. 12-week old male C57Bl6-N <i>ob/ob</i> mice displayed strain rate dysfunction and concentric remodeling, while no change was observed in fractional shortening or diastolic function. Increased lipid deposition but no fibrosis was measured in the <i>ob/ob</i> heart compared to WT. Electron microscopy analysis revealed that cardiac MAM length and width were similar between both groups. A trend towards an increased MAM protein content was measured in the <i>ob/ob</i> heart. MAM proteome analyses showed mainly increased processes in <i>ob/ob</i> hearts: cellular response to stress, lipid metabolism, ion transport and membrane organization. Functionally, MAM-driven Ca<sup>2+</sup> fluxes were unchanged but hypoxic stress induced a cell death increase in the <i>ob/ob</i> cardiomyocyte. Mitochondrial respiration, cardiomyocyte shortening, ATP and ROS content were similar between groups. To conclude, at that age, while being strongly hyperglycemic and insulin-resistant, the <i>ob/ob</i> mouse model rather displays a modest DCM without strong changes in MAMs: preserved structural and functional MAM Ca<sup>2+</sup> coupling but increased response to stress.
Authors
- Sylvie Ducreux (ORCID: https://orcid.org/0000-0003-3207-9537)
- Juliette Geoffray (ORCID: https://orcid.org/0000-0001-6849-085X)
- Claire Crola Da Silva (ORCID: https://orcid.org/0000-0002-2200-9511)
- Jennifer Rieusset (ORCID: https://orcid.org/0000-0002-1587-2253)
- Florentin Moulin (ORCID: https://orcid.org/0000-0001-8095-0724)
- Hala Guedouari (ORCID: https://orcid.org/0000-0001-6884-892X)
- Lucid Belmudes (ORCID: https://orcid.org/0000-0002-3515-0055)
- Lucas Givre
- Mélanie Paillard (ORCID: https://orcid.org/0000-0002-4912-4915)
- Christophe Chouabe (ORCID: https://orcid.org/0000-0003-1517-1438)
- Ludovic Gomez (ORCID: https://orcid.org/0000-0001-8509-4955)
- Christelle Léon (ORCID: https://orcid.org/0000-0001-8229-5401)
- J. Cao (ORCID: https://orcid.org/0000-0002-1491-5266)
- Maya Dia (ORCID: https://orcid.org/0000-0001-6531-9176)
- Stéphanie Chanon (ORCID: https://orcid.org/0000-0001-6930-6671)
- Hélène Thibault (ORCID: https://orcid.org/0000-0001-9784-0425)
- Yohann Couté (ORCID: https://orcid.org/0000-0003-3896-6196)
- Camille Brun
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Lebanese University (LB)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- CEA Grenoble (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Hospices Civils de Lyon (FR)
- Laboratoire de recherche en cardiovasculaire, métabolisme, diabétologie et nutrition (FR)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- Journal of Molecular and Cellular Cardiology Plus
- Published
- 2025-05-10
- DOI
- https://doi.org/10.1016/j.jmccpl.2025.100453
- Citations
- 1
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Fondation Lefoulon Delalande
- Azm and Saade Association
- Université Grenoble Alpes
- Agence Nationale de la Recherche
- Agence Universitaire de la Francophonie
- Fondation pour la Recherche Médicale
- Université Libanaise
- Fondation de France
- Conseil National de la Recherche Scientifique