Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise
Central to the development of heart failure with preserved ejection fraction (HFpEF) is the redox disruption of metabolic processes; however, the underlying mechanisms are not fully understood. This study utilized a murine model (ND6) carrying a homoplasmic mitochondrial DNA point mutation (ND6 G139...
| Autores: | , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Centro de Investigación Principe Felipe (CIPF) |
| Repositorio: | r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF) |
| OAI Identifier: | oai:cipf.fundanetsuite.com:p4530 |
| Acceso en línea: | https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4530 |
| Access Level: | acceso abierto |
| Palabra clave: | exercise HFpEF lipid metabolism mitochondria RET-ROS |
| Sumario: | Central to the development of heart failure with preserved ejection fraction (HFpEF) is the redox disruption of metabolic processes; however, the underlying mechanisms are not fully understood. This study utilized a murine model (ND6) carrying a homoplasmic mitochondrial DNA point mutation (ND6 G13997A), which maintains functional NADH oxidation but lacks the site-specific reactive oxygen species (ROS) generation via reverse electron transport (RET). We demonstrate that mice with RET-ROS deficiency have reduced exercise capacity despite higher lean body mass, impaired resilience to high-fat/high-sucrose dietary stress, and cardiac hypertrophy with diastolic dysfunction. Importantly, dobutamine-induced stress elevated succinate levels in the heart, accompanied by RET-ROS production in wild-type but not in ND6 mice. Furthermore, ND6 mice showed perturbation in metabolite profiles following dobutamine stress. Mechanistically, the ND6 heart had an upregulated expression of fatty acid transport, oxidation, and synthesis genes (CD36, Cpt1b, Acly, Fas, Elovl6, and Scd1) and increased protein levels of lipid metabolism regulators (acetyl-CoA carboxylase and perilipin 2). Interestingly, 8 wk of forced treadmill running increased acetyl-CoA abundance, alleviated metabolic stress, and improved diastolic function in RET-ROS mutant hearts. In summary, these findings reveal a critical role for RET-ROS in regulating exercise capacity and cardiometabolic health, identifying it as a potentially selective target for modulating cardiac metabolism. |
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