Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise
Por:
A. VUJIC, A. KOO, G. BIDAULT, J. MILJKOVIC, A. JAMES, A. DANNHORN, X. DUAN, L. DAVIS, J. ABE, J. VALADARES, J. LEE, A. DIAZ-VEGAS, K. TURNER, R. GOODWIN, D. FAZAKERLEY, A. VIDAL-PUIG, M. MURPHY and T. KRIEG
Publicada:
6 jul 2025
Resumen:
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.
Filiaciones:
A. VUJIC:
Univ Cambridge, Dept Med, Cambridge, England
Univ Cambridge, Victor Phillip Dahdaleh Heart & Lung Res Inst, Cambridge, England
A. KOO:
Univ Cambridge, Dept Med, Cambridge, England
G. BIDAULT:
Univ Cambridge, Inst Metab Sci, Cambridge, England
J. MILJKOVIC:
Univ Cambridge, MRC Mitochondrial Biol Unit, Cambridge, England
A. JAMES:
Univ Cambridge, MRC Mitochondrial Biol Unit, Cambridge, England
A. DANNHORN:
AstraZeneca, Integrated Bioanal Clin Pharmacol & Safety Sci, R&D, Cambridge, England
X. DUAN:
Univ Cambridge, Inst Metab Sci, Cambridge, England
L. DAVIS:
Univ Cambridge, Inst Metab Sci, Cambridge, England
J. ABE:
Univ Cambridge, Dept Med, Cambridge, England
Univ Cambridge, MRC Mitochondrial Biol Unit, Cambridge, England
J. VALADARES:
Univ Cambridge, MRC Mitochondrial Biol Unit, Cambridge, England
J. LEE:
Univ Cambridge, Dept Med, Cambridge, England
Univ Cambridge, MRC Mitochondrial Biol Unit, Cambridge, England
A. DIAZ-VEGAS:
Univ Sydney, Charles Perkins Ctr, Sch Life & Environm Sci, Sydney, NSW, Australia
K. TURNER:
Univ Cambridge, MRC Mitochondrial Biol Unit, Cambridge, England
R. GOODWIN:
AstraZeneca, Integrated Bioanal Clin Pharmacol & Safety Sci, R&D, Cambridge, England
D. FAZAKERLEY:
Univ Cambridge, Inst Metab Sci, Cambridge, England
:
Univ Cambridge, Inst Metab Sci, Cambridge, England
Univ Cambridge, Victor Phillip Dahdaleh Heart & Lung Res Inst, Cambridge, England
Ctr Invest Principe Felipe, Valencia, Spain
M. MURPHY:
Univ Cambridge, Dept Med, Cambridge, England
Univ Cambridge, MRC Mitochondrial Biol Unit, Cambridge, England
T. KRIEG:
Univ Cambridge, Dept Med, Cambridge, England
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