Abstract Body: Introduction: Mitochondrial Ca²⁺ flux has been extensively studied for its role in oxidative phosphorylation and necrotic cell death. Our recent studies in skeletal muscle suggest that enhanced mitochondrial Ca²⁺ flux increases glucose oxidation and inhibition of mitochondrial Ca²⁺ dynamics augments substrate use towards more fatty acid oxidation.
Hypothesis: We hypothesize that mitochondrial Ca²⁺ dynamics also regulates fuel selection in the heart.
Objective: To investigate the cardiometabolic consequences of altered mitochondrial Ca²⁺ dynamics in the heart.
Methods: We developed a cardiac-specific MCUb overexpression mouse model to drive MCUb expression from development. Additionally, we employed AAV-mediated gene delivery to overexpress various MCU components (Mcu, Mcub, and Micu3) to assess their individual contributions to cardiac metabolism.
Results: MCUb induction in the heart enhanced cardiac function, evidenced by increased cardiac output. Gravimetric and electron microscopy analyses revealed signs of cardiac hypertrophy. Metabolically, MCUb overexpression in the heart resulted in decreased malonyl CoA levels, suggesting increased fatty acid oxidation (FAO) although these mice unexpectedly had increased fat accumulation over time. We also observed increased total acetylation with MCUb overexpression, but pyruvate dehydrogenase (PDH) and its phosphorylation were unchanged. AAV-baesd gene of select MCU components showed that both MCUb and MICU3 overexpression resulted in reduced ATP production and reduced Krebs cycle flux, further highlighting the metabolic consequences of disrupted mitochondrial Ca²⁺ dynamics.
Conclusions: Our findings support a critical role for mitochondrial Ca²⁺ dynamics in regulating cardiac metabolism. Further studies are necessary to elucidate the molecular mechanisms driving the observed metabolic adaptations and to explore potential therapeutic implications.