Abstract Body: Background:
Primary mitochondrial cardiomyopathies are severe genetic disorders characterized by impaired mitochondrial energy metabolism and limited therapies targeting the underlying mitochondrial dysfunction. The mitochondrial phosphate carrier SLC25A3 transports inorganic phosphate into mitochondria to support oxidative phosphorylation and ATP synthesis. Cardiomyocyte-specific deletion of Slc25a3 impairs mitochondrial ATP production while total ATP levels remain preserved through metabolic compensation including increased glycolysis. Because metabolic remodeling may influence cardiac adaptation to mitochondrial dysfunction, we tested whether pharmacologic modulation of metabolism to promote glycolysis could improve cardiac function in the context primary mitochondrial disease.
Methods:
Cardiomyocyte-specific Slc25a3 knockout mice were treated with meclizine, an FDA-approved drug previously reported to shift cellular metabolism toward glycolysis. Cardiac function and structure were assessed by echocardiography and morphometric analyses. Mitochondrial ultrastructure was evaluated by transmission electron microscopy. Quantitative proteomics and biochemical assays assessed metabolic enzyme expression, mitochondrial membrane organization, and NAD/NADH redox balance.
Results:
Meclizine treatment attenuated cardiac hypertrophy and improved systolic function in Slc25a3 deficient hearts. Transmission electron microscopy showed restoration of mitochondrial ultrastructure with improved cristae organization. Unexpectedly, meclizine reduced glycolytic enzyme expression and decreased lactate accumulation, indicating that cardioprotection was not mediated by enhanced glycolysis. Instead, proteomic and biochemical analyses demonstrated increased expression of mitochondrial contact site and cristae organizing system (MICOS) complex components, preservation of mitochondrial membrane organization, and an increased NAD/NADH ratio consistent with improved redox balance.
Conclusions:
Meclizine improves cardiac function and mitochondrial architecture in mitochondrial cardiomyopathy through mechanisms independent of glycolytic enhancement, highlighting mitochondrial membrane organization and redox homeostasis as potential therapeutic targets.