Mitochondrial cardiomyopathy: bridging molecular mechanisms and clinical frontiers

Genetic cardiomyopathies caused by pathogenic variants in nuclear DNA (nDNA) that encodes contractile sarcomere proteins are among the best understood of all the cardiomyopathies. By contrast, mitochondrial cardiomyopathy is caused by a dysfunction in mitochondrial oxidative phosphorylation due to pathogenic variants in either nDNA or the maternal mitochondrial DNA (mtDNA). Unlike contractile protein defects, which generally follow predictable Mendelian inheritance patterns, mitochondrial cardiomyopathy is genetically complex as a result of the distinctive characteristics of the mitochondrial genome, which influence patterns of maternal inheritance, heteroplasmy and tissue-specific variations in mtDNA variant load. Both single-gene nDNA and mtDNA variants can impair cardiac energetics, resulting in a wide clinical spectrum ranging from severe, childhood-onset to milder, adult-onset cardiomyopathy. Furthermore, the intricate metabolic demands of the heart mean that mitochondrial dysfunction can be influenced by a broad array of genetic and environmental modifiers. A greater recognition of these complexities and the integration of genomic sequencing, novel biomarkers and functional imaging have advanced diagnostic and therapeutic approaches. Emerging treatment strategies, such as metabolic supplementation, gene therapy and genome editing, are under investigation. In this Review, we synthesize the molecular and clinical landscape of mitochondrial cardiomyopathy, highlighting the ongoing challenges and prospects of precision medicine in this rapidly evolving field.