Mitochondrial defects in cardiomyopathy and neuromuscular disease.

Over the past 11 years, a considerable body of evidence has accumulated implicating defects in the mitochondrial energy-generating pathway, oxidative phosphorylation, in a wide variety of degenerative diseases including myopathy and cardiomyopathy. Most classes of pathogenic mitochondrial DNA mutations affect the heart, in association with a variety of other clinical manifestations that can include skeletal muscle, the central nervous system (including eye), the endocrine system, and the renal system. To better understand the pathophysiologic basis of mitochondrial diseases and their role in myopathy and cardiomyopathy, several mouse models of mitochondrial disease have been prepared. Mitochondrial DNA mutations from cultured cells have been introduced into mice; nuclear DNA genes involved in mitochondrial energy production and reactive oxygen species detoxification have been genetically inactivated, which resulted in mice with hypertrophic and dilated cardiomyopathy, respectively. Physiologic characterization of these mice has confirmed the importance of decreased mitochondrial energy production, increased mitochondrial reactive oxygen species production, and the mitochondrial initiation of apoptosis in mitochondrial disease. With these insights, new therapeutic approaches for neuromuscular and cardiac disease have been suggested.