Mitochondrial DNA mutations in myocardial diseases

Recent genetic studies have revealed that some patients with primary cardiomyopathy (CIM) possess mutations in the mitochondrial (mt) DNA of the myocardium (mtCM). Somatically acquired mutations such as deletions in mtDNA are caused mainly by hydroxyl radical damage to mtDNA. Cumulative accumulation of these somatic mutations during the life of an individual causes a bioenergetic deficit leading to myocardial dysfunction and cell death. The base-sequencing of the entire mtDNA from 48 individuals revealed that germ-line point mutations accelerate oxygen free radical damage and deletions, leading to the generation of many hundreds of types of mtDNA minicircles. These accelerated somatic mutations are expressed as premature ageing of the patients with mtCM. The comprehensive analyses of the entire mtDNA, including the base-sequencing and deletions correlating to the oxygen free radical damage have revealed clear relationships between the genotype and its phenotype, with regard to, for example, the severity of clinical symptoms and the survival time of the patients Extensive generation of mtDNA minicircles caused by the hydroxyl radical implies a close relationship between somatic mtDNA mutation and the programmed cell-death machinery.