mtDNA damage in the development of heart failure

摘要

continuous atp generation is obligatory to support the massive energetic demand of contractility (20). Oxidative phosphory-lation (OXPHOS) mediated by electron transport across the inner mitochondrial membrane accounts for more than 90% of the ATP synthesized in cardiomyocytes (6). Each cardiomyo-cyte has thousands of mitochondria, and each mitochondrion contains its own DNA (22). Mitochondrial DNA (mtDNA) is a double-stranded circular genome comprised of ~16,600 base pairs that encodes 13 proteins of the electron transport chain (ETC), 2 ribosomal RNAs, and 22 transfer RNAs (22). Although mtDNA only encodes a small portion of ETC complex subunits, most ETC proteins are encoded by nuclear DNA, perturbations in mtDNA are associated with the pathogenesis of numerous diseases defined by impaired energy production (22). It is not surprising that the manifestations of mitochondrial diseases are most evident in organs that rely on a steady supply of ATP such as the brain, skeletal muscle, and heart. In fact, encephalopathy and cardiomyopathy are the most pronounced presentations of mitochondrial disease (19). There are several pathogenic mutations in mtDNA that are associated with heart disease and early lethality, highlighting the importance of mtDNA maintenance (Table 1) (14, 17). Although mtDNA mutations likely account for a very small percentage of mitochondrial-derived cardiomyopathies, with most mitochondrial contributions to disease originating in nuclear encoded proteins or being secondary to a primary insult that damages mitochondrial function, (16, 21) it has become clear that the accumulation of mtDNA damage is associated with the progression of adult-onset heart failure from diverse etiologies (10, 29). However, whether alterations in mtDNA are primary or secondary in the development of heart failure remains unknown.