Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction

Mitochondria are one of the enzymatic sources of reactive oxygen species (R OS) and could also be a major target for ROS-mediated damage. We hypothesiz ed that ROS may induce mitochondrial DNA (mtDNA) damage, which leads to def ects of mtDNA-encoded gene expression and respiratory chain complex enzymes and thus may contribute to the progression of left ventricular (LV) remode ling and failure after myocardial infarction (MI). In a murine model of MI and remodeling created by the left anterior descending coronary artery liga tion for 4 weeks, the LV was dilated and contractility was diminished. Hydr oxyl radicals, which originated from the superoxide anion, and lipid peroxi de formation in the mitochondria were both increased in the noninfarcted LV from MI mice. The mtDNA copy number relative to the nuclear gene (18S rRNA ) preferentially decreased by 44% in MI by a Southern blot analysis, associ ated with a parallel decrease (30% to 50% of sham) in the mtDNA-encoded gen e transcripts, including the subunits of complex I (ND1, 2, 3, 4, 4L, and 5 ), complex III (cytochrome b), complex IV (cytochrome c oxidase), and rRNA (12S and 16S). Consistent with these molecular changes, the enzymatic activ ity of complexes I, III, and IV decreased in MI, whereas, in contrast, comp lex II and citrate synthase, encoded only by nuclear DNA, both remained at normal levels. An intimate link among ROS, mtDNA damage, and defects in the electron transport function, which may lead to an additional generation of ROS, might play an important role in the development and progression of LV remodeling and failure.