Mitochondrial DNA Damage and Dysfunction Associated With Oxidative Stress in Failing Hearts After Myocardial Infarction

TLDR

Mitochondria generate reactive oxygen species and are also vulnerable to ROS‑mediated damage, creating a cycle that can impair electron transport and promote left ventricular remodeling and failure after myocardial infarction. We hypothesized that ROS may induce mitochondrial DNA damage, leading to defects in mtDNA‑encoded gene expression and respiratory chain enzymes, thereby contributing to LV remodeling and failure after MI. In a murine MI model induced by left anterior descending coronary artery ligation for 4 weeks, the left ventricle became dilated and contractility diminished. MI mice exhibited elevated mitochondrial hydroxyl radicals and lipid peroxidation, a 44 % reduction in mtDNA copy number, down‑regulation of mtDNA‑encoded respiratory subunits, and diminished activities of complexes I, III, and IV, while nuclear‑encoded complexes II and citrate synthase remained unchanged.

Abstract

Abstract —Mitochondria are one of the enzymatic sources of reactive oxygen species (ROS) and could also be a major target for ROS-mediated damage. We hypothesized that ROS may induce mitochondrial DNA (mtDNA) damage, which leads to defects of mtDNA-encoded gene expression and respiratory chain complex enzymes and thus may contribute to the progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). In a murine model of MI and remodeling created by the left anterior descending coronary artery ligation for 4 weeks, the LV was dilated and contractility was diminished. Hydroxyl radicals, which originated from the superoxide anion, and lipid peroxide 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, associated with a parallel decrease (30% to 50% of sham) in the mtDNA-encoded gene 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 activity of complexes I, III, and IV decreased in MI, whereas, in contrast, complex 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.