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

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.

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

“…This observation suggests early compensatory enhancement in mitochondrial homeostasis but that impairment in mitochondrial homeostasis and function develops and precedes the development of overt systolic dysfunction in concert with progressive ER. This is in line with what has been shown in children with right ventricular failure secondary to congenital heart disease48 and in mice with myocardial remodeling and failure postinfarction 49. It has been shown that PGC‐1α controls mitochondrial density50 and fatty acid oxidation51, 52 and its amount directly correlates with mitochondrial density, oxidative capacity,47 and the metabolic shift from fatty acid oxidation to glucose oxidation,51 which precedes cardiac decompensation 46.…”

“…Here we observed decreases in complex I and complex IV expression and COX IV activity in the MOD phenotype. The changes in ETC complexes in the MOD phenotype appeared out of proportion to the level of decrease in PGC‐1α expression, which was similar to sham, suggesting that other factors may be involved in disruption of ETC such as mitochondrial Ca 2+ overload and increased reactive oxygen species (ROS), both previously reported in the AAB model 49, 55. Moreover, CS activity increased progressively despite the progressive decrease in mitochondrial biogenesis and content across the 3 phenotypes.…”

Regulation of mitochondrial DNA content and cancer

“…Given these observations, it is likely that the inhibition of the repair system for ROSmediated damage to mtDNA, detoxification of ROS, or increase in ROS generation might be possible causes for point mutations of mtDNA, accumulation of large-deletion mutant mtDNA, and the depletion of mtDNA. Additionally, the report indicates that oxidative stress generated by myocardial infraction (Ide et al, 2001) and TNF (Suematsu et al, 2003) rapidly and directly induced depletion of mtDNA. It is likely that mtDNA depletion can be induced independent of mtDNA mutation.…”

Excitation-contraction coupling and mitochondrial energetics

“…Finally, mitochondria are the source for an increased production of ROS in failing hearts [97,98]. It has been proposed that increased mitochondrial ROS-production may lead to defects in mitochondrial DNA, which could contribute to reduced expression of ETC complexes in heart failure [96]. Fig.…”