Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial
T Ide1, H Tsutsui, S Hayashidani
1Departments of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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.
Insights
Reactive oxygen species (ROS) damage mitochondrial DNA (mtDNA) after heart attack, impairing gene expression and leading to heart failure. This study links ROS, mtDNA damage, and heart dysfunction in myocardial infarction.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Molecular Cardiology
Background:
- Mitochondria generate reactive oxygen species (ROS) and are susceptible to ROS-induced damage.
- Mitochondrial DNA (mtDNA) damage is implicated in various pathologies.
- Left ventricular (LV) remodeling and failure post-myocardial infarction (MI) require further mechanistic understanding.
Purpose of the Study:
- To investigate the role of ROS-induced mtDNA damage in LV remodeling and failure after MI.
- To determine if mtDNA defects affect mtDNA-encoded gene expression and respiratory chain function post-MI.
- To establish a link between ROS, mtDNA damage, and cardiac dysfunction.
Main Methods:
- Murine model of myocardial infarction (MI) induced by coronary artery ligation.
- Assessment of ROS markers (hydroxyl radicals, lipid peroxides) in mitochondria.
- Quantification of mtDNA copy number and mtDNA-encoded gene transcripts (e.g., ND1, cytochrome b, COX) using Southern blot and RT-PCR.
- Measurement of respiratory chain complex enzymatic activities (Complex I, III, IV, II) and citrate synthase activity.
Main Results:
- MI induced LV dilation and diminished contractility.
- Increased mitochondrial ROS and lipid peroxidation in non-infarcted LV post-MI.
- Significant reduction in mtDNA copy number (44%) and mtDNA-encoded gene expression (30-50%) in MI hearts.
- Decreased enzymatic activity of mitochondrial respiratory chain complexes I, III, and IV, while nuclear-encoded Complex II and citrate synthase remained normal.
Conclusions:
- ROS-induced mtDNA damage is a key event in post-MI LV remodeling and failure.
- Defects in mtDNA-encoded gene expression and respiratory chain function contribute to cardiac dysfunction.
- A vicious cycle of ROS generation, mtDNA damage, and impaired mitochondrial function exacerbates heart failure progression.
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