Abstract 511: Mitochondrial Complex I -Regulated Alteration of Carbohydrate Oxidation and Energy Metabolites Reduces Ischemia-reperfusion Injury in Hearts from Mice Exposed to Moderate Ethanol Intake
Background: Moderate alcohol consumption is cardioprotective in large part through mechanisms that converge on mitochondria. As a primary entry point for reducing equivalents into the respiratory chain, the state of complex I activation has important consequences for overall mitochondrial function and cell homeostasis.
Hypothesis: Complex I is a key control point in regulation of carbohydrate oxidation and energy production that influence the extent of cardiac injury in hearts from ethanol-fed animals subjected to ischemia-reperfusion (I/R).
Methods and Results: Isolated hearts from C57BL/6 mice fed 10% ethanol (vol/vol) as drinking water for 16 weeks (E) and age-matched controls were subjected to 30 min global ischemia and 30 min reperfusion. Hemodynamics showed E hearts had better contractile recovery (left ventricular developed pressure 62±6 vs. 24±5 mmHg) and less cell damage (creatine kinase release 0.32±0.1 vs. 0.65±0.1 U/min/g) than controls after reperfusion. Mitochondrial NADH-Oxidase (1.2±0.2 vs.0.58±0.1 μg/m/mg), NADH-ubiquinone reductase (complex I, 1.04±0.2 vs. 0.48±0.1 μg/m/mg), state 3 oxygen consumption rates (266±28 vs. 152 ± 18 ngAtomO/m/mg), respiratory control ratios (5.2±0.4 vs. 3.1±0.2), aconitase activity (0.73±0.2 vs. 0.48±0.1 μmol/m/mg), and lipid peroxidation (MDA 216±22 vs. 348±14 nmol/g ) were significantly improved in E hearts after I/R compared to control hearts (all P<0.05, n=3–12). EM showed that the severity of mitochondrial ultrastructure deformation in E hearts was attenuated. In addition, high resolution 1H NMR spectroscopy revealed that the myocardial metabolites alanine, glycine, creatine/phosphocreatine, NAD, total adenosine nucleotide, and ATP were better preserved, whereas lactate and succinate were reduced in E heart tissue extracts relative to control hearts.
Moderate alcohol consumption reduces myocardial I/R injury.
The mechanism of the cardioprotection in part depends on mitochondria -mediated survival pathways.
Within the mitochondria, preservation of complex I activity is critical for maintaining overall respiratory function and cardiac energy generation.