Abstract 143: The Inner Mitochondrial Membrane Protein Mpv17 is Crucial for Myocardial Recovery From Ischemia Reperfusion Injury

Abstract

Introduction: The MPV17 mutation in humans is an autosomal recessive disorder that results in mitochondrial DNA depletion syndromes (MDS) leading to hepatocerebral defects. Previously attributed to unknown functions, the MPV17 protein has recently been shown in the liver and kidney to be a non-selective channel in the inner membrane of mitochondria whose function is tied to membrane potential (ΔΨ m ), pH and reactive oxygen species (ROS) generation. These mitochondrial functions are critical in ischemia/reperfusion (I/R) injury caused by myocardial infarction, but despite this, however, Mpv17’s role in the myocardium is still unknown. We hypothesized that Mpv17 plays a critical role in cardiac responses to I/R injury. Methods: To investigate the role of cardiac Mpv17 protein in response to I/R injury, we measured cardiac functional recovery and myocardial infarct size in isolated hearts from in Mpv17 -/- and wildtype mice subjected to I/R. Additionally, we assessed mitochondrial ROS production, calcium retention capacity (CRC) required to induce mitochondrial permeability transition pore (mPTP) opening, ΔΨ m and cristae morphology in isolated mitochondria from the same mice. Results: We found that normal Mpv17 -/- mice exhibit similar cardiac and mitochondrial characteristics to wildtype, but after I/R, knockout mice show less cardiac functional recovery and increased myocardial infarct size. Mitochondria in these mice had more damaged cristae and reduced CRC, but surprisingly less ROS production compared to wildtype mice. Conclusion: These results shed more light onto the function of the Mpv17 protein and suggest it is critical in cardioprotection against I/R injury, and the cardiac mitochondrial response to I/R stress.