Eun Suh Cho

Post-injury, the proliferative ability of cardiomyocytes to replace damaged cells is very limited. As a result, it is important to understand energy production to prevent cell death. Cardiomyocytes primarily depend on ATP, a high energy molecule primarily produced in mitochondria that serves as the fuel source for all cells. Oxidative phosphorylation is the major contributor to ATP production in cardiomyocytes and calcium plays an important role as a signaling molecule in enhancing the activities of enzymes in the TCA cycle. However, excess amounts of mitochondrial calcium and reactive oxygen species have been shown to induce cell death by triggering prolonged opening of the mitochondrial permeability transition pore (mPTP). Although the identity of mPTP is controversial, cyclophilin D, a protein that induces mPTP opening, has been a target of interest for the inhibition of mPTP opening by genetic deletion or small molecule inhibitor (e.g. cyclosporin A). However, past literature has shown that while cyclophilin D deletion protected the heart from ischemia and reperfusion injury, knocking out the protein decreased its functionality. In particular, cyclophilin D knock out in Duchenne muscular dystrophy mouse models (mdx) led to greater levels of sudden death after acute energetic challenge, which was unexpected since dystrophin loss is thought to increase basal cytosolic and mitochondrial calcium levels due to a decrease in membrane integrity, increasing the risk of mPTP opening. The goal of this project is to investigate in isolated cardiac mitochondria from wild-type mice whether transient mPTP opening may act as a release valve for the buildup of ROS, potentially explaining some of the previously observed detrimental effects of cyclophilin D inhibition. These studies form the foundation for testing how the regulation of mPTP opening is disrupted in dystrophic hearts.