Mitochondrial dynamics in cardiac ischemia-reperfusion injury

Maintaining mitochondrial function is critical for everyday operation of the heart. Proper mitochondrial function requires maintaining regulated and selective permeability of the mitochondrial inner membrane to ions and metabolites. Mitochondrial permeability transition occurs when the inner membrane loses its selective permeability by opening of a large-conductance nonselective channel, the permeability transition pore (PTP). High concentrations of mitochondrial Ca2+ and reactive oxygen species (ROS) are known to open PTP. PTP opening depolarizes mitochondria and causes mitochondrial swelling; thus, sustained opening of PTP leads to mitochondrial dysfunction and cell death, which is associated with many cardiovascular diseases including ischemia-reperfusion (I-R) injury and heart failure. Therefore, understanding how PTP is regulated has significant clinical value. Recently, mitochondrial dynamics mediated by fission and fusion have been suggested to be involved in regulating PTP. However, the mechanism by which mitochondrial dynamics regulates PTP remains unknown. We have found a novel transient PTP opening (tPTP) that is regulated by mitochondrial dynamics proteins. Inhibition of the fission protein Drp1 markedly increases this novel tPTP. We also found that the novel tPTP requires the inner membrane fusion protein OPA1. Although Drp1 inhibition has been shown to decrease pathologic PTP opening and reduce I-R mediated myocardial infarction, the mechanism of this fission inhibition-mediated protection is unknown. We postulate that the mitochondrial dynamics-mediated novel tPTP is a structurally distinct entity from conventional PTP, and thus in pathological conditions, can serve as a relief valve for excess matrix Ca2+ and proton gradient that induces ROS overproduction; as such, it could thereby prevent pathologic opening of PTP. Supported by our recent findings, our Central Hypothesis is that mitochondrial dynamics regulates novel tPTP, and its interplay with conventional PTP determines cardiac I-R injury outcomes. Our proposed research will test this hypothesis by two specific aims: (1) to determine the mechanism of mitochondrial dynamics-regulated novel tPTP, and (2) to investigate the interplay between conventional PTP and novel tPTP in the pathological setting. The new findings will transform the current paradigm and provide mechanistic basis for a new therapeutic strategy to decrease heart I-R injury and other cardiovascular pathology. (AHA Program: Transformational Project Award)