Mitochondrial Dynamics: Exploring A Novel Target Against Myocardial Ischemia-Reperfusion Injury

MITOCHONDRIAL DYNAMICS: EXPLORING A NOVEL TARGET AGAINSTMYOCARDIAL ISCHEMIA-REPERFUSION INJURYbyYI DONGAugust 2014Advisor: Karin Przyklenk, Ph.D.Major: PhysiologyDegree: Doctor of PhilosophyMitochondrial fusion and fission, collectively termed mitochondrial dynamics, areamong the core mechanisms responsible for maintaining mitochondrial health andfunctional integrity. Dynamin-related protein 1 (DRP1) is a key regulator ofmitochondrial fission. Recent studies suggest that i) mitochondrial dynamics,particularly, mitochondrial fission, serves as a mediator of cell fate in the setting ofischemia-reperfusion (IR) injury, and, ii) inhibition of DRP1 and mitochondrial fissionprovides cardioprotection against IR injury. However, the precise role of DRP1translocation to mitochondria in the pathogenesis of myocardial ischemia-reperfusioninjury has not been established.Using an established model of hypoxia-reoxygenation (HR) in cultured HL-1cardiomyocytes, we tested three hypotheses:i. subcellular redistribution of DRP1 is i) triggered by HR, and ii) plays amechanistic role in HR-induced cytochrome c release and cell apoptosis;ii. inhibition of DRP1 translocation prior to hypoxia is cardioprotective;iii. inhibition of DRP1 in a time-frame that is relevant as a therapeutic strategy (i.e.,begun at reoxygenation) will also attenuate cardiomyocyte death, although