Cardioprotective RhoA Signaling in Mitochondrial Quality Control Mitochondrial fission and removal of smaller, damaged mitochondria by mitophagy are processes that play a significant role in mitochondrial quality control. Failure to engage mechanisms of mitochondrial quality control under cardiac stress results in mitochondrial dysfunction and cell death. Thus, mitochondrial fission and mitophagy are believed to serve cardioprotective function. Signaling by activation of the small molecular weight GTPase RhoA has previously been shown to prevent activation of mitochondrial death pathways, providing cardioprotection against ischemia/reperfusion injury and other cardiac damage. I hypothesize that activation of RhoA directly increases mitochondrial fission and mitophagy, and thus protects against cardiac ischemia/reperfusion injury through improved mitochondrial control. The proposed goals are to determine the mechanisms of RhoA signaling in regulation of cardiac mitochondrial fission and mitophagy, and to determine the involvement of RhoA regulated fission and mitophagy in cardioprotection from ischemia/reperfusion injury. Preliminary data strongly suggests that RhoA increases mitochondrial fission, and through the downstream kinase target Rho-associated Protein Kinase (ROCK) regulates the mitochondrial fission protein Dynamin-related Protein 1 (Drp1). There is also preliminary evidence that RhoA increases mitophagy, and through the downstream kinase target Protein Kinase D (PKD) regulates the mitophagy protein PTEN-induced Putative Kinase 1 (PINK1). The proposed study would demonstrate that, in addition to the known role of RhoA signaling in cell fate by preventing cardiac cell death signaling, RhoA also sustains mitochondrial quality control under the cardiac damage that would be induced by myocardial infarction, through parallel and cooperative increases in mitochondrial fission and mitophagy.
Heart attacks damage cardiac muscle cells from loss of oxygen to the heart (ischemia) as well as oxidative stress from restoration of blood flow (reperfusion), leading to heart failure if left untreated. Our proposed study's goal is to understand how a protective protein can regulate quality control of mitochondria, the primary energy producing source of heart muscle. Potential therapeutics that can stimulate this protein's effects would protect heart muscle during a heart attack, and thereby improve long-term survival.
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