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Role of RhoA in Cardiac Aging with a Focus on Autophagy and Mitophagy


Aging is commonly associated with the failure to maintain cellular homeostasis, including the maintenance of mitochondrial health. Mitochondrial health, and subsequently cellular homeostasis, can be compromised upon cellular stress and is, therefore, regulated through mitophagy, the mitochondria-specific form of autophagy which is the self-recycling system of the cell. The small GTPase protein, RhoA, participates in various cellular processes and has been shown to protect the heart against numerous stresses. In this study, we explore whether RhoA protects against aging in the heart and investigate the potential of RhoA in regulating the cellular homeostatic processes, autophagy and mitophagy. While investigating the role of RhoA in cardiac aging, 4 month old (young) cardiac-specific RhoA knockout mice did not show overt signs of cardiac dysfunction, but at 10 months of age (middle-aged) revealed early onsets of age-associated features in the heart such as hypertrophy and contractile dysfunction when compared to wildtype littermates. Although our data in RhoA knockout mice suggest that autophagy is not regulated by RhoA, adenoviral overexpression of RhoA in neonatal rat ventricular myocytes (NRVMs) increased both PINK1 and Parkin mitochondrial protein levels which lead to mitophagy. The observed accumulation of PINK1 was found to result from RhoA-mediated inhibition of PINK1 protein degradation, which was also discovered to involve the localization of active RhoA together with the activation of PKD, a RhoA downstream effector. Our findings suggest RhoA as both a protective signaling molecule against the progression of cardiac aging and a previously unidentified regulator of mitophagy in cardiomyocytes.

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