314 - Knockdown of the Mitochondrial Protein 18 (MTP18) Improves Cardiomyocyte Survival in Doxorubicin Cardiotoxicity

Abstract

Doxorubicin (Dox) is one of the most commonly used chemotherapeutic agents, however, its clinical usage is limited by the cumulative dose-related cardiac toxicity. One of the mechanisms of Dox-induced cardiac injury is the free radicle formation, which ultimately results in the alteration of mitochondrial dynamic and the activation of apoptotic signaling. Hence, it is critical to understand the molecular signalling underlying the Dox-induced cardiomyocyte apoptosis in order to effectively prevent cardiomyocyte loss during Dox treatment. Recently, a novel mitochondrial protein 18 (Mtp18) has been reported to be essential for the maintenance of mitochondrial integrity and be able to regulate apoptosis. In the current study, we examined the relevance of Mtp18 on cardiaomyocyte apoptosis and its underlying mechanism in a model of Dox-induced cardiac toxicity. Exposure of neonatal rat ventricular cardiomyocytes with Dox resulted in upregulation of Mtp18 expression in mitochondria. Enforced expression of Mtp18 dramatically increased the Dox sensitivity of cardiomyocytes to undergo mitochondrial fission and apoptosis. In contrast, knockdown of endogenous MTP18 increased the resistance of cardiomyocytes to undergo apoptotic cell death following Dox administration. In response to Dox, Drp1 translocated from cytosol to mitochondria, where it mediated the fission of mitochondrial membranes, leading to the cytochrome c release and subsequently activated downstream apoptotic cascade. Mtp18 promoted the Drp1 accumulation in the mitochondria and there by enhancing Drp1-mediated mitochondrial fission and apoptosis. In addition, we observed that overexpression of Mtp18 could not exert its pro-apoptotic effect on Dox exposure when Drp1 was knockdown, suggesting that Mtp18-mediated apoptosis is dependent on Drp1. In summary, our study provides evidence that Mtp18 plays a pro-apoptotic role in Dox-induced cardiomyocyte apoptosis and knocking down of endogenous Mtp18 can prevent Dox-induced cardiomyocyte loss. Our future direction is to explore whether long non-coding RNA (lncRNA) can target MTP18 in this process of free radicle-induced cardiotoxicity.