Mitochondrial Transplantation Ameliorates Doxorubicin-Induced Cardiac Dysfunction via Activating Glutamine Metabolism

Doxorubicin is a wildly used effective anticancer agent. However, doxorubicin use is also related to cardiotoxic side effect in some patients. Mitochondrial damage has been shown to be one of the pathogeneses of doxorubicin-induced myocardial injury. In this study, we test the hypothesis that mitochondrial transplantation might be a therapeutic strategy to prevent and ameliorate doxorubicin-induced cardiotoxicity. We demonstrated the deleterious effects of doxorubicin on mitochondrial structure and function in cardiomyocytes both in vitro and in vivo. Mitochondrial transplantation could inhibit doxorubicin-induced cardiotoxicity by directly supplying functional mitochondria. In vitro, mitochondrial transplantation improved contractile function and respiratory capacity, reduced cellular apoptosis and oxidative stress in cardiomyocytes. Mitochondria isolated from various sources, including mouse hearts, mouse and human arterial blood, and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), all exerted similar cardioprotective effects. Mechanically, mitochondrial transplantation activates glutamine metabolism in doxorubicin-treated cardiomyocytes and blocking glutamine metabolism attenuated the cardioprotective effects of mitochondrial transplantation. Overall, our study demonstrates that mitochondria isolated from arterial blood could be used for mitochondrial transplantation, which might serve as a feasible promising therapeutic option for patients with doxorubicin-induced cardiotoxicity.