Changes in mitochondrial dynamics have been recognized as being one of the mechanisms related to cardiotoxicity following a high cumulative dose of doxorubicin (DOX). A mitochondrial division inhibitor (Mdivi-1) and fusion promoter (M1) have been shown to be cardioprotective in a variety of cardiovascular settings, however their anti-cardiotoxic efficacy against DOX therapy remains unclear. We therefore investigated whether treatment with Mdivi-1 and M1 protect the heart against DOX-induced cardiotoxicity via mitochondria-targeted pathways. Male Wistar rats (n=40) received DOX (3 mg/kg, 6 doses, n=32) or 3% DMSO in the normal saline solution (NSS) (n=8) as a control. DOX-injected rats were given one of four treatments beginning with the first DOX injection via intraperitoneal injection: 1) 3% DMSO in NSS (n=8), 2) Mdivi-1 (1.2 mg/kg/day, n=8), 3) M1 (2 mg/kg/day, n=8), and 4) Mdivi-1+M1 (n=8) for 30 days. Cardiac function, mitochondrial function, oxidative stress, myocardial injury, and protein expression associated with inflammation, autophagy, mitophagy, apoptosis and mitochondrial dynamics were determined. DOX caused a significant deterioration in mitochondrial function and dynamic regulation, and an increase in markers of oxidative stress, inflammation, myocardial injury, apoptosis, autophagy, and mitophagy, resulting in impaired cardiac function. Co-treatment of DOX with Mdivi-1, M1, or a combination of the two mitigated these detrimental effects of DOX. These findings imply that either inhibiting fission or promoting fusion of mitochondria protects the heart from DOX-induced myocardial damage. Modulation of mitochondrial dynamics could be a novel therapeutic target in alleviating DOX-induced cytotoxic effects without compromising its anti-cancer efficacy.
Promoting mitochondrial fusion in doxorubicin-induced cardiotoxicity: a novel therapeutic target for cardioprotection
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Chayodom Maneechote, Thawatchai Khuanjing, Benjamin Ongnok, Apiwan Arinno, Nanthip Prathumsap, Titikorn Chunchai, Busarin Arunsak, Wichwara Nawara, Siriporn C Chattipakorn, Nipon Chattipakorn; Promoting mitochondrial fusion in doxorubicin-induced cardiotoxicity: a novel therapeutic target for cardioprotection. Clin Sci (Lond) 2022; CS20220074. doi: https://doi.org/10.1042/CS20220074
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