Restore mitophagy is essential to prevent cardiac oxidative stress during hypertrophy

Heart failure, mostly associated with cardiac hypertrophy, is still a major cause of illness and death. Oxidative stress causes contractile failure and the accumulation of reactive oxygen species leads to mitochondrial dysfunction, associated with aging and heart failure, suggesting that mitochondria-targeted therapies could be effective in this context. The purpose of this work was to characterize how mitochondrial oxidative stress is involved in cardiac hypertrophy development and to determine if mitochondria-targeted therapies could improve cardiac phenotypes. We used neonatal and adult rat cardiomyocytes (NCMs and ACMs) hypertrophied by isoproterenol (Iso) to induce an increase of mitochondrial superoxide anion. Superoxide dismutase 2 activity and mitochondrial biogenesis were significantly decreased after 24h of Iso treatment. To counteract the mitochondrial oxidative stress induced by hypertrophy, we evaluated the impact of two different anti-oxidants, mitoquinone (MitoQ) and EUK 134. Both significantly decreased mitochondrial superoxide anion and hypertrophy in hypertrophied NCMs and ACMs. Conversely to EUK 134 which preserved cell functions, MitoQ impaired mitochondrial function by decreasing maximal mitochondrial respiration, mitochondrial membrane potential and mitophagy (particularly Parkin expression) and altering mitochondrial structure. The same decrease of Parkin was found in human cardiomyocytes but not in fibroblasts suggesting a cell specificity deleterious effect of MitoQ. Our data showed the importance of mitochondrial oxidative stress in the development of cardiomyocyte hypertrophy. Interestingly, we observed that targeting mitochondria by an anti-oxidant (MitoQ) impaired metabolism specifically in cardiomyocytes. Conversely, the SOD mimic (EUK 134) decreased both oxidative stress and cardiomyocyte hypertrophy and restored impaired cardiomyocyte metabolism and mitochondrial biogenesis. ### Competing Interest Statement The authors have declared no competing interest. * SOD2acK68 : Acetylated form of SOD2 in lysine 68 ACMs : adult rat cardiomyocytes AA : antimycin A CCCP : carbonyl cyanide m-chlorophenyl hydrazine HF : heart failure HCMs : human cardiac myocytes Iso : isoproterenol HPRT : hypoxanthine phos^horibosyl transferase Mfn2 : mitofusin 2 Mfn2 : mitochondrial fission 1 proteinw MitoQ : mitoquinone NCFs : rat neonatal cardiac fibroblasts NCMs : neonatal rat cardiac myocytes NOX4 : NADPH Oxidase 4 NRF : nuclear respiratory factor PGC1α : peroxisome proliferator-activated receptor gamma coactivator 1-alpha Prx-1 : peroxiredoxin-1 ROS : reactive oxygen species RTCA : real time cell analysis SOD : superoxide dismutase