RT Journal Article
SR Electronic
T1 Restore mitophagy is essential to prevent cardiac oxidative stress during hypertrophy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.12.426366
DO 10.1101/2021.01.12.426366
A1 Victoriane Peugnet
A1 Maggy Chwastyniak
A1 Steve Lancel
A1 Laurent Bultot
A1 Natacha Fourny
A1 Olivia Beseme
A1 Anne Loyens
A1 Wilfried Heyse
A1 Philippe Amouyel
A1 Luc Bertrand
A1 Florence Pinet
A1 Emilie Dubois-Deruy
YR 2021
UL http://biorxiv.org/content/early/2021/01/12/2021.01.12.426366.abstract
AB 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 StatementThe authors have declared no competing interest.SOD2acK68Acetylated form of SOD2 in lysine 68ACMsadult rat cardiomyocytesAAantimycin ACCCPcarbonyl cyanide m-chlorophenyl hydrazineHFheart failureHCMshuman cardiac myocytesIsoisoproterenolHPRThypoxanthine phos^horibosyl transferaseMfn2mitofusin 2Mfn2mitochondrial fission 1 proteinwMitoQmitoquinoneNCFsrat neonatal cardiac fibroblastsNCMsneonatal rat cardiac myocytesNOX4NADPH Oxidase 4NRFnuclear respiratory factorPGC1αperoxisome proliferator-activated receptor gamma coactivator 1-alphaPrx-1peroxiredoxin-1ROSreactive oxygen speciesRTCAreal time cell analysisSODsuperoxide dismutase