Key result
EUK 134 reduces cardiomyocyte oxidative stress and hypertrophy while MitoQ impairs mitochondrial function.
Why the study?
To characterize how mitochondrial oxidative stress is involved in cardiac hypertrophy and determine whether mitochondria-targeted therapies could improve cardiac phenotypes.
Do mitochondria-targeted anti-oxidants (MitoQ and EUK 134) reduce oxidative stress and hypertrophy in isoproterenol-treated cardiomyocytes?
Do mitochondria-targeted anti-oxidants (MitoQ and EUK 134) reduce oxidative stress and hypertrophy in isoproterenol-treated cardiomyocytes?
While both anti-oxidants reduce hypertrophy and oxidative stress, EUK 134 preserves mitochondrial function whereas MitoQ exhibits deleterious, cell-specific impairment of mitophagy and metabolism in cardiomyocytes.
Hypothesis-generating for selective antioxidant effects in hypertrophy models; should not yet change clinical practice.
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.
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Peugnet et al. (2021) studied Cardiac hypertrophy. Mitoquinone (MitoQ) and EUK 134 vs. Isoproterenol alone was evaluated on Mitochondrial oxidative stress, hypertrophy, and mitochondrial function. EUK 134 decreased oxidative stress and cardiomyocyte hypertrophy and restored metabolism, whereas MitoQ impaired mitochondrial function and mitophagy specifically in cardiomyocytes.
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