Mitochondrial-Targeted Therapies Require Mitophagy to Prevent Oxidative Stress Induced by SOD2 Inactivation in Hypertrophied Cardiomyocytes

Antioxidants

Heiko Bugger¹  Paul Mulder²  Vincent Richard²  Edith Renguet³  Natacha Fourny³  Luc Bertrand³  Laurent Bultot³  Anne Loyens⁴  Maggy Chwastyniak⁵  Victoriane Peugnet⁵  Steve Lancel⁵  Olivia Beseme⁵  Wilfried Heyse⁵  Philippe Amouyel⁵  Emilie Dubois-Deruy⁵  Florence Pinet⁵ 

[1] Department of Cardiology and Angiology I, Heart Center Freiburg, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany;Normandie Univ, UNIROUEN, Inserm U1096, FHU-REMOD-HF, 76000 Rouen, France;Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, UCLouvain, 1200 Bruxelles, Belgium;Univ. Lille, CNRS, Inserm, CHU Lille, Institut de Recherche Contre le Cancer de Lille, UMR9020-UMR-S 1277-Canther-Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, France;Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, 59000 Lille, France;

关键词: oxidative stress;    mitochondrial dysfunction;    mitochondrial antioxidant;    superoxide dismutase 2;    acetylation;    mitophagy;   

DOI  :  10.3390/antiox11040723

来源: DOAJ

【 摘 要 】

Heart failure, mostly associated with cardiac hypertrophy, is a major cause of illness and death. Oxidative stress causes accumulation of reactive oxygen species (ROS), leading to mitochondrial dysfunction, suggesting that mitochondria-targeted therapies could be effective in this context. The purpose of this work was to determine whether mitochondria-targeted therapies could improve cardiac hypertrophy induced by mitochondrial ROS. We used neonatal (NCMs) and adult (ACMs) rat cardiomyocytes hypertrophied by isoproterenol (Iso) to induce mitochondrial ROS. A decreased interaction between sirtuin 3 and superoxide dismutase 2 (SOD2) induced SOD2 acetylation on lysine 68 and inactivation, leading to mitochondrial oxidative stress and dysfunction and hypertrophy after 24 h of Iso treatment. To counteract these mechanisms, we evaluated the impact of the mitochondria-targeted antioxidant mitoquinone (MitoQ). MitoQ decreased mitochondrial ROS and hypertrophy in Iso-treated NCMs and ACMs but altered mitochondrial structure and function by decreasing mitochondrial respiration and mitophagy. The same decrease in mitophagy was found in human cardiomyocytes but not in fibroblasts, suggesting a cardiomyocyte-specific deleterious effect of MitoQ. Our data showed the importance of mitochondrial oxidative stress in the development of cardiomyocyte hypertrophy. We observed that targeting mitochondria by MitoQ in cardiomyocytes impaired the metabolism through defective mitophagy, leading to accumulation of deficient mitochondria.

【 授权许可】

Unknown