Mitochondria-Targeted Antioxidant Prevents Cardiac Dysfunction Induced by Tafazzin Gene Knockdown in Cardiac Myocytes

Abstract

Tafazzin, a mitochondrial acyltransferase, plays an important role in cardiolipin side chain remodeling. Previous studies have shown that dysfunction of tafazzin reduces cardiolipin content, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome. Reactive oxygen species (ROS) have been implicated in the development of cardiomyopathy and are also the obligated byproducts of mitochondria. We hypothesized that tafazzin knockdown increases ROS production from mitochondria, and a mitochondria-targeted antioxidant prevents tafazzin knockdown induced mitochondrial and cardiac dysfunction. We employed cardiac myocytes transduced with an adenovirus containing tafazzin shRNA as a model to investigate the effects of the mitochondrial antioxidant, mito-Tempo. Knocking down tafazzin decreased steady state levels of cardiolipin and increased mitochondrial ROS. Treatment of cardiac myocytes with mito-Tempo normalized tafazzin knockdown enhanced mitochondrial ROS production and cellular ATP decline. Mito-Tempo also significantly abrogated tafazzin knockdown induced cardiac hypertrophy, contractile dysfunction, and cell death. We conclude that mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes and suggest mito-Tempo as a potential therapeutic for Barth syndrome and other dilated cardiomyopathies resulting from mitochondrial oxidative stress.

Barth Syndrome: Exploring Cardiac Metabolism with Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“…These cellular models facilitated the understanding of modes of tafazzin dysfunction and provided mechanistic insights regarding the phenotypic heterogeneity seen in BTHS [33] [34]. Other studies involved cellular models such as fibroblasts [35], lymphoblasts [36], neutrophils [37], neonatal ventricular fibroblasts [38], and cardiac myocytes [39]. Later, mouse models were generated and revealed multiple cardiac and muscle dysfunctions [40,41] and disruption of the interactions between the electron transport chain (ETC) and some fatty acid oxidation enzymes [42].…”

Mitochondrial dysfunction and oxidative stress in metabolic disorders — A step towards mitochondria based therapeutic strategies

“…The mitochondria targeted antioxidants therapies could be potential treatment for a number of pathologic conditions including neurodegenerative or metabolic diseases. Recently, in vivo and in vitro studies done in experimental animals and humans, reported ameliorative role of mitochondria targeted antioxidants against metabolic disorders [209-212]. The commonly used vitamins (vitamin E and C) and other chemical compounds with antioxidant properties such as coenzyme Q, a-lipoic acid, N-acetylcysteine (NAC) have been used to reduce the excess generation of ROS in various metabolic conditions [213-215].…”

Diastolic Dysfunction

“…64 Injecting animals with a mitochondria-targeted antioxidant, mitoTEMPO, prevented diabetic-associated diastolic dysfunction. 65 Other mitochondria-targeted antioxidants that have shown beneficial effects in muscle include MitoQ10 66 and the mitochondria-selective peptide, SS-31. 67 Any of these may represent a novel therapeutic strategy for diastolic dysfunction.…”