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.

• Authors: Quan He, Nicole Harris, Jun Ren, Xianlin Han
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2014 Pg. 654198 ( 2014) ISSN: 1942-0994 [Electronic] United States
• PMID: 25247053 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Cyclic N-Oxides
• Reactive Oxygen Species
• Transcription Factors
• Adenosine Triphosphate
• Acyltransferases
• TAFAZZIN protein, human
• TEMPO

Topics

• Acyltransferases
• Adenosine Triphosphate (metabolism)
• Animals
• Antioxidants (pharmacology)
• Barth Syndrome (drug therapy, genetics, metabolism, therapy)
• Cardiomegaly (drug therapy, genetics, metabolism, prevention & control)
• Cyclic N-Oxides (pharmacology)
• Gene Knockdown Techniques
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondria (drug effects, enzymology, metabolism)
• Reactive Oxygen Species (metabolism)
• Transcription Factors (deficiency, genetics)