Modulation of mitochondrial complex I activity by reversible Ca2+ and NADH mediated superoxide anion dependent inhibition

Biochemistry
Hesham A SadekLuke I Szweda

Abstract

Complex I, a key component of the mitochondrial respiratory chain, exhibits diminished activity as a result of cardiac ischemia/reperfusion. Cardiac ischemia/reperfusion is associated with increases in the levels of mitochondrial Ca(2+) and pro-oxidants. In the current in vitro study, we sought evidence for a mechanistic link between Ca(2+), pro-oxidants, and inhibition of complex I utilizing mitochondria isolated from rat heart. Our results indicate that addition of Ca(2+) to solubilized mitochondria results in loss in complex I activity. Ca(2+) induced a maximum decrease in complex I activity of approximately 35% at low micromolar concentrations over a narrow physiologically relevant pH range. Loss in activity required reducing equivalents in the form of NADH and was not reversed upon addition of EGTA. The antioxidants N-acetylcysteine and superoxide dismutase, but not catalase, prevented inhibition, indicating the involvement of superoxide anion (O2(*-)) in the inactivation process. Importantly, the sulfhydryl reducing agent DTT was capable of fully restoring complex I activity implicating the formation of sulfenic acid and/or disulfide derivatives of cysteine in the inactivation process. Finally, complex I can reactivate en...Continue Reading

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Citations

May 20, 2008·Journal of Proteome Research·Jun ZhangPeipei Ping
Feb 4, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ying-Jie PengNanduri R Prabhakar
Oct 24, 2006·Trends in Pharmacological Sciences·Vera Adam-Vizi, Christos Chinopoulos
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May 29, 2013·The FEBS Journal·Vilmante BorutaiteGuy C Brown
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