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Unmasking peroxidase activity of cytochrome c in mitochondria: role of cardiolipin.

Basova-LV; Kurnikov-IV; Wang-L; Ritov-VB; Vlasova-II; Belikova-NA; Pacheco-AA; Bayir-H; Waldeck-DH; Kagan-VE
Toxicologist 2007 Mar; 96(1):61-62
Redox properties of cyt c are critical to its normal electron transport function in mitochondria, as well as to its participation in apoptotic signaling via the peroxidase oxidation of two anionic phospholipids, cardiolipin (CL) and phosphatidylserine (PS). Peroxidation of CL contributes to the permeabilization of mitochondrial membranes, and subsequent cyt c release into the cytosol. How cyt c changes its role from an electron shuttle to a peroxidase is currently unknown. Previous work has established that upon interaction with CL, cyt c loses its tertiary structure, and its peroxidase activity dramatically increases. During apoptosis, the fraction of CL bound cyt c markedly increases. Consequently, we have hypothesized that binding of CL to cyt c acts as a switch that turns off its electron transport function, while simultaneously turning on its peroxidase catalytic function. The redox behavior of cyt c bound to CL-containing membranes was studied using direct voltammetry of cyt c adsorbed on alkanethiol monolayers and equilibrium redox titrations in the presence and absence of CL. The effects of CL binding on the redox potential of cyt c in liver and brain mitochondria, as well as on the regulation of electron transport activity in the mitochondrial electron transport chain, were examined by EPR and UV-Vis spectroscopy. The data shows that binding of cyt c to CL causes: 1) significant (~350-400 mV) negative shift of the redox potential of cyt c; 2) inhibition of cyt c reduction in mitochondria, 3) interruption of mitochondrial electron transport; and 4) inability to oxidize superoxide and ascorbate. These findings suggest that CL acts as a switch and regulates cyt c's mitochondrial redox functions.
Cell-alteration; Cell-damage; Cellular-reactions; Cell-biology; Cell-function; Cell-metabolism; Cell-morphology; Cell-transformation; Chemical-analysis; Chemical-composition
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The Toxicologist. Society of Toxicology 46th Annual Meeting and ToxExpo, March 25-29, 2007, Charlotte, North Carolina
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University of Pittsburgh at Pittsburgh