Contribution of peroxidized cardiolipin to inactivation of bovine heart cytochrome c oxidase.
The lipid-soluble peroxides, tert-butyl hydroperoxide and peroxidized cardiolipin, each react with bovine cytochrome c oxidase and cause a loss of electron-transport activity. Coinciding with loss of activity is oxidation of Trp19 and Trp48 within subunits VIIc and IV, and partial dissociation of subunits VIa and VIIa. tert-Butyl hydroperoxide initiates these structural and functional changes of cytochrome c oxidase by three mechanisms: (1) radical generation at the binuclear center; (2) direct oxidation of Trp19 and Trp48; and (3) peroxidation of bound cardiolipin. All three mechanisms contribute to inactivation since blocking a single mechanism only partially prevents oxidative damage. The first mechanism is similar to that described for hydrogen peroxide [Biochemistry43:1003-1009; 2004], while the second and third mechanism are unique to organic hydroperoxides. Peroxidized cardiolipin inactivates cytochrome c oxidase in the absence of tert-butyl hydroperoxide and oxidizes the same tryptophans within the nuclear-encoded subunits. Peroxidized cardiolipin also inactivates cardiolipin-free cytochrome c oxidase rather than restoring full activity. Cardiolipin-free cytochrome c oxidase, although it does not contain cardiolipin, is still inactivated by tert-butyl hydroperoxide, indicating that the other oxidation products contribute to the inactivation of cytochrome c oxidase. We conclude that both peroxidized cardiolipin and tert-butyl hydroperoxide react with and triggers a cascade of structural alterations within cytochrome c oxidase. The summation of these events leads to cytochrome c oxidase inactivation.
Musatov
Andrej
A
Department of Biochemistry, The University of Texas Health Science Center, 7703 Floyd Curl Drive San Antonio, TX 78229-3900, USA. musatov@uthscsa.edu
D000818:Animals; D002308:Cardiolipins / Q000378:metabolism*; D002417:Cattle; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D015227:Lipid Peroxidation; D008054:Lipid Peroxides / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology*; D010084:Oxidation-Reduction; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013858:Thiobarbiturates / Q000378:metabolism
D002308:Cardiolipins; D008054:Lipid Peroxides; D013858:Thiobarbiturates; D003576:Electron Transport Complex IV; C029684:thiobarbituric acid