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Here we analyze the specific effect of nitration of tyrosines 46 and 48 on the dual role of cytochrome c in cell survival and cell death. Our findings reveal that nitration of these two solvent-exposed resi-dues has a negligible effect on the rate of electron transfer from cytochrome c to cytochrome c oxidase, but impairs the ability of the heme protein to activate caspase-9 by assembling a non-functional apop-tosome. It seems that cytochrome c nitration under cellular stress counteracts apoptosis in light of the small amount of modified protein. We conclude that other changes such as increased peroxidase activity prevail and allow the execution of apoptosis. 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. peroxynitrite, which is formed by reaction between superoxide an-ion and nitric oxide. Peroxynitrite serves as an in vivo nitrating agent [4] that mainly promotes nitration of tyrosines in mitochondrial plexes [16]. However, the pro-apoptotic stimuli make C c bind to and oxidize the mitochondria-specific phospholipid cardiolipin (CL) [17], which in turn allows the translocation of C c into the cyto-plasm so as to trigger the apoptosis signalling pathway upon binding to the apoptosis protease-activation factor (Apaf-1) and apopto-some assembly [18,19]. In vitro nitration of human C c tyrosine residues at positions 67, 74 and 97 impairs the two antagonist func-tions of C c in cell life (respiration) and cell death (apoptosis) [20,21], in agreement with previous data obtained in vivo with Tyr67-nitrated C c [22]. In contrast, tyrosine nitration can increase the peroxidase activity of C c [21,23,24], an example of gain-of-functio