Specific nitration of tyrosines 46 and 48 makes cytochrome c assemble a non‐functional apoptosome

Abstract

a b s t r a c tUnder nitroxidative stress, a minor fraction of cytochrome c can be modified by tyrosine nitration. 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 residues 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 apoptosome. 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.

Structural basis of mitochondrial dysfunction in response to cytochrome c phosphorylation at tyrosine 48

“…Notably, nitration of this residue also hinders the ability of Cc to activate Apaf-1 (28)(29)(30). Thus, these posttranslational modifications alter both mitochondrial and cytoplasmic functions of Cc.…”

Respiratory complexes III and IV can each bind two molecules of cytochrome c at low ionic strength

“…Apart their role in respiration, Cc and Cc 1 are clearly involved in the development of programmed cell death [9][10][11][12][13][14][15]. Such a dual role of Cc is regulated by post-translational modifications -namely, phosphorylation and nitration of tyrosine residues -that affect the binding of Cc to its physiological counterparts, either in the mitochondria or in the cytoplasm [16][17][18][19][20][21][22][23].…”

Mimicking Tyrosine Phosphorylation in Human Cytochrome c by the Evolved tRNA Synthetase Technique

“…Under oxidative stress conditions, C c acts as a programmed cell death (PCD) inductor, targeting several proteins in the cell cytoplasm and nucleus 11–14. Both activities are regulated by post‐translational modifications such as nitration15–19 or phosphorylation of tyrosine residues 20. 21 In particular, phosphorylation of Tyr48 has been shown to impair the oxidative phosphorylation process 22…”

“…[9,10] Cc is as mall, soluble heme-protein localized in the intermembrane mitochondrials pace.I t participates in the electron-transportc hain (ETC) by transferring electrons from the cytochrome bc 1 complex (Cbc 1 )t oc ytochrome c oxidase (CcO).U nder oxidative stress conditions, Cc acts as ap rogrammedcell death (PCD) inductor,t argeting several proteins in the cell cytoplasm and nucleus. [11][12][13][14] Both activities are regulated by post-translational modifications such as nitration [15][16][17][18][19] or phosphorylation of tyrosiner esidues. [20,21] In particular, phosphorylation of Tyr48 has been shown to impair the oxidative phosphorylation process.…”