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Cytochrome c auto-catalyzed carbonylation in the presence of hydrogen peroxide and cardiolipins.
Journal of Biological Chemistry 2018 December 13
Cytochrome c (cyt c) is a small hemoprotein involved in electron shuttling in the mitochondrial respiratory chain and is now also recognized as an important mediator of apoptotic cell death. Its role in inducing programmed cell death is closely associated with the formation of a complex with the mitochondrion-specific phospholipid cardiolipin (CL), leading to a gain of peroxidase activity. Yet the molecular mechanisms behind this gain and eventual cyt c auto-inactivation via its release from mitochondria membranes remains largely unknown. Here, we examined the kinetics of the H2O2-mediated peroxidase activity of cyt c both in the presence and absence of tetraoleoyl cardiolipin- (TOCL-) and tetralinoleoyl cardiolipin- (TLCL-) () containing liposomes to evaluate the role of cyt c-CL complex formation in the induction and stimulation of cyt c peroxidase activity. Moreover, we examined peroxide-mediated cyt c heme degradation to gain insights into the mechanisms by which cyt c self-limits its- peroxidase activity. Bottom-up proteomics revealed > 50 oxidative modifications on cyt c upon peroxide reduction. Of note, one of these by-products was the Tyr-based "cofactor" trihydroxyphenylalanine quinone (TPQ) capable of inducing deamination of Lys ε-amino groups and formation of the carbonylated product aminoadipic semialdehyde. In view of these results, we propose that auto-induced carbonylation, and thus removal of a positive charge in Lys, abrogates binding of cyt c to negatively charged CL. The proposed mechanism may be responsible for release of cyt c from mitochondrial membranes and ensuing inactivation of its peroxidase activity.
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