Regulation of mitochondrial activity allows cells to adapt to changing
conditions and to control oxidative stress, and its dysfunction can
lead to hypoxia-dependent pathologies such as ischemia and cancer.
Although cytochrome c phosphorylation—in particular, at tyrosine
48—is a key modulator of mitochondrial signaling, its action and
molecular basis remain unknown. Here we mimic phosphorylation
of cytochrome c by replacing tyrosine 48 with p-carboxy-methylL-phenylalanine
(pCMF). The NMR structure of the resulting mutant
reveals significant conformational shifts and enhanced dynamics
around pCMF that could explain changes observed in its functionality:
The phosphomimetic mutation impairs cytochrome c diffusion
between respiratory complexes, enhances hemeprotein peroxidase
and reactive oxygen species scavenging activities, and hinders
caspase-dependent apoptosis. Our findings provide a framework to
further investigate the modulation of mitochondrial activity by phosphorylated
cytochrome c and to develop novel therapeutic approaches
based on its prosurvival effects.España, MINECO BFU2015-71017-P/BMC and BFU2015- 19451/BMCUnión Europea, Bio-NMR-00130 and CALIPSO-312284España, Ministerio de Educación AP2009-409
