Oxidative stress is tightly regulated by cytochrome c phosphorylation and respirasome factors in mitochondria
Respiratory cytochrome c undergoes phosphorylation at tyrosine 97 during the insulin-induced neurologic protection response to brain ischemic injuries. This report hints to cytochrome c phosphorylation aiding neuronal survival by modulating mitochondrial metabolism — damping the generation of reactive oxygen species — and cell homeostasis.
Guerra-Castellano A, Diaz-Quintana A, Perez-Mejias G, Elena-Real CA, Gonzalez-Arzola K, Garcia-Maurino SM, De la Rosa MA, Diaz-Moreno I.
Proc Natl Acad Sci USA 2018 Jul; 115: 7955.
Respiratory cytochrome c has been found to be phosphorylated at tyrosine 97 in the postischemic brain upon neuroprotective insulin treatment, but how such posttranslational modification affects mitochondrial metabolism is unclear. Here, we report the structural features and functional behavior of a phosphomimetic cytochrome c mutant, which was generated by site-specific incorporation at position 97 of p-carboxymethyl-l-phenylalanine using the evolved tRNA synthetase method. We found that the point mutation does not alter the overall folding and heme environment of cytochrome c, but significantly affects the entire oxidative phosphorylation process. In fact, the electron donation rate of the mutant heme protein to cytochrome c oxidase, or complex IV, within respiratory supercomplexes was higher than that of the wild-type species, in agreement with the observed decrease in reactive oxygen species production. Direct contact of cytochrome c with the respiratory supercomplex factor HIGD1A (hypoxia-inducible domain family member 1A) is reported here, with the mutant heme protein exhibiting a lower affinity than the wild-type species. Interestingly, phosphomimetic cytochrome c also exhibited a lower caspase-3 activation activity. Altogether, these findings yield a better understanding of the molecular basis for mitochondrial metabolism in acute diseases, such as brain ischemia, and thus could allow the use of phosphomimetic cytochrome c as a neuroprotector with therapeutic applications.
PubMed: 30018060. Doi: 10.1073/pnas.1806833115. Free PMC article
