Oxidative stress is tightly regulated by cytochrome c phosphorylation and respirasome factors in mitochondria
|Author/s||Guerra Castellano, Alejandra
Díaz Quintana, Antonio Jesús
Pérez Mejías, Gonzalo
Elena-Real, Carlos A.
González Arzola, Katiuska
García Mauriño, Sofía M.
Rosa Acosta, Miguel Ángel de la
Díaz Moreno, Irene
|Department||Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular|
|Abstract||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 ...
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.
|Funding agencies||Junta de Andalucía
Ministerio de Economía y Competitividad (MINECO). España
|Citation||Guerra Castellano, A., Díaz Quintana, A.J., Pérez Mejías, G., Elena-Real, C.A., González Arzola, K., García Mauriño, S.M.,...,Díaz Moreno, I. (2018). Oxidative stress is tightly regulated by cytochrome c phosphorylation and respirasome factors in mitochondria. Proceedings of the National Academy of Sciences, 115 (31), 7955-7960.|