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

DOI: 10.1073/pnas.1618008114 DOI Help

Authors: Blas Moreno-beltrán (Universidad de Sevilla–Spanish National Scientific Council (CSIC)) , Alejandra Guerra-castellano (Universidad de Sevilla–Spanish National Scientific Council (CSIC)) , Antonio Diaz-quintana (Universidad de Sevilla–Spanish National Scientific Council (CSIC)) , Rebecca Del Conte (University of Florence) , Sofía M. García-mauriño (Universidad de Sevilla–Spanish National Scientific Council (CSIC)) , Sofia Diaz-moreno (Diamond Light Source) , Katiuska González-arzola (Universidad de Sevilla–Spanish National Scientific Council (CSIC)) , Carlos Santos-ocaña (Universidad Pablo de Olavide–CSIC) , Adrián Velázquez-campoy (Universidad de Zaragoza) , Miguel A. De La Rosa (Universidad de Sevilla–Spanish National Scientific Council (CSIC)) , Paola Turano (University of Florence) , Irene Diaz-moreno (Universidad de Sevilla–Spanish National Scientific Council (CSIC))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences

State: Published (Approved)
Published: March 2017
Diamond Proposal Number(s): 6011

Abstract: 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-methyl-l-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.

Journal Keywords: cytochrome c; mitochondrial dysfunction; nuclear magnetic resonance; phosphorylation; respiratory supercomplexes

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I20-Scanning-X-ray spectroscopy (XAS/XES)