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

Proc Natl Acad Sci U S A. 2017 Apr 11;114(15):E3041-E3050. doi: 10.1073/pnas.1618008114. Epub 2017 Mar 27.


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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytochromes c / chemistry
  • Cytochromes c / genetics
  • Cytochromes c / metabolism*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mutation
  • Oxidative Stress*
  • Peroxidases / metabolism
  • Phenylalanine / analogs & derivatives
  • Phenylalanine / chemistry
  • Phenylalanine / metabolism
  • Phosphorylation
  • Protein Conformation
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction
  • Tyrosine / chemistry*
  • Tyrosine / genetics
  • Tyrosine / metabolism


  • Reactive Oxygen Species
  • 4-carboxymethylphenylalanine
  • Tyrosine
  • Phenylalanine
  • Cytochromes c
  • Peroxidases

Associated data

  • PDB/2N3Y