Protein phosphorylation and prevention of cytochrome oxidase inhibition by ATP: coupled mechanisms of energy metabolism regulation

Cell Metab. 2011 Jun 8;13(6):712-9. doi: 10.1016/j.cmet.2011.03.024.


Rapid regulation of oxidative phosphorylation is crucial for mitochondrial adaptation to swift changes in fuels availability and energy demands. An intramitochondrial signaling pathway regulates cytochrome oxidase (COX), the terminal enzyme of the respiratory chain, through reversible phosphorylation. We find that PKA-mediated phosphorylation of a COX subunit dictates mammalian mitochondrial energy fluxes and identify the specific residue (S58) of COX subunit IV-1 (COXIV-1) that is involved in this mechanism of metabolic regulation. Using protein mutagenesis, molecular dynamics simulations, and induced fit docking, we show that mitochondrial energy metabolism regulation by phosphorylation of COXIV-1 is coupled with prevention of COX allosteric inhibition by ATP. This regulatory mechanism is essential for efficient oxidative metabolism and cell survival. We propose that S58 COXIV-1 phosphorylation has evolved as a metabolic switch that allows mammalian mitochondria to rapidly toggle between energy utilization and energy storage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / pharmacology*
  • Adenosine Triphosphate / physiology
  • Allosteric Regulation
  • Animals
  • Binding Sites
  • Cell Line
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Electron Transport Complex IV / antagonists & inhibitors
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism*
  • Energy Metabolism*
  • Molecular Dynamics Simulation
  • Mutagenesis, Site-Directed
  • Mutant Proteins / metabolism
  • Oxidative Phosphorylation
  • Phosphorylation
  • Protein Processing, Post-Translational*
  • Protein Structure, Tertiary
  • Rats


  • Mutant Proteins
  • Adenosine Triphosphate
  • Electron Transport Complex IV
  • Cyclic AMP-Dependent Protein Kinases