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

Rebeca Acin-Perez, Domenico L. Gatti, Yidong Bai, Giovanni Manfredi

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)712-719
Number of pages8
JournalCell Metabolism
Volume13
Issue number6
DOIs
StatePublished - Jun 8 2011

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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