Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects

Rebeca Acin-Perez, Eric Salazar, Sonja Brosel, Hua Yang, Eric A. Schon, Giovanni Manfredi

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Phosphorylation of respiratory chain components has emerged as a mode of regulation of mitochondrial energy metabolism, but its mechanisms are still largely unexplored. A recently discovered intramitochondrial signalling pathway links CO2 generated by the Krebs cycle with the respiratory chain, through the action of a mitochondrial soluble adenylyl cyclase (mt-sAC). Cytochrome oxidase (COX), whose deficiency causes a number of fatal metabolic disorders, is a key mitochondrial enzyme activated by mt-sAC. We have now discovered that the mt-sAC pathway modulates mitochondrial biogenesis in a reactive oxygen species dependent manner, in cultured cells and in animals with COX deficiency. We show that upregulation of mt-sAC normalizes ROS production and mito- chondrial biogenesis, thereby restoring mitochondrial function. This is the first example of manipulation of a mitochondrial signalling pathway to achieve a direct positive modulation of COX, with clear implications forthe development of novel approaches to treat mitochondrial diseases.

Original languageEnglish (US)
Pages (from-to)392-406
Number of pages15
JournalEMBO Molecular Medicine
Volume1
Issue number8-9
DOIs
StatePublished - Nov 2009

Keywords

  • Cytochrome oxidase
  • Mitochondria
  • ROS
  • mtDNA
  • sAC

ASJC Scopus subject areas

  • Molecular Medicine

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