Cyclic AMP Produced inside Mitochondria Regulates Oxidative Phosphorylation

Rebeca Acin-Perez, Eric Salazar, Margarita Kamenetsky, Jochen Buck, Lonny R. Levin, Giovanni Manfredi

Research output: Contribution to journalArticlepeer-review

383 Scopus citations


Mitochondria constantly respond to changes in substrate availability and energy utilization to maintain cellular ATP supplies, and at the same time control reactive oxygen radical (ROS) production. Reversible phosphorylation of mitochondrial proteins has been proposed to play a fundamental role in metabolic homeostasis, but very little is known about the signaling pathways involved. We show here that protein kinase A (PKA) regulates ATP production by phosphorylation of mitochondrial proteins, including subunits of cytochrome c oxidase. The cyclic AMP (cAMP), which activates mitochondrial PKA, does not originate from cytoplasmic sources but is generated within mitochondria by the carbon dioxide/bicarbonate-regulated soluble adenylyl cyclase (sAC) in response to metabolically generated carbon dioxide. We demonstrate for the first time the existence of a CO2-HCO3--sAC-cAMP-PKA (mito-sAC) signaling cascade wholly contained within mitochondria, which serves as a metabolic sensor modulating ATP generation and ROS production in response to nutrient availability.

Original languageEnglish (US)
Pages (from-to)265-276
Number of pages12
JournalCell Metabolism
Issue number3
StatePublished - Mar 4 2009

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology


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