Cyclic AMP Produced inside Mitochondria Regulates Oxidative Phosphorylation

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 m...

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Bibliographic Details
Published in:	Cell metabolism 2009-03, Vol.9 (3), p.265-276
Main Authors:	Acin-Perez, Rebeca, Salazar, Eric, Kamenetsky, Margarita, Buck, Jochen, Levin, Lonny R., Manfredi, Giovanni
Format:	Article
Language:	eng
Subjects:	Adenylyl Cyclases - genetics Adenylyl Cyclases - metabolism Animals Carbon Dioxide - metabolism Cyclic AMP - metabolism Cyclic AMP-Dependent Protein Kinases - metabolism HeLa Cells Humans Membrane Potential, Mitochondrial - physiology Mice Mice, Transgenic Mitochondria - metabolism Mitochondrial Proteins - metabolism Oxidation-Reduction Oxidative Phosphorylation Reactive Oxygen Species - metabolism Signal Transduction - physiology
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Summary:	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 CO 2-HCO 3 −-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.
ISSN:	1550-4131 1932-7420