Cyclic AMP Produced inside Mitochondria Regulates Oxidative Phosphorylation

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

doi:10.1016/j.cmet.2009.01.012

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 journal › Article › peer-review

391 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	265-276
Number of pages	12
Journal	Cell Metabolism
Volume	9
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2009.01.012
State	Published - Mar 4 2009

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

Access to Document

10.1016/j.cmet.2009.01.012

Cite this

@article{82135a15465a44daac73c8cb82842cef,

title = "Cyclic AMP Produced inside Mitochondria Regulates Oxidative Phosphorylation",

abstract = "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.",

author = "Rebeca Acin-Perez and Eric Salazar and Margarita Kamenetsky and Jochen Buck and Levin, {Lonny R.} and Giovanni Manfredi",

note = "Funding Information: This work was supported by NIH (G.M., D.B., L.R.L., and J.B.), the Muscular Dystrophy Association (G.M.), American Diabetes Association (L.R.L.), Spanish Ministry of Education Fulbright Fellowship (R.A.-P.), United Mitochondrial Disease Foundation (R.-A.P.), Milstein Foundation, and MSTP funding (E.R.S.). ",

year = "2009",

month = mar,

day = "4",

doi = "10.1016/j.cmet.2009.01.012",

language = "English (US)",

volume = "9",

pages = "265--276",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Cyclic AMP Produced inside Mitochondria Regulates Oxidative Phosphorylation

AU - Acin-Perez, Rebeca

AU - Salazar, Eric

AU - Kamenetsky, Margarita

AU - Buck, Jochen

AU - Levin, Lonny R.

AU - Manfredi, Giovanni

N1 - Funding Information: This work was supported by NIH (G.M., D.B., L.R.L., and J.B.), the Muscular Dystrophy Association (G.M.), American Diabetes Association (L.R.L.), Spanish Ministry of Education Fulbright Fellowship (R.A.-P.), United Mitochondrial Disease Foundation (R.-A.P.), Milstein Foundation, and MSTP funding (E.R.S.).

PY - 2009/3/4

Y1 - 2009/3/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=60649095658&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=60649095658&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2009.01.012

DO - 10.1016/j.cmet.2009.01.012

M3 - Article

C2 - 19254571

AN - SCOPUS:60649095658

SN - 1550-4131

VL - 9

SP - 265

EP - 276

JO - Cell Metabolism

JF - Cell Metabolism

IS - 3

ER -

Cyclic AMP Produced inside Mitochondria Regulates Oxidative Phosphorylation

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this