Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio

Brooke M. Emerling; Frank Weinberg; Colleen Snyder; Zach Burgess; Gökhan M. Mutlu; Benoit Viollet; G. R.Scott Budinger; Navdeep S. Chandel

doi:10.1016/j.freeradbiomed.2009.02.019

Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio

Brooke M. Emerling, Frank Weinberg, Colleen Snyder, Zach Burgess, Gökhan M. Mutlu, Benoit Viollet, G. R.Scott Budinger, Navdeep S. Chandel^*

^*Corresponding author for this work

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

276 Scopus citations

Abstract

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status found in metazoans that is known to be activated by stimuli that increase the cellular AMP/ATP ratio. Full activation of AMPK requires specific phosphorylation within the activation loop of the catalytic domain of the α-subunit by upstream kinases such as the serine/threonine protein kinase LKB1. Here we show that hypoxia activates AMPK through LKB1 without an increase in the AMP/ATP ratio. Hypoxia increased reactive oxygen species (ROS) levels and the antioxidant EUK-134 abolished the hypoxic activation of AMPK. Cells deficient in mitochondrial DNA (ρ⁰ cells) failed to activate AMPK during hypoxia but are able to in the presence of exogenous H₂O₂. Furthermore, we provide genetic evidence that ROS generated within the mitochondrial electron transport chain and not oxidative phosphorylation is required for hypoxic activation of AMPK. Collectively, these data indicate that oxidative stress and not an increase in the AMP/ATP ratio is required for hypoxic activation of AMPK.

Original language	English (US)
Pages (from-to)	1386-1391
Number of pages	6
Journal	Free Radical Biology and Medicine
Volume	46
Issue number	10
DOIs	https://doi.org/10.1016/j.freeradbiomed.2009.02.019
State	Published - May 15 2009

Funding

This work is supported in part by National Institutes of Health Grants (CA123067-03) to NSC. BME was supported by a fellowship from the American Heart Association Grant 0610044Z. We thank Carlos Moraes and I.F.M. de Coo for the cytochrome b mutant cells. We thank Dr. Ronald Depinho and Dr. Nabeel Bardeesy for the Lkb1 -/- MEFs.

Keywords

AMP-activated kinase
Free radicals
Hypoxia
LKB1
Mitochondria
Reactive oxygen species

ASJC Scopus subject areas

Physiology (medical)
Biochemistry

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10.1016/j.freeradbiomed.2009.02.019

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title = "Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio",

abstract = "AMP-activated protein kinase (AMPK) is a sensor of cellular energy status found in metazoans that is known to be activated by stimuli that increase the cellular AMP/ATP ratio. Full activation of AMPK requires specific phosphorylation within the activation loop of the catalytic domain of the α-subunit by upstream kinases such as the serine/threonine protein kinase LKB1. Here we show that hypoxia activates AMPK through LKB1 without an increase in the AMP/ATP ratio. Hypoxia increased reactive oxygen species (ROS) levels and the antioxidant EUK-134 abolished the hypoxic activation of AMPK. Cells deficient in mitochondrial DNA (ρ0 cells) failed to activate AMPK during hypoxia but are able to in the presence of exogenous H2O2. Furthermore, we provide genetic evidence that ROS generated within the mitochondrial electron transport chain and not oxidative phosphorylation is required for hypoxic activation of AMPK. Collectively, these data indicate that oxidative stress and not an increase in the AMP/ATP ratio is required for hypoxic activation of AMPK.",

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author = "Emerling, {Brooke M.} and Frank Weinberg and Colleen Snyder and Zach Burgess and Mutlu, {G{\"o}khan M.} and Benoit Viollet and Budinger, {G. R.Scott} and Chandel, {Navdeep S.}",

note = "Funding Information: This work is supported in part by National Institutes of Health Grants (CA123067-03) to NSC. BME was supported by a fellowship from the American Heart Association Grant 0610044Z. We thank Carlos Moraes and I.F.M. de Coo for the cytochrome b mutant cells. We thank Dr. Ronald Depinho and Dr. Nabeel Bardeesy for the Lkb1 -/- MEFs. Copyright: Copyright 2009 Elsevier B.V., All rights reserved.",

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AU - Viollet, Benoit

AU - Budinger, G. R.Scott

AU - Chandel, Navdeep S.

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PY - 2009/5/15

Y1 - 2009/5/15

N2 - AMP-activated protein kinase (AMPK) is a sensor of cellular energy status found in metazoans that is known to be activated by stimuli that increase the cellular AMP/ATP ratio. Full activation of AMPK requires specific phosphorylation within the activation loop of the catalytic domain of the α-subunit by upstream kinases such as the serine/threonine protein kinase LKB1. Here we show that hypoxia activates AMPK through LKB1 without an increase in the AMP/ATP ratio. Hypoxia increased reactive oxygen species (ROS) levels and the antioxidant EUK-134 abolished the hypoxic activation of AMPK. Cells deficient in mitochondrial DNA (ρ0 cells) failed to activate AMPK during hypoxia but are able to in the presence of exogenous H2O2. Furthermore, we provide genetic evidence that ROS generated within the mitochondrial electron transport chain and not oxidative phosphorylation is required for hypoxic activation of AMPK. Collectively, these data indicate that oxidative stress and not an increase in the AMP/ATP ratio is required for hypoxic activation of AMPK.

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Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio

Abstract

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Keywords

ASJC Scopus subject areas

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