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

Research output: Contribution to journalArticlepeer-review

204 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 languageEnglish (US)
Pages (from-to)1386-1391
Number of pages6
JournalFree Radical Biology and Medicine
Volume46
Issue number10
DOIs
StatePublished - May 15 2009

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio'. Together they form a unique fingerprint.

Cite this