AMPK Maintains Cellular Metabolic Homeostasis through Regulation of Mitochondrial Reactive Oxygen Species

Cell Rep. 2017 Oct 3;21(1):1-9. doi: 10.1016/j.celrep.2017.09.026.

Abstract

Reactive oxygen species (ROS) are continuously produced as a by-product of mitochondrial metabolism and eliminated via antioxidant systems. Regulation of mitochondrially produced ROS is required for proper cellular function, adaptation to metabolic stress, and bypassing cellular senescence. Here, we report non-canonical regulation of the cellular energy sensor AMP-activated protein kinase (AMPK) by mitochondrial ROS (mROS) that functions to maintain cellular metabolic homeostasis. We demonstrate that mitochondrial ROS are a physiological activator of AMPK and that AMPK activation triggers a PGC-1α-dependent antioxidant response that limits mitochondrial ROS production. Cells lacking AMPK activity display increased mitochondrial ROS levels and undergo premature senescence. Finally, we show that AMPK-PGC-1α-dependent control of mitochondrial ROS regulates HIF-1α stabilization and that mitochondrial ROS promote the Warburg effect in cells lacking AMPK signaling. These data highlight a key function for AMPK in sensing and resolving mitochondrial ROS for stress resistance and maintaining cellular metabolic balance.

Keywords: AMPK; LKB1; PGC-1α; ROS; ULK1; mitochondria; nutrient signaling energy stress; oxidative stress; senescence.

MeSH terms

  • AMP-Activated Protein Kinases / deficiency
  • AMP-Activated Protein Kinases / genetics*
  • Animals
  • Autophagy-Related Protein-1 Homolog / genetics
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Cellular Senescence / genetics
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression Regulation
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism
  • HEK293 Cells
  • Homeostasis / genetics*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Metabolic Networks and Pathways / genetics*
  • Mice
  • Mice, Transgenic
  • Mitochondria / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / deficiency
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics*
  • Primary Cell Culture
  • Protein Stability
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1 / genetics
  • Superoxide Dismutase-1 / metabolism
  • Uncoupling Protein 2 / genetics
  • Uncoupling Protein 2 / metabolism
  • Uncoupling Protein 3 / genetics
  • Uncoupling Protein 3 / metabolism

Substances

  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Reactive Oxygen Species
  • Ucp2 protein, mouse
  • Ucp3 protein, mouse
  • Uncoupling Protein 2
  • Uncoupling Protein 3
  • glutathione peroxidase GPX1
  • Glutathione Peroxidase
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • superoxide dismutase 2
  • AMPK alpha1 subunit, mouse
  • Autophagy-Related Protein-1 Homolog
  • Ulk1 protein, mouse
  • AMP-Activated Protein Kinases