Anoxia-reoxygenation regulates mitochondrial dynamics through the hypoxia response pathway, SKN-1/Nrf, and stomatin-like protein STL-1/SLP-2

PLoS Genet. 2013;9(12):e1004063. doi: 10.1371/journal.pgen.1004063. Epub 2013 Dec 26.

Abstract

Many aerobic organisms encounter oxygen-deprived environments and thus must have adaptive mechanisms to survive such stress. It is important to understand how mitochondria respond to oxygen deprivation given the critical role they play in using oxygen to generate cellular energy. Here we examine mitochondrial stress response in C. elegans, which adapt to extreme oxygen deprivation (anoxia, less than 0.1% oxygen) by entering into a reversible suspended animation state of locomotory arrest. We show that neuronal mitochondria undergo DRP-1-dependent fission in response to anoxia and undergo refusion upon reoxygenation. The hypoxia response pathway, including EGL-9 and HIF-1, is not required for anoxia-induced fission, but does regulate mitochondrial reconstitution during reoxygenation. Mutants for egl-9 exhibit a rapid refusion of mitochondria and a rapid behavioral recovery from suspended animation during reoxygenation; both phenotypes require HIF-1. Mitochondria are significantly larger in egl-9 mutants after reoxygenation, a phenotype similar to stress-induced mitochondria hyperfusion (SIMH). Anoxia results in mitochondrial oxidative stress, and the oxidative response factor SKN-1/Nrf is required for both rapid mitochondrial refusion and rapid behavioral recovery during reoxygenation. In response to anoxia, SKN-1 promotes the expression of the mitochondrial resident protein Stomatin-like 1 (STL-1), which helps facilitate mitochondrial dynamics following anoxia. Our results suggest the existence of a conserved anoxic stress response involving changes in mitochondrial fission and fusion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aerobiosis / genetics*
  • Aerobiosis / physiology
  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / physiology
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Hypoxia / genetics
  • Cell Hypoxia / physiology
  • Dynamins / metabolism
  • Hypoxia / genetics
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / physiology*
  • Mitochondrial Dynamics / genetics
  • Mitochondrial Proteins / genetics*
  • NF-E2-Related Factor 1 / genetics*
  • NF-E2-Related Factor 1 / metabolism
  • Neurons / cytology
  • Neurons / metabolism
  • Neurons / physiology*
  • Oxidation-Reduction
  • Oxidative Stress / genetics
  • Transcription Factors / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • Egl-9 protein, C elegans
  • HIF-1 protein, C elegans
  • Mitochondrial Proteins
  • NF-E2-Related Factor 1
  • STL-1 protein, C elegans
  • Transcription Factors
  • Dynamins
  • dynamin-related protein 1, C elegans