Hypoxia disrupts proteostasis in Caenorhabditis elegans

Aging Cell. 2015 Feb;14(1):92-101. doi: 10.1111/acel.12301. Epub 2014 Dec 16.


Oxygen is fundamentally important for cell metabolism, and as a consequence, O₂ deprivation (hypoxia) can impair many essential physiological processes. Here, we show that an active response to hypoxia disrupts cellular proteostasis - the coordination of protein synthesis, quality control, and degradation that maintains the functionality of the proteome. We have discovered that specific hypoxic conditions enhance the aggregation and toxicity of aggregation-prone proteins that are associated with neurodegenerative diseases. Our data indicate this is an active response to hypoxia, rather than a passive consequence of energy limitation. This response to hypoxia is partially antagonized by the conserved hypoxia-inducible transcription factor, hif-1. We further demonstrate that exposure to hydrogen sulfide (H₂S) protects animals from hypoxia-induced disruption of proteostasis. H₂S has been shown to protect against hypoxic damage in mammals and extends lifespan in nematodes. Remarkably, our data also show that H₂S can reverse detrimental effects of hypoxia on proteostasis. Our data indicate that the protective effects of H₂S in hypoxia are mechanistically distinct from the effect of H₂S to increase lifespan and thermotolerance, suggesting that control of proteostasis and aging can be dissociated. Together, our studies reveal a novel effect of the hypoxia response in animals and provide a foundation to understand how the integrated proteostasis network is integrated with this stress response pathway.

Keywords: C. elegans; H2S; Polyglutamine; hypoxia; oxygen; protein aggregation; proteostasis.

Publication types

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

MeSH terms

  • Adaptation, Physiological / drug effects
  • Animals
  • Caenorhabditis elegans / cytology*
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Hypoxia / drug effects
  • Disease Models, Animal
  • Homeostasis* / drug effects
  • Hydrogen Sulfide / pharmacology
  • Nerve Degeneration / pathology
  • Paralysis / pathology
  • Peptides / metabolism
  • Protein Aggregates / drug effects
  • Protein Aggregation, Pathological / pathology


  • Caenorhabditis elegans Proteins
  • Peptides
  • Protein Aggregates
  • polyglutamine
  • Hydrogen Sulfide