title: Hypoxia disrupts proteostasis in Caenorhabditis elegans.
abstract: 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.
authors.affiliation: Graduate Program in Molecular and Cellular Biology, University of Washington School of Medicine, Seattle, WA, 98195-7350, USA.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Fawcett
authors.forename: Jill M
authors.initials: JM
authors.lastname: Hoyt
authors.forename: Jenna K
authors.initials: JK
authors.lastname: Johnson
authors.forename: Dana L
authors.initials: DL
authors.lastname: Miller
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects; D004195:Disease Models, Animal; D006706:Homeostasis / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000494:pharmacology; D009410:Nerve Degeneration / Q000473:pathology; D010243:Paralysis / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects; D066263:Protein Aggregation, Pathological / Q000473:pathology
chemical_list: D029742:Caenorhabditis elegans Proteins; D010455:Peptides; D066329:Protein Aggregates; C097188:polyglutamine; D006862:Hydrogen Sulfide
keywords: C. elegans; H2S; Polyglutamine; hypoxia; oxygen; protein aggregation; proteostasis