Loss of hif-1 promotes resistance to the exogenous mitochondrial stressor ethidium bromide in Caenorhabditis elegans.
Mitochondrial dysfunction is one of the leading causes of neurological disorders in humans. Mitochondrial perturbations lead to adaptive mechanisms that include HIF-1 stabilization, though the consequences of increased levels of HIF-1 following mitochondrial stress remain poorly understood.



Using Caenorhabditis elegans, we show that a hif-1 loss-of-function mutation confers resistance towards the mitochondrial toxin ethidium bromide (EtBr) and suppresses EtBr-induced production of ROS. In mammals, the PD-related gene DJ-1 is known to act as a redox sensor to confer protection against antioxidants and mitochondrial inhibitors. A deletion mutant of the C. elegans homolog djr-1.1 also showed increased resistance to EtBr. Furthermore, our data implicates p38 MAP kinase as an indispensable factor for survival against mitochondrial stress in both hif-1 and djr-1.1 mutants.



We propose that EtBr-induced HIF-1 activates pathways that are antagonistic in conferring protection against EtBr toxicity and that blocking HIF-1 activity may promote survival in cells with compromised mitochondrial function.
Department of Biology, York University, Toronto, Canada.|Present address: Department of Molecular Genetics, University of Toronto, Toronto, Canada.
Muntasir
M
Kamal
Department of Biology, York University, Toronto, Canada.
Dayana R
DR
D'Amora
Department of Biology, York University, Toronto, Canada. tkubises@yorku.ca.|Department of Neuroscience, York University, Toronto, Canada. tkubises@yorku.ca.
Terrance J
TJ
Kubiseski
D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D004996:Ethidium / Q000494:pharmacology*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; C541178:HIF-1 protein, C elegans; D051793:Hypoxia-Inducible Factor 1; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000445:Aldehyde Oxidoreductases; C577306:DJR-1.1 protein, C elegans; D004996:Ethidium
C. elegans; DJ-1; Hypoxia inducible factor; Mitochondria; p38 MAPK