Loss of hif-1 promotes resistance to the exogenous mitochondrial stressor ethidium bromide in Caenorhabditis elegans

Abstract

BackgroundMitochondrial 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.ResultsUsing 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. ConclusionsWe 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.

Cell Biology of the Mitochondrion

“…Using a mitochondrial membrane permeabilization assay, they found that several organophosphate compounds used in flame retardants caused defects in mitochondrial function in the nematode. Kamal et al (2016) showed an interaction between hif-1 and the mitochondrial dysfunction caused by ethidium bromide in the nematode. While these studies are of divergent compounds, they again show the usefulness of a strong genetic model such as the nematode for performing initial studies of the interactions between genetics and environmental toxicology.…”

Albuterol extends lifespan of Caenorhabditis elegans

“…A prominent theory used to explain the aging process is the "free radical theory of aging" (1). This theory is based on findings that the cumulative oxidative damage caused by oxygen free radicals, a byproduct of cellular respiration occurring in mitochondria, speeds up the aging process (2)(3). Specifically, during cellular respiration, oxygen free radicals are released as a side product of oxidative phosphorylation, the process used to generate ATP.…”