Journal
CELL METABOLISM
Volume 29, Issue 5, Pages 1182-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2019.01.022
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Funding
- Damon Runyon Cancer Research Foundation [DRG-2213-15]
- NIH [NIH AG16636]
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In Caenorhabditis elegans, mitochondrial dysfunction caused by mutation or toxins activates programs of detoxification and immune response. A genetic screen for mutations that constitutively induce C. elegans mitochondrial defense revealed reduction-of-function mutations in the mitochondrial chaperone hsp-6/mtHSP70 and gain-of-function mutations in the Mediator component mdt-15/MED15. The activation of detoxification and immune responses is transcriptionally mediated by mdt-15/MED15 and nuclear hormone receptor nhr-45. Mitochondrial dysfunction triggers redistribution of intestinal mitochondria, which requires the mitochondrial Rho GTPase miro-1 and its adaptor trak1/TRAK1, but not nhr-45-regulated responses. Disabling the mdt-15/nhr-45 pathway renders animals more susceptible to a mitochondrial toxin or pathogenic Pseudomonas aeruginosa but paradoxically improves health and extends lifespan in animals with mitochondrial dysfunction caused by a mutation. Thus, some of the health deficits in mitochondrial disorders may be caused by the ineffective activation of detoxification and immune responses, which may be inhibited to improve health.
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