DLK-1, SEK-3 and PMK-3 Are Required for the Life Extension Induced by Mitochondrial Bioenergetic Disruption in C. elegans

Erin Munkácsy, Maruf H. Khan, Rebecca K. Lane, Megan B. Borror, Jae H. Park, Alex F. Bokov, Alfred L. Fisher, Christopher D. Link, Shane L. Rea

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Mitochondrial dysfunction underlies numerous age-related pathologies. In an effort to uncover how the detrimental effects of mitochondrial dysfunction might be alleviated, we examined how the nematode C. elegans not only adapts to disruption of the mitochondrial electron transport chain, but in many instances responds with extended lifespan. Studies have shown various retrograde responses are activated in these animals, including the well-studied ATFS-1-dependent mitochondrial unfolded protein response (UPRmt). Such processes fall under the greater rubric of cellular surveillance mechanisms. Here we identify a novel p38 signaling cascade that is required to extend life when the mitochondrial electron transport chain is disrupted in worms, and which is blocked by disruption of the Mitochondrial-associated Degradation (MAD) pathway. This novel cascade is defined by DLK-1 (MAP3K), SEK-3 (MAP2K), PMK-3 (MAPK) and the reporter gene Ptbb-6::GFP. Inhibition of known mitochondrial retrograde responses does not alter induction of Ptbb-6::GFP, instead induction of this reporter often occurs in counterpoint to activation of SKN-1, which we show is under the control of ATFS-1. In those mitochondrial bioenergetic mutants which activate Ptbb-6::GFP, we find that dlk-1, sek-3 and pmk-3 are all required for their life extension.

Original languageEnglish (US)
Article numbere1006133
JournalPLoS genetics
Volume12
Issue number7
DOIs
StatePublished - Jul 2016

Fingerprint

bioenergetics
electron transport chain
Electron Transport
Life Expectancy
energy metabolism
Energy Metabolism
mitogen-activated protein kinase kinase kinase
unfolded protein response
Unfolded Protein Response
electron
Mitochondrial Proteins
pathology
Reporter Genes
reporter genes
nematode
Nematoda
Pathology
mutants
degradation
protein

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Munkácsy, E., Khan, M. H., Lane, R. K., Borror, M. B., Park, J. H., Bokov, A. F., ... Rea, S. L. (2016). DLK-1, SEK-3 and PMK-3 Are Required for the Life Extension Induced by Mitochondrial Bioenergetic Disruption in C. elegans. PLoS genetics, 12(7), [e1006133]. https://doi.org/10.1371/journal.pgen.1006133

DLK-1, SEK-3 and PMK-3 Are Required for the Life Extension Induced by Mitochondrial Bioenergetic Disruption in C. elegans. / Munkácsy, Erin; Khan, Maruf H.; Lane, Rebecca K.; Borror, Megan B.; Park, Jae H.; Bokov, Alex F.; Fisher, Alfred L.; Link, Christopher D.; Rea, Shane L.

In: PLoS genetics, Vol. 12, No. 7, e1006133, 07.2016.

Research output: Contribution to journalArticle

Munkácsy, Erin ; Khan, Maruf H. ; Lane, Rebecca K. ; Borror, Megan B. ; Park, Jae H. ; Bokov, Alex F. ; Fisher, Alfred L. ; Link, Christopher D. ; Rea, Shane L. / DLK-1, SEK-3 and PMK-3 Are Required for the Life Extension Induced by Mitochondrial Bioenergetic Disruption in C. elegans. In: PLoS genetics. 2016 ; Vol. 12, No. 7.
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