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

• Published in: PLoS genetics Vol. 12; no. 7; p. e1006133
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2016; Public Library of Science (PLoS)
• Subjects: Alzheimer's disease; Alzheimers disease; Animals; Bioenergetics; Biology and Life Sciences; Biosynthesis; Caenorhabditis elegans; Caenorhabditis elegans - physiology; Caenorhabditis elegans Proteins - physiology; DNA sequencing; Electron Transport; Electron Transport Chain Complex Proteins - physiology; Funding; Gene expression; Gene Expression Regulation; Genes, Reporter; Genetic aspects; Green Fluorescent Proteins - metabolism; MAP Kinase Kinase Kinases - physiology; Medicine and Health Sciences; Methods; Mitochondria; Mitochondria - metabolism; Mitochondrial DNA; Mitogen-Activated Protein Kinases - physiology; Mutation; Nematoda; Nematodes; Oxidative stress; p38 Mitogen-Activated Protein Kinases - metabolism; Pathogens; Phosphotransferases; Physiological aspects; Proteins; Research and Analysis Methods; RNA Interference; Signal Transduction; Surveillance; Unfolded Protein Response; Worms
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006133

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.