title: DLK-1, SEK-3 and PMK-3 Are Required for the Life Extension Induced by Mitochondrial Bioenergetic Disruption in C. elegans.
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.
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.|Department of Cellular & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Erin
authors.identifier: 0000-0002-0255-2576
authors.initials: E
authors.lastname: Munkácsy
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.|Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.|Department of Medicine (Division of Geriatrics, Gerontology, and Palliative Medicine), University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Maruf H
authors.initials: MH
authors.lastname: Khan
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Lane
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Megan B
authors.initials: MB
authors.lastname: Borror
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Jae H
authors.identifier: 0000-0001-9436-1752
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Alex F
authors.initials: AF
authors.lastname: Bokov
authors.affiliation: Department of Medicine (Division of Geriatrics, Gerontology, and Palliative Medicine), University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.|Geriatric Research, Education and Clinical Center, South Texas VA Health Care System, San Antonio, Texas, United States of America.|Center for Healthy Aging, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Alfred L
authors.identifier: 0000-0001-6451-2644
authors.initials: AL
authors.lastname: Fisher
authors.affiliation: Institute for Behavioral Genetics & Department of Integrative Physiology, University of Colorado at Boulder, Boulder, Colorado, United States of America.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Link
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.|Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Shane L
authors.initials: SL
authors.lastname: Rea
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000502:physiology*; D004579:Electron Transport; D045222:Electron Transport Chain Complex Proteins / Q000502:physiology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009154:Mutation; D034622:RNA Interference; D015398:Signal Transduction; D056811:Unfolded Protein Response; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D045222:Electron Transport Chain Complex Proteins; D049452:Green Fluorescent Proteins; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C445124:pmk-3 protein, C elegans; C000615824:sek-3 protein, C elegans; C498050:DLK-1 protein, C elegans; D020930:MAP Kinase Kinase Kinases