title: Caenorhabditis elegans UCP4 protein controls complex II-mediated oxidative phosphorylation through succinate transport.
abstract: The novel uncoupling proteins (UCP2-5) are implicated in the mitochondrial control of oxidant production, insulin signaling, and aging. Attempts to understand their functions have been complicated by overlapping expression patterns in most organisms. Caenorhabditis elegans nematodes are unique because they express only one UCP ortholog, ceUCP4 (ucp4). Here, we performed detailed metabolic analyzes in genetically modified nematodes to define the function of the ceUCP4. The knock-out mutant ucp4 (ok195) exhibited sharply decreased mitochondrial succinate-driven (complex II) respiration. However, respiratory coupling and electron transport chain function were normal in ucp4 mitochondria. Surprisingly, isolated ucp4 mitochondria showed markedly decreased succinate uptake. Similarly, ceUCP4 inhibition blocked succinate respiration and import in wild type mitochondria. Genetic and pharmacologic inhibition of complex I function was selectively lethal to ucp4 worms, arguing that ceUCP4-regulated succinate transport is required for optimal complex II function in vivo. Additionally, ceUCP4 deficiency prolonged lifespan in the short-lived mev1 mutant that exhibits complex II-generated oxidant production. These results identify a novel function for ceUCP4 in the regulation of complex II-based metabolism through an unexpected mechanism involving succinate transport.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin, Texas 78712, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pfeiffer
authors.forename: Ernst-Bernhard
authors.initials: EB
authors.lastname: Kayzer
authors.forename: Xianmei
authors.initials: X
authors.lastname: Yang
authors.forename: Ellen
authors.initials: E
authors.lastname: Abramson
authors.forename: M Alexander
authors.initials: MA
authors.lastname: Kenaston
authors.forename: Cory U
authors.initials: CU
authors.lastname: Lago
authors.forename: Herng-Hsiang
authors.initials: HH
authors.lastname: Lo
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Sedensky
authors.forename: Adam
authors.initials: A
authors.lastname: Lunceford
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Clarke
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Wu
authors.forename: Chris
authors.initials: C
authors.lastname: McLeod
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
authors.forename: Philip G
authors.initials: PG
authors.lastname: Morgan
authors.forename: Edward M
authors.initials: EM
authors.lastname: Mills
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D042963:Electron Transport Complex II / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D017136:Ion Transport / Q000502:physiology; D008136:Longevity / Q000502:physiology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000502:physiology; D019802:Succinic Acid / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D019802:Succinic Acid; D042963:Electron Transport Complex II