TY - JOUR
T1 - Caenorhabditis elegans UCP4 protein controls complex II-mediated oxidative phosphorylation through succinate transport
AU - Pfeiffer, Matthew
AU - Kayzer, Ernst Bernhard
AU - Yang, Xianmei
AU - Abramson, Ellen
AU - Kenaston, M. Alexander
AU - Lago, Cory U.
AU - Lo, Herng Hsiang
AU - Sedensky, Margaret M.
AU - Lunceford, Adam
AU - Clarke, Catherine F.
AU - Wu, Sarah J.
AU - McLeod, Chris
AU - Finkel, Toren
AU - Morgan, Philip G.
AU - Mills, Edward M.
PY - 2011/10/28
Y1 - 2011/10/28
N2 - 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. GeneticandpharmacologicinhibitionofcomplexIfunction 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.
AB - 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. GeneticandpharmacologicinhibitionofcomplexIfunction 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.
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U2 - 10.1074/jbc.M111.271452
DO - 10.1074/jbc.M111.271452
M3 - Article
C2 - 21862587
AN - SCOPUS:80054822256
VL - 286
SP - 37712
EP - 37720
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 43
ER -