Mechanistic insights into the function of the mitochondrial uncoupling protein in Caenorhabditis elegans

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Title: Mechanistic insights into the function of the mitochondrial uncoupling protein in Caenorhabditis elegans
Author: Pfeiffer, Matthew Edwin
Abstract: The prototype uncoupling protein 1 (UCP1 ) mediates proton leak -dependent thermogenesis in mammals , but the physiological functions of the novel UCP2 -5 are unclear . Nematodes only express one uncoupling protein that is most similar to UCP4 in the human brain , which is believed to be the most evolutionarily conserved of the uncoupling proteins . Consistent with reported UCP functions in mammals , we observed that ceUCP4 -null nematodes had decreased metabolic rates and increased adiposity compared to wild type . Surprisingly , these phenotypes corresponded to decreased succinate -mediated mitochondrial respiration without apparent changes in mitochondrial uncoupling . ceUCP4 -null mitochondria exhibited normal electron transport chain functions , but had a decreased capacity for succinate import . Supporting the functional importance of ceUCP4 -dependent complex II regulation in vivo , ceUCP4 deficiency was demonstrated to result in a selectively lethal response to genetic and pharmacological inhibition of Complex I . Similarly , ceUCP4 -deficiency significantly prolonged lifespan in the short -lived mev -1 mutant that generates deleterious complex II -derived reactive oxidants . These results define a new physiological function for the ancestral ceUCP4 in the regulation of complex II -mediated oxidative phosphorylation through an unexpected effect on mitochondrial succinate transport . The data described in this dissertation also describe a novel mechanism by which uncoupling proteins mediate mitochondrial bioenergetics .
URI: http : / /hdl .handle .net /2152 /ETD -UT -2010 -08 -1949
Date: 2010-10-27

Citation

Mechanistic insights into the function of the mitochondrial uncoupling protein in Caenorhabditis elegans. Doctoral dissertation, University of Texas at Austin. Available electronically from http : / /hdl .handle .net /2152 /ETD -UT -2010 -08 -1949 .

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