Mitochondrial DNA variant in COX1 subunit significantly alters energy metabolism of geographically divergent wild isolates in Caenorhabditis elegans Journal Article


Authors: Dingley, S. D.; Polyak, E.; Ostrovsky, J.; Srinivasan, S; Lee, I.; Rosenfeld, A. B.; Tsukikawa, M.; Xiao, R.; Selak, M. A.; Coon, J. J.; Hebert, A. S.; Grimsrud, P. A.; Kwon, Y. J.; Pagliarini, D. J.; Gai, X.; Schurr, T. G.; Huttemann, M.; Nakamaru-Ogiso, E.; Falk, M. J.
Article Title: Mitochondrial DNA variant in COX1 subunit significantly alters energy metabolism of geographically divergent wild isolates in Caenorhabditis elegans
Abstract: Mitochondrial DNA (mtDNA) sequence variation can influence the penetrance of complex diseases and climatic adaptation. While studies in geographically defined human populations suggest that mtDNA mutations become fixed when they have conferred metabolic capabilities optimally suited for a specific environment, it has been challenging to definitively assign adaptive functions to specific mtDNA sequence variants in mammals. We investigated whether mtDNA genome variation functionally influences Caenorhabditis elegans wild isolates of distinct mtDNA lineages and geographic origins. We found that, relative to N2 (England) wild-type nematodes, CB4856 wild isolates from a warmer native climate (Hawaii) had a unique p.A12S amino acid substitution in the mtDNA-encoded COX1 core catalytic subunit of mitochondrial complex IV (CIV). Relative to N2, CB4856 worms grown at 20 degrees C had significantly increased CIV enzyme activity, mitochondrial matrix oxidant burden, and sensitivity to oxidative stress but had significantly reduced lifespan and mitochondrial membrane potential. Interestingly, mitochondrial membrane potential was significantly increased in CB4856 grown at its native temperature of 25 degrees C. A transmitochondrial cybrid worm strain, chpIR (M, CB4856>N2), was bred as homoplasmic for the CB4856 mtDNA genome in the N2 nuclear background. The cybrid strain also displayed significantly increased CIV activity, demonstrating that this difference results from the mtDNA-encoded p.A12S variant. However, chpIR (M, CB4856>N2) worms had significantly reduced median and maximal lifespan relative to CB4856, which may relate to their nuclear-mtDNA genome mismatch. Overall, these data suggest that C. elegans wild isolates of varying geographic origins may adapt to environmental challenges through mtDNA variation to modulate critical aspects of mitochondrial energy metabolism.
Keywords: Male; Animals; Geography; CB4856; N2; adaptation; bioenergetics; mitochondria; Models, Molecular; Animals, Genetically Modified; DNA, Mitochondrial/genetics; Genetic Variation; Amino Acid Substitution/genetics; Caenorhabditis elegans/enzymology/genetics/isolation purification; Caenorhabditis elegans Proteins/genetics/metabolism; Cell Respiration/genetics; Electron Transport Complex IV/chemistry/genetics/metabolism; Energy Metabolism/genetics; Mitochondria/enzymology
Journal Title: Journal of Molecular Biology
Volume: 426
Issue: 11
ISSN: 1089-8638; 0022-2836
Publisher: Elsevier Inc  
Journal Place: England
Date Published: 2014
Start Page: 2199
End Page: 2216
Language: eng
DOI/URL:
Notes: LR: 20150529; CI: Copyright (c) 2014; GR: K08 DK073545/DK/NIDDK NIH HHS/United States; GR: K08-DK073545/DK/NIDDK NIH HHS/United States; GR: R01 DK098672/DK/NIDDK NIH HHS/United States; GR: R01 GM097409/GM/NIGMS NIH HHS/United States; GR: R01 HD065858/HD/NICHD NIH HHS/United States; GR: R01-HD065858-01A1/HD/NICHD NIH HHS/United States; JID: 2985088R; 0 (Caenorhabditis elegans Proteins); 0 (DNA, Mitochondrial); EC 1.9.3.1 (Electron Transport Complex IV); NIHMS569487; OID: NLM: NIHMS569487; OID: NLM: PMC4067970; OTO: NOTNLM; 2013/12/19 [received]; 2014/02/05 [revised]; 2014/02/06 [accepted]; 2014/02/14 [aheadofprint]; ppublish