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J Mol Biol. 2014 May 29;426(11):2199-216. doi: 10.1016/j.jmb.2014.02.009. Epub 2014 Feb 14.

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

Author information

1
Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
2
Department of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
3
Dankook University College of Medicine, Yongin-si, Gyeonggi-do, South Korea.
4
Department of Molecular Pharmacology and Therapeutics, Loyola University Health Sciences Division, Maywood, IL, 60153, USA.
5
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
6
Mitochondria Research Core Facility, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, 19104, USA.
7
Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA; Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA; Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI, 53706, USA.
8
Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA; Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI, 53706, USA.
9
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
10
Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. Electronic address: kwonyo@sas.upenn.edu.
11
Department of Anthropology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
12
Center for Molecular Medicine and Genetics and Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
13
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA.
14
Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. Electronic address: falkm@email.chop.edu.

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°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°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:

CB4856; N2; adaptation; bioenergetics; mitochondria

PMID:
24534730
PMCID:
PMC4067970
DOI:
10.1016/j.jmb.2014.02.009
[Indexed for MEDLINE]
Free PMC Article

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