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°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.
authors.affiliation: 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.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Dingley
authors.affiliation: 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.
authors.forename: Erzsebet
authors.initials: E
authors.lastname: Polyak
authors.affiliation: 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.
authors.forename: Julian
authors.initials: J
authors.lastname: Ostrovsky
authors.affiliation: Department of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Satish
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Dankook University College of Medicine, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: Icksoo
authors.initials: I
authors.lastname: Lee
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Loyola University Health Sciences Division, Maywood, IL, 60153, USA.
authors.forename: Amy B
authors.initials: AB
authors.lastname: Rosenfeld
authors.affiliation: 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.
authors.forename: Mai
authors.initials: M
authors.lastname: Tsukikawa
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Xiao
authors.affiliation: Mitochondria Research Core Facility, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, 19104, USA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Selak
authors.affiliation: 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.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Coon
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA; Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI, 53706, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Hebert
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Grimsrud
authors.affiliation: 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.
authors.forename: Young Joon
authors.initials: YJ
authors.lastname: Kwon
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Pagliarini
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Loyola University Health Sciences Division, Maywood, IL, 60153, USA.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Gai
authors.affiliation: Department of Anthropology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Schurr
authors.affiliation: Center for Molecular Medicine and Genetics and Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
authors.forename: Maik
authors.initials: M
authors.lastname: Hüttemann
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA.
authors.forename: Eiko
authors.initials: E
authors.lastname: Nakamaru-Ogiso
authors.affiliation: 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.
authors.forename: Marni J
authors.initials: MJ
authors.lastname: Falk
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics / Q000302:isolation & purification; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D019069:Cell Respiration / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics*; D014644:Genetic Variation; D005843:Geography; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D008958:Models, Molecular
chemical_list: D029742:Caenorhabditis elegans Proteins; D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV
keywords: CB4856; N2; adaptation; bioenergetics; mitochondria