title: Direct linkage of mitochondrial genome variation to risk factors for type 2 diabetes in conplastic strains.
abstract: Recently, the relationship of mitochondrial DNA (mtDNA) variants to metabolic risk factors for diabetes and other common diseases has begun to attract increasing attention. However, progress in this area has been limited because (1) the phenotypic effects of variation in the mitochondrial genome are difficult to isolate owing to confounding variation in the nuclear genome, imprinting phenomena, and environmental factors; and (2) few animal models have been available for directly investigating the effects of mtDNA variants on complex metabolic phenotypes in vivo. Substitution of different mitochondrial genomes on the same nuclear genetic background in conplastic strains provides a way to unambiguously isolate effects of the mitochondrial genome on complex traits. Here we show that conplastic strains of rats with identical nuclear genomes but divergent mitochondrial genomes that encode amino acid differences in proteins of oxidative phosphorylation exhibit differences in major metabolic risk factors for type 2 diabetes. These results (1) provide the first direct evidence linking naturally occurring variation in the mitochondrial genome, independent of variation in the nuclear genome and other confounding factors, to inherited variation in known risk factors for type 2 diabetes; and (2) establish that spontaneous variation in the mitochondrial genome per se can promote systemic metabolic disturbances relevant to the pathogenesis of common diseases.
authors: Institute of Physiology, Academy of Sciences of the Czech Republic, Prague 142 20, Czech Republic.
authors: Michal
authors: M
authors: Pravenec
authors: Masaya
authors: M
authors: Hyakukoku
authors: Josef
authors: J
authors: Houstek
authors: Vaclav
authors: V
authors: Zidek
authors: Vladimir
authors: V
authors: Landa
authors: Petr
authors: P
authors: Mlejnek
authors: Ivan
authors: I
authors: Miksik
authors: Kristyna
authors: K
authors: Dudová-Mothejzikova
authors: Petr
authors: P
authors: Pecina
authors: Marek
authors: M
authors: Vrbacky
authors: Zdenek
authors: Z
authors: Drahota
authors: Alena
authors: A
authors: Vojtiskova
authors: Tomas
authors: T
authors: Mracek
authors: Ludmila
authors: L
authors: Kazdova
authors: Olena
authors: O
authors: Oliyarnyk
authors: Jiaming
authors: J
authors: Wang
authors: Christopher
authors: C
authors: Ho
authors: Nathan
authors: N
authors: Qi
authors: Ken
authors: K
authors: Sugimoto
authors: Theodore
authors: T
authors: Kurtz
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D004272:DNA, Mitochondrial / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics; D018628:Gene Dosage; D014644:Genetic Variation; D016678:Genome; D006239:Haplotypes; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D011110:Polymorphism, Genetic; D051381:Rats; D011914:Rats, Inbred BN; D011918:Rats, Inbred SHR; D012307:Risk Factors; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV
references: Annu Rev Genet. 2005;39:359-407
references: 16285865
references: Nat Genet. 2006 May;38(5):576-82
references: 16582907
references: Am J Hum Genet. 2006 Jul;79(1):54-61
references: 16773565
references: Diabetes. 2006 Dec;55(12):3309-19
references: 17130474
references: Am J Hum Genet. 2007 Mar;80(3):407-15
references: 17273962
references: Diabetes Care. 2007 Mar;30(3):753-9
references: 17327355
references: Biochem J. 2004 Nov 1;383(Pt. 3):561-71
references: 15265003
references: Ann Med. 2005;37(3):213-21
references: 16019720
references: Trends Genet. 2000 Jun;16(6):276-7
references: 10827456
references: Mol Genet Metab. 2000 Sep-Oct;71(1-2):93-9
references: 11001802
references: Nat Genet. 2001 Feb;27(2):156-8
references: 11175782
references: Hypertension. 2001 Apr;37(4):1147-52
references: 11304517
references: Diabet Med. 2002 Feb;19(2):89-98
references: 11874423
references: Biochem J. 2002 Jun 1;364(Pt 2):369-76
references: 12023879
references: Biotechniques. 2002 Jun;32(6):1372-4, 1376, 1378-9
references: 12074169
references: Trends Genet. 2003 May;19(5):257-62
references: 12711217
references: Am J Hum Genet. 2003 Jun;72(6):1515-26
references: 12730827
references: J Biol Chem. 2003 Nov 14;278(46):45209-15
references: 12944409
references: N Engl J Med. 2004 Feb 12;350(7):664-71
references: 14960743
references: Diabet Med. 2004 Jul;21(7):759-62
references: 15209770
references: Anal Biochem. 1977 Jun;80(2):401-8
references: 889080
references: Metabolism. 1978 Aug;27(8):885-8
references: 672612
references: N Engl J Med. 1990 Jan 25;322(4):223-8
references: 2403659
references: Comput Appl Biosci. 1996 Dec;12(6):543-8
references: 9021275
references: Nat Genet. 1998 Feb;18(2):108
references: 9462736
references: Proc Soc Exp Biol Med. 1998 Nov;219(2):97-108
references: 9790166
references: Diabetologia. 1999 Jan;42(1):35-40
references: 10027575
references: J Clin Invest. 1999 Jun;103(12):1651-7
references: 10377171
references: Science. 2004 Nov 12;306(5699):1190-4
references: 15498972
references: Science. 2005 Jan 21;307(5708):384-7
references: 15662004