title: Nonsynonymous variants in mt-Nd2, mt-Nd4, and mt-Nd5 are linked to effects on oxidative phosphorylation and insulin sensitivity in rat conplastic strains.
abstract: Common inbred strains of the laboratory rat can be divided into four different mitochondrial DNA haplotype groups represented by the SHR, BN, LEW, and F344 strains. In the current study, we investigated the metabolic and hemodynamic effects of the SHR vs. LEW mitochondrial genomes by comparing the SHR to a new SHR conplastic strain, SHR-mt(LEW); these strains are genetically identical except for their mitochondrial genomes. Complete mitochondrial DNA (mtDNA) sequence analysis comparing the SHR and LEW strains revealed gene variants encoding amino acid substitutions limited to a single mitochondrial enzyme complex, NADH dehydrogenase (complex I), affecting subunits 2, 4, and 5. Two of the variants in the mt-Nd4 subunit gene are located close to variants known to be associated with exercise intolerance and diabetes mellitus in humans. No variants were found in tRNA or rRNA genes. These variants in mt-Nd2, mt-Nd4, and mt-Nd5 in the SHR-mt(LEW) conplastic strain were linked to reductions in oxidative and nonoxidative glucose metabolism in skeletal muscle. In addition, SHR-mt(LEW) conplastic rats showed increased serum nonesterified fatty acid levels and resistance to insulin stimulated incorporation of glucose into adipose tissue lipids. These results provide evidence that inherited variation in mitochondrial genes encoding respiratory chain complex I subunits, in the absence of variation in the nuclear genome and other confounding factors, can influence glucose and lipid metabolism when expressed on the nuclear genetic background of the SHR strain.
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Houštek
authors.forename: Kateřina
authors.initials: K
authors.lastname: Hejzlarová
authors.forename: Marek
authors.initials: M
authors.lastname: Vrbacký
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Drahota
authors.forename: Vladimír
authors.initials: V
authors.lastname: Landa
authors.forename: Václav
authors.initials: V
authors.lastname: Zídek
authors.forename: Petr
authors.initials: P
authors.lastname: Mlejnek
authors.forename: Miroslava
authors.initials: M
authors.lastname: Šimáková
authors.forename: Jan
authors.initials: J
authors.lastname: Šilhavy
authors.forename: Ivan
authors.initials: I
authors.lastname: Mikšík
authors.forename: Ludmila
authors.initials: L
authors.lastname: Kazdová
authors.forename: Olena
authors.initials: O
authors.lastname: Oliyarnyk
authors.forename: Theodore
authors.initials: T
authors.lastname: Kurtz
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology; D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D004272:DNA, Mitochondrial / Q000235:genetics*; D004040:Dietary Carbohydrates / Q000008:administration & dosage / Q000378:metabolism; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005632:Fructose / Q000008:administration & dosage / Q000378:metabolism; D014644:Genetic Variation; D006239:Haplotypes; D006339:Heart Rate; D040941:Heredity; D006973:Hypertension / Q000097:blood / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000201:enzymology; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010641:Phenotype; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D011918:Rats, Inbred SHR
chemical_list: D000227:Adenine Nucleotides; D001786:Blood Glucose; D004272:DNA, Mitochondrial; D004040:Dietary Carbohydrates; D005230:Fatty Acids, Nonesterified; D007328:Insulin; C098483:NADH dehydrogenase subunit 4; D005632:Fructose; D009245:NADH Dehydrogenase; C574662:NADH dehydrogenase subunit 2, rat; C574663:NADH dehydrogenase subunit 5, rat