Nonsynonymous Variants in Mt-Nd2, Mt-Nd4, and Mt-Nd5 Are Linked to Effects on Oxidative Phosphorylation and Insulin Sensitivity in Rat Conplastic Strains

Overview

Journal Physiol Genomics

Publisher American Physiological Society

Specialties Genetics
Molecular Biology

Date 2012 Mar 15

PMID 22414913

Citations 11

Authors

Josef Houstek

Katerina Hejzlarova

Marek Vrbacky

Zdenek Drahota

Vladimir Landa

Vaclav Zidek

Petr Mlejnek

Miroslava Simakova

Jan Silhavy

Ivan Miksik

Ludmila Kazdova

Olena Oliyarnyk

Theodore Kurtz

Michal Pravenec

Affiliations

Soon will be listed here.

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.

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