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EBioMedicine. 2018 Oct;36:316-328. doi: 10.1016/j.ebiom.2018.08.036. Epub 2018 Sep 16.

Mitochondrial - nuclear genetic interaction modulates whole body metabolism, adiposity and gene expression in vivo.

Author information

1
Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
2
Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
3
Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
4
Department of Comparative Biomedical Science, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, United States.
5
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
6
Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
7
Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address: scottballinger@uabmc.edu.

Abstract

We hypothesized that changes in the mitochondrial DNA (mtDNA) would significantly influence whole body metabolism, adiposity and gene expression in response to diet. Because it is not feasible to directly test these predictions in humans we used Mitochondrial-Nuclear eXchange mice, which have reciprocally exchanged nuclear and mitochondrial genomes between different Mus musculus strains. Results demonstrate that nuclear-mitochondrial genetic background combination significantly alters metabolic efficiency and body composition. Comparative RNA sequencing analysis in adipose tissues also showed a clear influence of the mtDNA on regulating nuclear gene expression on the same nuclear background (up to a 10-fold change in the number of differentially expressed genes), revealing that neither Mendelian nor mitochondrial genetics unilaterally control gene expression. Additional analyses indicate that nuclear-mitochondrial genome combination modulates gene expression in a manner heretofore not described. These findings provide a new framework for understanding complex genetic disease susceptibility.

KEYWORDS:

Adipose; Gene expression; Metabolism; Mitochondrial DNA; Mitochondrial gene therapy; Mitochondrial – nuclear exchange; Nuclear–mitochondrial interaction; Obesity

PMID:
30232024
PMCID:
PMC6197375
DOI:
10.1016/j.ebiom.2018.08.036
[Indexed for MEDLINE]
Free PMC Article

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