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

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.

Mitochondrial genetics regulate nuclear gene expression through metabolites

“…From this mito-Mendelian perspective, variants within mitochondrial genes in both genomes, nuclear and mitochondrial, likely modify the responses of the mitochondrion to stimuli such as endogenous or exogenous factors (e.g., cytokines or environmental factors, respectively), and therefore represent an area that, as of yet, remains largely unexplored. Further, these studies and others (8–10) strongly suggest the need for greater contemplation of how to interpret results from experiments utilizing genetic models having different mtDNA backgrounds. In fact, mitochondrial genetic diversity may be a key missing link in our understanding of how genetic–environmental interactions impact disease risk, in that it would now include a mito-Mendelian perspective.…”

“…In Drosophila melanogaster , exposure to hypoxia induced gene expression changes that differed by mitochondrial haplotype, suggesting that environmental exposures impact mitochondrial signaling responses differently based upon the mitochondrial haplotype (7). Similarly, a series of studies utilizing mitochondrial−nuclear exchange models, wherein different mtDNA genetic backgrounds were paired with the same nuclear genetic background, have directly shown that disease susceptibility, bioenergetic function, oxidant production, and, importantly, gene expression are significantly changed in vivo (8–10). Importantly, the findings of Kopinski et al (1) provide a likely explanation for these observed differences in that they link mtDNA genetics with nuclear epigenomic modulation via changes in metabolic intermediates—further providing evidence of systemic molecular mechanisms that are defined by mtDNA genetics, which modulate transcriptional control of the nuclear genome.…”

Bioenergetics and translational metabolism: implications for genetics, physiology and precision medicine

“…These “mito-Mendelian” genetic interactions enabled genetic adaptation to change in environment by modulating the utilization of electron flow molecular and thermal energy (ATP and heat), and signaling (oxidants and metabolites) important for survival (Figure 1). This paradigm for explaining the genetic – physiologic basis in medicine remains controversial despite a growing number of studies showing the impact of different mtDNA backgrounds on disease, using both in vitro and in vivo approaches (Dunham-Snary et al, 2018; Fetterman et al, 2013; Ishikawa et al, 2008). Early studies in the cancer literature were among the earliest reports showing the influence of the mtDNA on tumor growth and metastasis using in vitro approaches (Ishikawa et al, 2008; Petros et al, 2005).…”

“…These interactions can be demonstrated experimentally in the Mitochondrial – Nuclear eXchanged (MNX) models. These systems directly generate reciprocal combinations of different mtDNA-nuclear DNA combinations and have shown that mtDNA background significantly influences disease development in mice having isogenic nuclear backgrounds in vivo (Dunham-Snary et al, 2018; Fetterman et al, 2013). They also provide evidence that mtDNA – nDNA combination can be important for overall mitochondrial “economy” and thus, impacts organelle bioenergetic efficiency and oxidant generation (Fetterman et al, 2013).…”

“…They also provide evidence that mtDNA – nDNA combination can be important for overall mitochondrial “economy” and thus, impacts organelle bioenergetic efficiency and oxidant generation (Fetterman et al, 2013). It has recently been shown that whole body metabolism, body composition and nuclear gene expression are influenced by mtDNA background between isogenic (nuclear) animals (Dunham-Snary et al, 2018). The observation that nuclear transcriptome can be influenced by mtDNA background provides a complementary explanation for the “common genes, common disease” hypothesis employed to explain individual variation in common disease susceptibility (Hirschhorn et al, 2005).…”