Changes of Gut Microbiota by Natural mtDNA Variant Differences Augment Susceptibility to Metabolic Disease and Ageing

We recently reported on two mouse strains carrying different single nucleotide variations in the mitochondrial complex I gene, i.e., B6-mt(BPL) mice carrying m.11902T>C and B6-mt(ALR) carrying m.4738C>A. B6-mt(BPL) mice exhibited a longer lifespan and a lower metabolic disease susceptibility despite mild mitochondrial functional differences in steady-state. As natural polymorphisms in the mitochondrial DNA (mtDNA) are known to be associated with distinct patterns of gut microbial composition, we further investigated the gut microbiota composition in these mice strains. In line with mouse phenotypes, we found a significantly lower abundance of Proteobacteria, which is positively associated with pathological conditions, in B6-mt(BPL) compared to B6-mt(ALR) mice. A prediction of functional profile of significantly differential bacterial genera between these strains revealed an involvement of glucose metabolism pathways. Whole transcriptome analysis of liver samples from B6-mt(BPL) and B6-mt(ALR) mice confirmed these findings. Thus, both host gene expression and gut microbial changes caused by the mtDNA variant differences may contribute to the ageing and metabolic phenotypes observed in these mice strains. Since gut microbiota are easier to modulate, compared with mtDNA variants, identification of such mtDNA variants, specific gut bacterial species and bacterial metabolites may be a potential intervention to modulate common diseases, which are differentially susceptible to individuals with different mtDNA variants.

Automated summary

This study reported on two mouse strains carrying single nucleotide variations in the mitochondrial complex I gene. Despite mild mitochondrial functional differences, the mice carrying specific variants exhibited longer lifespan and lower susceptibility to metabolic diseases. Analysis of gut microbiota composition revealed an association with mouse phenotypes, and predictions of functional profile suggested involvement of glucose metabolism pathways. These findings suggest that both host gene expression and gut microbial changes caused by mtDNA variant differences may contribute to the aging and metabolic phenotypes observed in these mice strains.