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

Axel Künstner,Misa Hirose,Paul Schilf,Saleh M Ibrahim,Hauke Busch

doi:10.3390/ijms23031056

Axel Künstner, Misa Hirose + Show 3 more

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https://doi.org/10.3390/ijms23031056

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Abstract

We recently reported on two mouse strains carrying different single nucleotide variations in the mitochondrial complex I gene, i.e., B6-mtBPL mice carrying m.11902T>C and B6-mtALR carrying m.4738C>A. B6-mtBPL 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-mtBPL compared to B6-mtALR 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-mtBPL and B6-mtALR 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.

Highlights

The mammalian mitochondrial DNA encodes 37 genes, including 13 proteincoding genes for oxidative phosphorylation (OXPHOS) machinery, 22 transfer RNA genes and 2 ribosomal RNA genes [1]
Studies demonstrating that the association of mitochondrial DNA (mtDNA) variants with common complex diseases, including ageing and age-associated diseases, have been reported in humans [6], and these are supported by a number of experimental observations using mammalian models, including conplastic mouse strains that carry distinct variants in mtDNA [7,8,9,10,11]
A total of 13 mice were fed with high-fat diet (HFD) and 6 mice with control diet (CD) in each of B6-mtBPL and B6-mtALR mice for 8 weeks

Summary

Introduction

The mammalian mitochondrial DNA (mtDNA) encodes 37 genes, including 13 proteincoding genes for oxidative phosphorylation (OXPHOS) machinery, 22 transfer RNA genes and 2 ribosomal RNA genes [1]. Some variations (both mutations and polymorphisms) are known to cause dysfunction in mitochondria, such as increased ROS production and reduced OXPHOS activities, and result in pathological conditions including primary mitochondrial diseases [2,3,4,5]. Our group and others have revealed previously that mtDNA variants are associated with the composition of the gut microbiome [14,15]. One study demonstrated that differential mitochondrial ROS levels caused by ageing or mtDNA mutations are associated with the abundance of specific bacterial species [15]. A mouse model with accelerated ageing due to a knock-in mutation at the proofreading domain of the mtDNA polymerase gamma had changes in gut microbiota composition in addition to mitochondrial dysfunction [16]. We recently reported that two mouse strains that carry two nucleotide single nucleotide variants in the mtDNA-coded mitochondrial complex I gene, i.e., B6-mtALR mice carry m.4738C>A and B6-mtBPL mice with m.11902T>C, do not exhibit major mitochondrial dysfunction in steady-state [17]

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