The mitochondrial genome sequence of Mus terricolor: Comparison with Mus musculus domesticus and implications for xenomitochondrial mouse modeling

Abstract

Knowledge of the mitochondrial DNA (mtDNA) sequence of divergent murine species is critical from both a phylogenetic perspective and in understanding nuclear-mitochondrial interactions, particularly as the latter influences our xenocybrid models of mitochondrial disease. To this end, the sequence of the mitochondrial genome of the murine species Mus terricolor (formerly Mus dunni) is reported and compared with the published sequence for the common laboratory mouse Mus musculus domesticus strain C57BL/6J. These species are of interest because xenomitochondrial cybrid mice were created that harbor M. terricolor mtDNA in a M. m. domesticus nuclear background. Although the total of 1763 nucleotide substitutions represents striking heterogeneity, the majority of these are silent, leading to highly conserved protein sequences with only 159 amino acid differences. Moreover, 58% of these amino acid differences represented conservative substitutions. All of the tRNA genes and rRNA genes have homology of 91% or greater. The control region shows the greatest heterogeneity, as expected, with 85% homology overall. Regions of 100% homology were found for Conserved Sequence Block I, Conserved Sequence Block III and the L-strand origin of replication. Complex I genes showed the greatest degree of difference among protein-coding genes with amino acid homology of 91-97% among the seven mitochondrial genes. Complexes III and IV genes show high homology ranging from 98-100%. From these data, complex I differences appear most critical for the viability of M. m. domesticus: M. terricolor cybrids. Moreover, the sequence information reported here should be useful in identifying critical regions for mitochondrial transfer between species, for furthering the understanding of mitochondrial dynamics and pathology in transmitochondrial organisms, and for the study of Mus genus origins.

D-Galactose Effectiveness in Modeling Aging and Therapeutic Antioxidant Treatment in Mice

“…Mice were maintained in an Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC)-accredited specific pathogen-free barrier facility, in ventilated microisolator-style caging with ad libitum access to water and feed on a 14:10 light:dark cycle. 14,15 All mouse procedures, including euthanasia, conformed to Institutional Animal Care and Use Committee (IACUC) guidelines and the Guide for the Care and Use of Laboratory Animals, under Office for Laboratory Animal Welfare (OLAW) assurance #A3152-01.…”

Animal models of human mitochondrial DNA mutations

“…The transfer of mitochondria from an evolutionarily divergent species (xenomitochondrial transfer) is postulated to result in mitochondrial dysfunction due to structural mismatches between the nuclear encoded respiratory subunits of one species and the mitochondrial encoded subunits of the other [28, 60]. Mitochondria isolated from Mus spretus (2 million years diverged from Mus musculus domesticus ) were injected into M. m. domesticus zygotes.…”

“…A less extreme defect was anticipated, as M. terricolor only diverged from M. m. domesticus six million years ago, as opposed to greater than ten million years ago for R. norvegicus [28, 60, 74, 75, 77]. Early in vitro studies showed a relationship between increased lactate production (indicative of mitochondrial dysfunction) and evolutionary divergence of introduced mitochondria in xenomitochondrial cell lines [77].…”

“…Sequencing of M. terricolor mtDNA revealed 159 amino acid changes compared to M. m domesticus . The 12S and 16S rRNAs had 31 and 124 nucleotide changes, respectively, while tRNA homology ranged from 93%–100% [60]. …”

Mitochondrial disorders and the eye

“…Mismatching of nuclear and mitochondrial encoded oxidative phosphorylation subunits in cybrid models takes advantage of evolutionary divergence, which is sufficient to cause mitochondrial dysfunction. [176][177][178] Thus, the successful delivery of human ND4 subunits into the mitochondrion does not necessarily provide a functional benefit to the murine mitochondria, nor does it guarantee correct assembly into functional oxidative phosphorylation complexes. These findings have also raised questions on whether AAV delivery of highly hydrophobic complex I subunits would be correctly assembled into mitochondrial membranes in vivo.…”