The maternally inherited DNA that is found in cytoplasmic organelles called mitochondria encodes the central proteins involved in energy production––the main function of this organelle. Yet, it has been assumed that the extraordinarily high sequence variability of mitochondrial DNA is of little consequence. In the main article [below], Latorre-Pellicer et al. dispel this erroneous notion.
The authors transferred mitochondrial DNA (mtDNA) from a mouse strain called NZB to the nuclear DNA (nDNA) background of another strain, C57BL/6, and then compared C57BL/6 mice that carried NZB versus C57BL/6 mtDNA. The two mtDNA sequences differ in genetic variants that confer 12 amino-acid substitutions and 12 changes in RNA molecules involved in mitochondrial protein synthesis. Comparison of these two mouse lines––throughout their lives––revealed large differences in mitochondrial function, insulin signaling, obesity and longevity. This, and related studies, clearly demonstrate that naturally-occurring mtDNA variation is NOT neutral, and that the interaction between mtDNA sequence variants and nDNA can have profound effects on mammalian biology.
Human mtDNA also shows extensive within-population sequence variability. Many studies suggest that mtDNA variants may be associated with aging and diseases, although mechanistic evidence at the molecular level is lacking. Mitochondrial replacement before fertilization of the oocyte––has the potential to prevent transmission of disease-causing oocyte mtDNA. However, extension of this technology requires a comprehensive understanding of the physiological relevance of mtDNA sequence variability and its match with the nDNA-encoded genes that produce mitochondrial proteins.
Studies in conplastic animals (i.e. backcrossing the male nuclear genome of an inbred strain into the female cytoplasm of another inbred strain) have allowed comparison of individuals with the same nuclear genome but different mtDNA variants, and have provided both supporting and refuting evidence that mtDNA variation influences organismal physiology. However, most of these studies never confirmed the conplastic status, focused on younger animals, and did not investigate the full range of physiological and phenotypic variability likely to be influenced by mitochondria.
In this exciting paper, authors systematically characterized conplastic mice throughout their lifespan––using transcriptomic, proteomic, metabolomic, biochemical, physiological and phenotyping studies. They showed that mtDNA haplotype profoundly influences mitochondrial proteostasis and reactive oxygen species (ROS) generation, insulin signaling, obesity, and aging parameters including telomere shortening and mitochondrial dysfunction, resulting in profound differences in healtht longevity between conplastic strains.
Nature 28 July 2o16; 535: 561–565 & News-n-Views pp 498–500