Heteroplasmy of Mouse mtDNA Is Genetically Unstable and Results in Altered Behavior and Cognition

Abstract

SUMMARY Maternal inheritance of mtDNA is the rule in most animals, but the reasons for this pattern remain unclear. To investigate the consequence of overriding uniparental inheritance, we generated mice containing an admixture (heteroplasmy) of NZB and 129S6 mtDNAs in the presence of a congenic C57BL/6J nuclear background. Analysis of the segregation of the two mtDNAs across subsequent maternal generations revealed that proportion of NZB mtDNA was preferentially reduced. Ultimately, this segregation process produced NZB-129 heteroplasmic mice and their NZB or 129 mtDNA homo-plasmic counterparts. Phenotypic comparison of these three mtDNA lines demonstrated that the NZB-129 heteroplasmic mice, but neither homoplasmic counterpart, had reduced activity, food intake, respiratory exchange ratio; accentuated stress response; and cognitive impairment. Therefore, admixture of two normal but different mouse mtDNAs can be genetically unstable and can produce adverse physiological effects, factors that may explain the advantage of uniparental inheritance of mtDNA.

Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals

“…Mitochondrial heteroplasmy has been shown to be implicated in a large spectrum of human diseases. Besides classical mitochondrial diseases such as mitochondrial myopathy, myoclonic epilepsy with ragged red fibers, and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, mitochondrial heteroplasmy also plays roles in complex disorders, including type 2 diabetes mellitus, aging, cancer, and late-onset neurodegenerative diseases (1)(2)(3)(4)(5)(6)(7). Of the over 500 mtDNA point mutations reported so far that are implicated in disease, ∼55% were observed at known heteroplasmic sites (7).…”

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

“…The mammalian mitochondria contains a 16.6-kb circular chromosome known as mitochondrial DNA (mtDNA), which encodes 37 genes in total, 13 of which code for proteins essential to the function of the mitochondrial electron transport chain. Mutations in the mtDNA have been linked to serious diseases that show a marked effect on the central nervous system in both humans and mouse model systems (11,12). Steroid hormone receptors, including estrogen receptors and GRs, translocate into brain mitochondria.…”

Reproductive medicine: The power of three

“…The health implications for the children are unclear: studies suggest that mice with such mixed mitochondria develop hypertension and obesity in middle age 9 , and have impaired cognition -they escape from mazes more slowly than normal mice, for example 10 . One of the babies born as a result of the procedure was diagnosed with an autism spectrum disorder, and two further fetuses had a genetic defect known as Turner syndrome (one was miscarried, the other aborted).…”