Modulation of mtDNA copy number ameliorates the pathological consequences of a heteroplasmic mtDNA mutation in the mouse

Abstract

Heteroplasmic mtDNA mutations typically act in a recessive way and cause mitochondrial disease only if present above a certain threshold level. We have experimentally investigated to what extent the absolute levels of wild-type (WT) mtDNA influence disease manifestations by manipulating TFAM levels in mice with a heteroplasmic mtDNA mutation in the tRNAAla gene. Increase of total mtDNA levels ameliorated pathology in multiple tissues, although the levels of heteroplasmy remained the same. A reduction in mtDNA levels worsened the phenotype in postmitotic tissues, such as heart, whereas there was an unexpected beneficial effect in rapidly proliferating tissues, such as colon, because of enhanced clonal expansion and selective elimination of mutated mtDNA. The absolute levels of WT mtDNA are thus an important determinant of the pathological manifestations, suggesting that pharmacological or gene therapy approaches to selectively increase mtDNA copy number provide a potential treatment strategy for human mtDNA mutation disease.

Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging

“…The oxidative stress response causes damage to mtDNA replication enzymes and thus aggravates the decrease in mtDNA-CN further [78]. In pressure-overload-induced HF mice, increased mtDNA-CN induced by the overexpression of Twinkle or TFAM-alleviated fibrosis of the left ventricle, limited mitochondrial oxidative stress, and improved cardiac function [79,80]. One study observed an inverse association between mtDNA-CN and coronary artery disease in a Chinese population, especially among smokers, and found an inverse correlation between mtDNA-CN and ROS production.…”

Intimate Relations—Mitochondria and Ageing

“…A high level of neocortical superoxide was seen in the double mutants compared with the single mutants. Simple increase in the copy number of mtDNA (achieved by manipulating TFAM expression) reduces the severity of pathology in a heteroplasmic mouse bearing a mutation in mt tRNA Ala although the levels of heteroplasmy remained the same [ 284 ]. Conversely, a reduction in mtDNA levels worsened the phenotype in postmitotic tissues, such as heart, although enhanced clonal expansion and selective elimination of mutated mtDNA lead to a beneficial effect in rapidly proliferating tissues, such as colon.…”

The Mitochondrial Genome–on Selective Constraints and Signatures at the Organism, Cell, and Single Mitochondrion Levels

“…This scheme experienced another level of complexity, due to the existence of multiple mitochondria per cell, the mtDNAs of which may vary in sequence (heteroplasmy). Specifically, heteroplasmy patterns and their phenotypic consequences notably differs between dividing (mitotic) and post-mitotic tissues (Kowald and Kirkwood, 2013;Filograna et al, 2019). Therefore, mitochondrial phenotypic implications should be considered not only at the level of the organism which has been widely discussed in the past (Meiklejohn et al, 2007;Levin et al, 2014), but also at the level of the cell, and even in the single mitochondrion (Figure 1).…”