Intracellular quality control of mitochondrial DNA: evidence and limitations

Abstract

Eukaryotic cells can harbour mitochondria with markedly different transmembrane potentials. Intracellular mitochondrial quality-control mechanisms (e.g. mitophagy) rely on this intracellular variation to distinguish functional and damaged (depolarized) mitochondria. Given that intracellular mitochondrial DNA (mtDNA) genetic variation can induce mitochondrial heterogeneity, mitophagy could remove deleterious mtDNA variants in cells. However, the reliance of mitophagy on the mitochondrial transmembrane potential suggests that mtDNAs with deleterious mutations in ATP synthase can evade the control. This evasion is possible because inhibition of ATP synthase can increase the mitochondrial transmembrane potential. Moreover, the linkage of the mtDNA genotype to individual mitochondrial performance is expected to be weak owing to intracellular mitochondrial intercomplementation. Nonetheless, I reason that intracellular mtDNA quality control is possible and crucial at the zygote stage of the life cycle. Indeed, species with biparental mtDNA inheritance or frequent 'leakage' of paternal mtDNA can be vulnerable to invasion of selfish mtDNAs at the stage of gamete fusion. Here, I critically review recent findings on intracellular mtDNA quality control by mitophagy and discuss other mechanisms by which the nuclear genome can affect the competition of mtDNA variants in the cell. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.

Keywords: epistasis; heterogeneity; heteroplasmy; mtDNA; selection; zygote.

Figure 1.

Three extreme cases of mtDNA genotype-to-phenotype relationship inside the cell. (a) Genotype-to-phenotype linkage is possible in the absence of mitochondrial dynamics. Mitochondria phenotypes (e.g. value of transmembrane potential) associated with specific mtDNA genotypes are indicated by corresponding colours of the mitochondrial matrix; (b) mitochondria and all mtDNAs function as a single cellular unit owing to mitochondria intercomplementation; and (c) mitochondrial heterogeneity uncorrelated to mtDNA variation. For example, a high load of mutant mtDNAs can inhibit protein import to the mitochondria and reveal non-genetic mitochondrial heterogeneity. Intermediate states between these three cases are possible.

Figure 2.

Intracellular- and whole-cell levels of mtDNA selection differentially contribute to the removal of deleterious mutations in mitochondrial ATP synthase and other genes. Genotype-to-phenotype linkage makes it possible to select out deleterious mtDNA variants that decrease ΔΨ. Some mutations in ATP-synthase genes increase ΔΨ and therefore cannot be purged by intracellular mtDNA quality control. However, the high load of such mtDNAs in the cell should decrease cell fitness owing to a decrease in ATP levels.