Abstract
Mitochondrial RNA editing has evolved independently in numerous eukaryotic lineages, where it generally restores conserved sequences and functional reading frames in mRNA transcripts derived from altered or disrupted mitochondrial protein-coding genes. In contrast to this "restorative" RNA editing in mitochondria, most editing of nuclear mRNAs introduces novel sequence variants and diversifies the proteome. This Perspective addresses the hypothesis that these completely opposite effects of mitochondrial vs. nuclear RNA editing arise from the enormous difference in gene number between the respective genomes. Because mitochondria produce a much smaller transcriptome, they likely create less opportunity for off-target editing, which has been supported by recent experimental work expressing mitochondrial RNA editing machinery in foreign contexts. In addition, there is recent evidence that the size and complexity of RNA targets may slow the kinetics and reduce efficiency of on-target RNA editing. These findings suggest that efficient targeting and a low risk of off-target editing have facilitated the repeated emergence of disrupted mitochondrial genes and associated restorative RNA editing systems via (potentially non-adaptive) evolutionary pathways that are not feasible in larger nuclear transcriptomes due to lack of precision.