DNA topoisomerases in mtDNA maintenance and ageing

AbstractDNA topoisomerases pass DNA strands through each other, a function essential for all DNA metabolic processes that create supercoils or entanglements of DNA. Topoisomerases play an ambivalent role in nuclear genome maintenance: Deficiency compromises gene transcription, replication and chromosome segregation, while the inherent DNA-cleavage activity of the enzymes endangers DNA integrity. Indeed, many DNA-damaging agents act through enhancing topoisomerase DNA cleavage. Mitochondrial DNA (mtDNA) clearly requires topoisomerase activity for transcription and replication, because it is a closed, double-stranded DNA molecule. Three topoisomerases have so far been found in mammalian mitochondria (I, IIβ, IIIα), but their precise role in mtDNA metabolism, mitochondrial maintenance and respiratory function remains mostly unclear. It is a reasonable surmise that these enzymes exhibit similar ambiguity with respect to genome maintenance and gene transcription as their nuclear counterparts. Here, we review what is known about the physiological roles of mitochondrial topoisomerases and draft three scenarios of how these enzymes possibly contribute to ageing-related mtDNA attrition and respiratory chain dysfunction. These scenarios are: mtDNA attrition by exogenously stimulated topoisomerase DNA cleavage, unbalancing of mitochondrial and nuclear transcription by direct effects on mitochondrial transcription, and contributions to enhanced mtDNA entanglement and recombination