Mitochondrial maintenance under oxidative stress depends on mitochondrial but not nuclear α isoform of OGG1

Abstract

Accumulation of 8-oxoG in mtDNA and mitochondrial dysfunction have been observed in cells deficient for the DNA glycosylase OGG1 exposed to oxidative stress. In human cells up to eight mRNAs for OGG1 can be generated by alternative splicing and it is still unclear which of them codes for the protein that ensures the repair of 8-oxoG in mitochondria. Here, we show that the α-OGG1 isoform, considered up to now to be exclusively nuclear, has a functional mitochondrial targeting signal and is imported in mitochondria. We analyzed the submitochondrial localisation of α-OGG1 with unprecedented resolution and we show that the DNA glycosylase is associated with DNA in the nucleoids. We show that the presence of α-OGG1 inside mitochondria and its enzymatic activity are required to preserve mitochondrial network in cells exposed to oxidative stress. Altogether, these results unveil a new role of α-OGG1 in the mitochondria and indicate that the same isoform ensures the repair of 8-oxoG in both nuclear and mitochondrial genomes and that its activity in mitochondria is sufficient for the recovery of the organelle function after oxidative stress.