How do mitochondria recover from sunburns?

Like a genetic time capsule, mitochondria contain the secrets of their ancient bacterial origins in their own genomes (mtDNA), separate from the nuclear genomes (nucDNA) that tend to be in the spotlight. mtDNA is especially vulnerable to UV damage as the cellular powerhouses are located in the cytoplasm, near the thin cell membrane. While UV damage to nuclear DNA triggers the nucleotide excision repair (NER) pathway to replace the damaged segment, mtDNA has more limited repair mechanisms and may instead rely on degradation to mitigate the damage.

Recent research published in the May issue of GENETICS by Waneka et al. revisits this assumption, reporting evidence that mitochondria may have unique DNA repair pathways to address UV damage in Arabidopsis thaliana and Saccharomyces cerevisiae.

UV damage produces cyclobutane pyrimidine dimers (CPDs), which result in bulky distortions in the DNA structure. In response, NER creates single-stranded incisions upstream and downstream of the dimer to excise the damaged fragment, which is then replaced by a polymerase using the opposite strand as a template.

The excision process results in damage-containing oligonucleotides with distinct size distributions, which is a useful characteristic for investigating damage repair. Bacterial NER produces fragments of ~10 to 13 nt, while eukaryotic nuclear NER produces fragments of ~23 to 30 nt. In an approach called excision repair sequencing (XR-seq), antidamage antibodies recognize and capture the fragments for subsequent sequencing analysis, allowing researchers to map the locations of active DNA repair across the genome.

To explore the effects of UV damage on mitochondrial DNA in plants, yeast, and flies, Waneka et al. analyzed previously published XR-seq datasets from UV-irradiated A. thaliana, S. cerevisiae, and D. melanogaster S2 cells. They found that mtDNA fragments had distinct size distributions compared to nucDNA fragments. In S. cerevisiae, the mtDNA fragments were predominantly 26 nt in size, while in A. thaliana, they were 28 nt. Both species also had additional fragment peaks at regular size intervals—2 nt in S. cerevisiae and 4 nt in A. thaliana. In D. melanogaster, however, mtDNA fragments did not follow the same size patterns.

Among the most frequent fragments, the CPDs were located in common positions relative to the read end. This suggests that UV damage results in mtDNA fragments of specific sizes and positions relative to the damaged location—a known characteristic of NER.

However, Waneka et al. also presented an alternative explanation, hypothesizing that the distinct fragment sizes could also be produced by a yet uncharacterized damage-induced mtDNA degradation pathway. They emphasized that many questions remain as the bacterial origins of mtDNA make it difficult to predict which genes may be involved in the response to UV damage.

What we do know is that the accumulation of mutations in mtDNA can contribute to metabolic and neurodegenerative diseases, and that UV damage to mtDNA is linked to skin aging and melanoma. Thus, further research is needed to understand the yet-unrevealed damage-induced NER and/or degradation mechanisms which may protect mitochondrial DNA. Either of these possibilities point to the exciting prospect of novel maintenance or processing in response to exogenous damage.