Human mitochondrial RNA modifications associate with tissue-specific changes in gene expression, and are affected by...

RNA-DNA differences (RDD) have previously been identified in the human mitochondrial RNA (mt-RNA) transcripts, yet their functional impact is poorly understood. By analyzing 4928 RNA-seq samples from 23 body sites, we found that mtDNA gene expression negatively correlated with the levels of both m¹A 947 16 S rRNA modification (mtDNA position 2617) and the m¹A 1812 ND5 mRNA modification (mtDNA position 13,710) in 15 and 14 body sites, respectively. Such correlation was not evident in all tested brain tissues, thus suggesting a tissue-specific impact of these modifications on mtDNA gene expression. To assess the response of the tested modifications to environmental cues, we analyzed pairs of skin samples that were either exposed to the sun or not. We found that the correlations of mtDNA gene expression with both mt-RNA modifications were compromised upon sun exposure. As a first step to explore the underlying mechanism, we analyzed RNA-seq data from keratinocytes that were exposed to increasing doses of UV irradiation. Similar to sun exposure, we found a significant decrease in mtDNA gene expression upon increase in UV dosage. In contrast, there was a significant increase in the m¹A 947 16 S rRNA modification levels upon elevation in UV dose. Finally, we identified candidate modulators of such responses. Taken together, our results indicate that mt-RNA modifications functionally correlate with mtDNA gene expression, and responds to environmental cues, hence supporting their physiological importance.