Mitochondrial RNA Sequencing Variation in Age-Related Pathologies
Background. Mitochondrial function has been implicated in a number of age-related disease pathologies, and post-transcriptional sequence modifications in mitochondrial RNA (mtRNA) have been correlated with variation in the mitochondrial function. One of the most significant modifications is methylation of mitochondrial transfer RNAs (tRNA) at their 9th position (termed “p9 sites”). Post-transcriptional modifications to these tRNAs are known to alter efficiency of translation and protein synthesis, affecting downstream mitochondrial function. The impact that these modifications to the mitochondrial transcriptome have on risk for age-related disease has not been previously explored. Purpose. The purpose of this study was to determine if altered post-transcriptional modification rates to mitochondrial p9 tRNA sites is associated with risk for age-related disease pathologies. Methods. RNA sequencing and genotyping data was analyzed from cerebellar tissue of 275 Caucasian subjects consisting of elderly controls, and individuals with diagnosed AD, progressive supranuclear palsy or pathological aging. Data were obtained through the Synapse data repository and were collected by the Mayo RNAseq study, led by Dr. Nilüfer Ertekin-Taner, Mayo Clinic, Jacksonville, FL as part of the multi-PI U01 AG046139 (MPIs Golde, Ertekin-Taner, Younkin, Price). Heteroplasmy in mtRNA was measured using the VarScan software tool. Variants in the nuclear-encoded gene MRPP3 were analyzed for association with altered p9 methylation rates. Results. Average number and rate of heteroplasmy at the 13 sites were compared across control and case groups. A higher rate of heteroplasmy was observed at the p9 sites, indicating the presence of methylation within these tRNAs. Concluding Remarks. Post-transcriptional modification of mtRNA occurs under normal, non-pathologic states; alteration of methylation rate at the p9 site of mitochondrial tRNAs may be associated with aging pathology. The rate of p9 methylation has been associated with genetic factors encoded in the nuclear DNA (Hodgkinson et al., 2014). Targeting methylation of mitochondrial tRNA could prove to be a viable therapeutic approach for deficits in mitochondrial function.