biostudies-literatureMaharjan SNIA NIH HHSFoundation for the National Institutes of HealthNCI NIH HHSNIGMS NIH HHS9008https://www.ebi.ac.uk/biostudies/studies/S-EPMC11489592biostudies-literatureUnknown15(1)Human mitochondrial tRNAs (mt-tRNAs), critical for mitochondrial biogenesis, are frequently associated with pathogenic mutations. These mt-tRNAs have unusual sequence motifs and require post-transcriptional modifications to stabilize their fragile structures. However, whether a modification that stabilizes a wild-type (WT) mt-tRNA would also stabilize its pathogenic variants is unknown. Here we show that the N¹-methylation of guanosine at position 9 (m¹G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has a destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated, as removal of the m¹G9 methylation, while damaging to the WT tRNature communicationsPost-transcriptional methylation of mitochondrial-tRNA differentially contributes to mitochondrial pathology.PMC11489592R35 GM149336R35 GM134931R01 AG078814R01 GM123771R01 CA259635Maharjan SSuzuki TChristian TSeifert ELi NSGamper HHou YMWanunu MYamaki YHenley RYWallace DCPiccirilli JAfalsePost-transcriptional methylation of mitochondrial-tRNA differentially contributes to mitochondrial pathology.Human mitochondrial tRNAs (mt-tRNAs), critical for mitochondrial biogenesis, are frequently associated with pathogenic mutations. These mt-tRNAs have unusual sequence motifs and require post-transcriptional modifications to stabilize their fragile structures. However, whether a modification that stabilizes a wild-type (WT) mt-tRNA would also stabilize its pathogenic variants is unknown. Here we show that the N¹-methylation of guanosine at position 9 (m¹G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has a destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated, as removal of the m¹G9 methylation, while damaging to the WT tR2024-01-01T00:00:00Z2024 Oct2026-06-03T07:18:32.077Z2025-04-06T09:33:37.982ZS-EPMC114895923942479810.1038/s41467-024-53318-x