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Post-Transcriptional Methylation of Mitochondrial-tRNA Differentially Contributes to Mitochondrial Pathology.

Sunita MaharjanHoward GamperYuka YamakiRobert Y HenleyNan-Sheng LiTakeo SuzukiTsutomu SuzukiJoseph A PiccirilliMeni WanunuErin SeifertDouglas C WallaceYa-Ming Hou
Published in: bioRxiv : the preprint server for biology (2023)
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 structure would also stabilize its pathogenic variants is unknown. Here we show that the N 1 -methylation of guanosine at position 9 (m 1 G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has an opposite and destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated by the observation that demethylation of m 1 G9, while damaging to the WT tRNA, is beneficial to the major pathogenic variant, improving its structure and activity. These results have new therapeutic implications, suggesting that the N 1 -methylation of mt-tRNAs at position 9 is a determinant of pathogenicity and that controlling the methylation level is an important modulator of mt-tRNA-associated diseases.
Keyphrases
  • oxidative stress
  • dna methylation
  • genome wide
  • gene expression
  • endothelial cells
  • wild type
  • atrial fibrillation
  • high resolution
  • biofilm formation
  • subarachnoid hemorrhage
  • heat shock protein