AI Article Synopsis

  • * The study found that N-methylation of guanosine at position 9 (mG9) stabilizes wild-type mt-Leu(UAA) tRNA but destabilizes certain pathogenic variants associated with MELAS.
  • * Findings suggest that modifying the methylation level of mt-tRNAs could be a potential therapeutic approach for mt-tRNA-related diseases by impacting their stability and functionality.

Article Abstract

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 N-methylation of guanosine at position 9 (mG9) 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 mG9 methylation, while damaging to the WT tRNA, is beneficial to the major pathogenic variant, improving the structure and activity of the variant. These results have therapeutic implications, suggesting that the N-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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11489592PMC
http://dx.doi.org/10.1038/s41467-024-53318-xDOI Listing

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