Post-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 N<sup>1</sup>-methylation of guanosine at position 9 (m<sup>1</sup>G9) 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 m<sup>1</sup>G9 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<sup>1</sup>-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.
Authors
- Tsutomu Suzuki (ORCID: https://orcid.org/0000-0002-9731-1731)
- Sunita Maharjan (ORCID: https://orcid.org/0000-0002-7099-1802)
- Howard Gamper (ORCID: https://orcid.org/0000-0001-9007-8546)
- Meni Wanunu (ORCID: https://orcid.org/0000-0002-9837-0004)
- Robert Y. Henley (ORCID: https://orcid.org/0000-0003-2201-8474)
- Nan‐Sheng Li (ORCID: https://orcid.org/0000-0002-1185-3688)
- Ya‐Ming Hou (ORCID: https://orcid.org/0000-0001-6546-2597)
- Yuka Yamaki (ORCID: https://orcid.org/0000-0003-2457-7296)
- Douglas C. Wallace (ORCID: https://orcid.org/0000-0002-7480-8278)
- Joseph A. Piccirilli (ORCID: https://orcid.org/0000-0002-0541-6270)
- Takeo Suzuki (ORCID: https://orcid.org/0000-0002-2747-4076)
- Erin L. Seifert
- Thomas Christian
Institutions
- Northeastern University (US)
- Children's Hospital of Philadelphia (US)
- Thomas Jefferson University (US)
- University of the Ryukyus (JP)
- University of Chicago (US)
- Jefferson Institute (US)
- The University of Tokyo (JP)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-18
- DOI
- https://doi.org/10.1038/s41467-024-53318-x
- Citations
- 2
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.47
Funders
- Foundation for the National Institutes of Health
- National Institutes of Health
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Exploratory Research for Advanced Technology