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

Authors

Sunita Maharjan, Thomas Jefferson UniversityFollow
Howard Gamper, Thomas Jefferson UniversityFollow
Yuka Yamaki, Thomas Jefferson UniversityFollow
Thomas W. Christian, Thomas Jefferson UniversityFollow
Robert Y. Henley
Nan-Sheng Li
Takeo Suzuki
Tsutomu Suzuki
Joseph A. Piccirilli
Meni Wanunu
Erin L. Seifert, Thomas Jefferson UniversityFollow
Douglas C. Wallace
Ya-Ming Hou, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

10-18-2024

Comments

This article is the author's final published version in Nature communications, Volume 15, Issue 1, 2024, Article number 9008.

The published version is available at https://doi.org/10.1038/s41467-024-53318-x.

Copyright © The Author(s) 2024

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 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 tRNA, is beneficial to the major pathogenic variant, improving the structure and activity of the variant. These results have therapeutic implications, suggesting that the N¹-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.

Recommended Citation

Maharjan, Sunita; Gamper, Howard; Yamaki, Yuka; Christian, Thomas W.; Henley, Robert Y.; Li, Nan-Sheng; Suzuki, Takeo; Suzuki, Tsutomu; Piccirilli, Joseph A.; Wanunu, Meni; Seifert, Erin L.; Wallace, Douglas C.; and Hou, Ya-Ming, "Post-Transcriptional Methylation of Mitochondrial-tRNA Differentially Contributes to Mitochondrial Pathology" (2024). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 270.
https://jdc.jefferson.edu/bmpfp/270

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

39424798

Language

English