Post-transcriptional methylation of mitochondrial-tRNA differentially contributes to mitochondrial pathology.

Autor: Maharjan S; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA., Gamper H; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA., Yamaki Y; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA., Christian T; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA., Henley RY; Department of Physics, Northeastern University, Boston, MA, USA., Li NS; Department of Chemistry, University of Chicago, Chicago, IL, USA., Suzuki T; Faculty of Medicine, University of the Ryukyus, Okinawa, Japan., Suzuki T; Department of Chemistry and Biotechnology, University of Tokyo, Tokyo, Japan., Piccirilli JA; Department of Chemistry, University of Chicago, Chicago, IL, USA., Wanunu M; Department of Physics, Northeastern University, Boston, MA, USA., Seifert E; Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA., Wallace DC; Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Department of Pediatrics, Division of Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Hou YM; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA. ya-ming.hou@jefferson.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Oct 18; Vol. 15 (1), pp. 9008. Date of Electronic Publication: 2024 Oct 18.
DOI: 10.1038/s41467-024-53318-x
Abstrakt: 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 1 -methylation of guanosine at position 9 (m 1 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 1 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 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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