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

Sunita Maharjan, Howard Gamper, Yuka Yamaki, Thomas Christian, Robert Y. Henley, Nan-Sheng Li, Takeo Suzuki, Tsutomu Suzuki, Joseph A. Piccirilli, Meni Wanunu, Erin Seifert, Douglas C. Wallace and Ya-Ming Hou ()
Additional contact information
Sunita Maharjan: Thomas Jefferson University
Howard Gamper: Thomas Jefferson University
Yuka Yamaki: Thomas Jefferson University
Thomas Christian: Thomas Jefferson University
Robert Y. Henley: Northeastern University
Nan-Sheng Li: University of Chicago
Takeo Suzuki: University of the Ryukyus
Tsutomu Suzuki: University of Tokyo
Joseph A. Piccirilli: University of Chicago
Meni Wanunu: Northeastern University
Erin Seifert: Thomas Jefferson University
Douglas C. Wallace: University of Pennsylvania
Ya-Ming Hou: Thomas Jefferson University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53318-x

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