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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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. Wall, 2024. "Post-transcriptional methylation of mitochondrial-tRNA differentially contributes to mitochondrial pathology," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53318-x
    DOI: 10.1038/s41467-024-53318-x
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    References listed on IDEAS

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    1. Takeo Suzuki & Yuka Yashiro & Ittoku Kikuchi & Yuma Ishigami & Hironori Saito & Ikuya Matsuzawa & Shunpei Okada & Mari Mito & Shintaro Iwasaki & Ding Ma & Xuewei Zhao & Kana Asano & Huan Lin & Yohei K, 2020. "Complete chemical structures of human mitochondrial tRNAs," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    2. Raphael J. Morscher & Gregory S. Ducker & Sophia Hsin-Jung Li & Johannes A. Mayer & Zemer Gitai & Wolfgang Sperl & Joshua D. Rabinowitz, 2018. "Mitochondrial translation requires folate-dependent tRNA methylation," Nature, Nature, vol. 554(7690), pages 128-132, February.
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