{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:41:39Z","timestamp":1768509699304,"version":"3.49.0"},"posted":{"date-parts":[[2023,12,10]]},"group-title":"Cell Biology","reference-count":79,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,12,10]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  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 structure would also stabilize its pathogenic variants is unknown. Here we show that the\n                  <jats:italic>N<\/jats:italic>\n                  <jats:sup>1<\/jats:sup>\n                  -methylation of guanosine at position 9 (m\n                  <jats:sup>1<\/jats:sup>\n                  G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has an opposite and destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated by the observation that demethylation of m\n                  <jats:sup>1<\/jats:sup>\n                  G9, while damaging to the WT tRNA, is beneficial to the major pathogenic variant, improving its structure and activity. These results have new therapeutic implications, suggesting that the\n                  <jats:italic>N<\/jats:italic>\n                  <jats:sup>1<\/jats:sup>\n                  -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.\n                <\/jats:p>","DOI":"10.1101\/2023.12.09.569632","type":"posted-content","created":{"date-parts":[[2023,12,10]],"date-time":"2023-12-10T23:38:07Z","timestamp":1702251487000},"source":"Crossref","is-referenced-by-count":1,"title":["Post-Transcriptional Methylation of Mitochondrial-tRNA Differentially Contributes to Mitochondrial Pathology"],"prefix":"10.64898","author":[{"given":"Sunita","family":"Maharjan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Howard","family":"Gamper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuka","family":"Yamaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert Y.","family":"Henley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan-Sheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeo","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsutomu","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph 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