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<p>Mitochondrial transfer RNA (mt-tRNA) modification determines organelle translation and function. GTPBP3 and MTO1 catalyze 5-taurinomethyluridine (τm<sup>5</sup>U) modification at wobble uridine of five mt-tRNAs. τm<sup>5</sup>U hypomodification causes mitochondrial encephalomyopathy, but the underlying pathogenesis and intervention strategy due to GTPBP3 mutations are lacking. In this study, we identify two genetic variants (c.689 A &gt; C (p.Q230P) and c.1120 A &gt; G (p.N374D)) of <i>GTPBP3</i> in a Chinese proband with metabolic disorders and multisystem dysfunction. Mechanistically, Q230P and N374D mutations induce protein multimerization/aggregation, protease degradation, decreased GTPase activity, and tRNA modification to varying degrees, affecting mitochondrial translation, respiration, dynamics, and function. Homozygous N374D mutations in mice cause embryonic lethality; homozygous E230P or compound heterozygous E230P/N374D knock-in mice develop cardiac and muscular dysfunction due to altered mitochondrial translation. Mitochondrial dysfunction and pathology are efficiently reversed by virus-mediated GTPBP3 expression in cells and animals. This study provides valuable insights into the etiology of and promising intervention strategies for GTPBP3-related diseases.</p>

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Molecular pathogenesis and gene therapy-based intervention of GTPBP3-related mitochondrial disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月9日

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  • Yong Zhang,
  • Shi-Ying Yao,
  • Jing Li,
  • Tingting Yu,
  • Hao Liu,
  • Nanlin Zhu,
  • Gui-Xin Peng,
  • Wen-Qiang Zheng,
  • Chun-Rui Ma,
  • En-Duo Wang,
  • Cui Song,
  • Xiao-Long Zhou

摘要

Mitochondrial transfer RNA (mt-tRNA) modification determines organelle translation and function. GTPBP3 and MTO1 catalyze 5-taurinomethyluridine (τm5U) modification at wobble uridine of five mt-tRNAs. τm5U hypomodification causes mitochondrial encephalomyopathy, but the underlying pathogenesis and intervention strategy due to GTPBP3 mutations are lacking. In this study, we identify two genetic variants (c.689 A > C (p.Q230P) and c.1120 A > G (p.N374D)) of GTPBP3 in a Chinese proband with metabolic disorders and multisystem dysfunction. Mechanistically, Q230P and N374D mutations induce protein multimerization/aggregation, protease degradation, decreased GTPase activity, and tRNA modification to varying degrees, affecting mitochondrial translation, respiration, dynamics, and function. Homozygous N374D mutations in mice cause embryonic lethality; homozygous E230P or compound heterozygous E230P/N374D knock-in mice develop cardiac and muscular dysfunction due to altered mitochondrial translation. Mitochondrial dysfunction and pathology are efficiently reversed by virus-mediated GTPBP3 expression in cells and animals. This study provides valuable insights into the etiology of and promising intervention strategies for GTPBP3-related diseases.