Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, No. 107 West Wenhua Road Jinan, Jinan, Shandong, 250012, China.
Qingdao Key Laboratory of Mitochondrial Medicine and Rare Disease, Qilu Hospital (Qingdao), Shandong University, Qingdao, Shandong, 266035, China.
J Transl Med. 2024 Aug 22;22(1):780. doi: 10.1186/s12967-024-05574-0.
Mitochondrial tRNA (mt-tRNA) variants have been found to cause disease. Post-transcriptional queuosine (Q) modifications of mt-tRNA can promote efficient mitochondrial mRNA translation. Q modifications of mt-tRNA have recently been identified. Here, the therapeutic effectiveness of queuine was investigated in cells from patients with mt-tRNA variants.
Six patients (from four families) carrying mt-tRNA variants were included in the study. Queuine levels were quantified by mass spectrometry. Clinical, genetic, histochemical, biochemical, and molecular analysis was performed on muscle tissues and lymphoblastoid cell lines (LCLs) from patients to investigate the pathogenicity of the novel m.5708 C > T variant. The use of queuine in mitigating mitochondrial dysfunction resulting from the mt-tRNA variants was evaluated.
The variants included the m.5701 delA, m.5708 C > T, m.5709 C > T, and m.5698 G > A variants in mt-tRNA. The pathogenicity of the novel m.5708 C > T variant was confirmed, as demonstrated by a decreased steady-state level of mt-tRNA, mtDNA-encoded protein levels, oxygen consumption rate (OCR), and the respiratory complex activity. Notably, the serum queuine level was significantly reduced in these patients and in vitro queuine supplementation was found to restore the reductions in mitochondrial protein activities, mitochondrial membrane potential, OCR, and increases in reactive oxygen species.
The study not only confirmed the pathogenicity of the m.5708 C > T variant but also explored the therapeutic potential of queuine in individuals with mt-tRNA variants. The recognition of the novel m.5708 C > T variant's pathogenic nature contributes to our comprehension of mitochondrial disorders. Furthermore, the results emphasize queuine supplementation as a promising approach to enhance the stability of mt-tRNA and rescue mitochondrial dysfunction caused by mt-tRNA variants, indicating potential implications for the development of targeted therapies for patients with mt-tRNA variants.
已发现线粒体 tRNA (mt-tRNA) 变体可导致疾病。mt-tRNA 的转录后 queuosine (Q) 修饰可促进有效的线粒体 mRNA 翻译。最近已经鉴定出 mt-tRNA 的 Q 修饰。在此，研究了在携带 mt-tRNA 变体的细胞中 queuine 的治疗效果。
研究纳入了携带 mt-tRNA 变体的 6 名患者（来自 4 个家族）。通过质谱法定量 queuine 水平。对患者的肌肉组织和淋巴母细胞系 (LCL) 进行临床、遗传、组织化学、生化和分子分析，以研究新型 m.5708 C> T 变体的致病性。评估了 queuine 在减轻由 mt-tRNA 变体引起的线粒体功能障碍方面的作用。
变体包括 mt-tRNA 中的 m.5701 delA、m.5708 C> T、m.5709 C> T 和 m.5698 G> A 变体。新型 m.5708 C> T 变体的致病性得到证实，表现为 mt-tRNA 的稳态水平降低、mtDNA 编码蛋白水平降低、耗氧率 (OCR) 和呼吸复合物活性降低。值得注意的是，这些患者的血清 queuine 水平显著降低，体外 queuine 补充可恢复线粒体蛋白活性、线粒体膜电位、OCR 的降低以及活性氧的增加。
该研究不仅证实了 m.5708 C> T 变体的致病性，还探索了 queuine 在携带 mt-tRNA 变体的个体中的治疗潜力。对新型 m.5708 C> T 变体致病性的认识有助于我们理解线粒体疾病。此外，结果强调了 queuine 补充作为增强 mt-tRNA 稳定性和挽救 mt-tRNA 变体引起的线粒体功能障碍的有前途的方法，表明对携带 mt-tRNA 变体的患者开发靶向治疗具有潜在意义。
