Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
Cell Metab. 2011 Sep 7;14(3):428-34. doi: 10.1016/j.cmet.2011.07.010.
The metazoan mitochondrial translation machinery is unusual in having a single tRNA(Met) that fulfills the dual role of the initiator and elongator tRNA(Met). A portion of the Met-tRNA(Met) pool is formylated by mitochondrial methionyl-tRNA formyltransferase (MTFMT) to generate N-formylmethionine-tRNA(Met) (fMet-tRNA(met)), which is used for translation initiation; however, the requirement of formylation for initiation in human mitochondria is still under debate. Using targeted sequencing of the mtDNA and nuclear exons encoding the mitochondrial proteome (MitoExome), we identified compound heterozygous mutations in MTFMT in two unrelated children presenting with Leigh syndrome and combined OXPHOS deficiency. Patient fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of MTFMT. Furthermore, patient fibroblasts have dramatically reduced fMet-tRNA(Met) levels and an abnormal formylation profile of mitochondrially translated COX1. Our findings demonstrate that MTFMT is critical for efficient human mitochondrial translation and reveal a human disorder of Met-tRNA(Met) formylation.
真核生物线粒体翻译机制不同寻常，其中只有一种 tRNA（甲硫氨酸）同时具有起始和延伸 tRNA（甲硫氨酸）的双重功能。一部分 Met-tRNA（甲硫氨酸）池通过线粒体甲硫氨酰-tRNA 甲酰基转移酶（MTFMT）甲酰化，生成 N-甲酰甲硫氨酰-tRNA（甲硫氨酸）（fMet-tRNA（met）），用于翻译起始；然而，甲酰化对于人类线粒体起始的必要性仍存在争议。我们通过靶向测序 mtDNA 和编码线粒体蛋白质组的核外显子（MitoExome），在两名患有 Leigh 综合征和 OXPHOS 缺陷的非相关儿童中鉴定出 MTFMT 的复合杂合突变。患者成纤维细胞表现出严重的线粒体翻译缺陷，通过外源性表达 MTFMT 可以得到挽救。此外，患者成纤维细胞的 fMet-tRNA（met）水平显著降低，线粒体翻译的 COX1 甲酰化谱异常。我们的研究结果表明，MTFMT 对于有效的人类线粒体翻译至关重要，并揭示了人类 Met-tRNA（met）甲酰化的一种疾病。
