Mitochondrial diseases linked to mutations in mitochondrial (mt)tRNA sequences are abundant. However, the contributions of these tRNA mutations to the development of diseases is mostly unknown. Mutations may affect interactions with (mt)tRNA maturation enzymes or protein synthesis machinery leading to mitochondrial dysfunction. In human mitochondria, the first step of tRNA processing is the removal of the 5'end of precursor tRNAs (pre-tRNA) catalyzed by the three-component enzyme, mtRNase P. Additionally, one sub-component of mtRNase P, mitochondrial RNase P protein 1 (MRPP1) catalyzes methylation of the R9 base in pre-tRNAs. Despite the central role of 5' end processing in mitochondrial tRNA maturation, the link between mtRNase P and diseases is mostly unexplored. Here we investigate how 11 different human disease-linked mutations in (mt)pre-tRNAs affect the activities of mtRNase P. We find that several mutations weaken the pre-tRNA binding affinity, while the majority of mutations decrease 5' end processing and methylation activity catalyzed by mtRNase P. Furthermore, all of the investigated mutations in (mt)pre-tRNALeu(UUR) alter the tRNA fold which contributes to the partial loss of function of mtRNase P. Overall, these results reveal an etiological link between early steps of (mt)tRNA-substrate processing and mitochondrial disease.

中文翻译：

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线粒体前体tRNA中与疾病相关的突变影响mtRNase P的结合，m1R9甲基化和tRNA加工

与线粒体（mt）tRNA序列突变相关的线粒体疾病丰富。然而，这些tRNA突变对疾病发展的贡献大多是未知的。突变可能影响与（mt）tRNA成熟酶或蛋白质合成机制的相互作用，从而导致线粒体功能障碍。在人类线粒体中，tRNA加工的第一步是去除由三组分酶mtRNase P催化的前体tRNA（pre-tRNA）的5'末端。此外，mtRNase P的一个亚组分即线粒体RNase P蛋白1（MRPP1）催化pre-tRNA中R9碱基的甲基化。尽管5'末端加工在线粒体tRNA成熟中起着核心作用，但mtRNase P和疾病之间的联系大多尚未被探索。