Mitochondrial tRNA 3′ end metabolism and human disease
Mitochondrial tRNA 3′ end metabolism and human disease
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DOI：
10.1093/nar/gkh884
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发表时间：
2004-01-01
影响因子：
14.9
通讯作者：
Florentz, C
中科院分区：
文献类型：
--
作者：
Levinger, L;Mörl, M;Florentz, C
线粒体基因组中超过150个突变已被证明与人类疾病有关。值得注意的是，它们中的三分之二存在于tRNA基因中，而tRNA基因只占线粒体基因组的十分之一。总共有22个tRNA在基因组中标点，并与11个mRNA和2个rRNA一起从几乎没有间隔区的长多顺反子初级转录物产生。因此，前体tRNA需要精确的核酸内切切除。此外，形成所有tRNA的3'端的CCA三联体不被编码，而是必须在3'端切割后由CCA添加酶合成。氨基酸与成熟tRNA的CCA的连接是由氨酰-tRNA合成酶完成的，氨酰-tRNA合成酶与前面的加工酶一样，是由核编码并输入线粒体的。在这里，我们严格审查的有效性和可靠性的证据，从反应与体外转录，发病机制相关的突变体线粒体tRNA可以导致缺陷的tRNA 3'端代谢（3'端切割，CCA添加和氨酰化）对人类tRNA疾病的分子机制的理解。这些缺陷可能单独和累积地导致人类线粒体疾病的进展。
Over 150 mutations in the mitochondrial genome have been shown to be associated with human disease. Remarkably, two-thirds of them are found in tRNA genes, which constitute only one-tenth of the mitochondrial genome. A total of 22 tRNAs punctuate the genome and are produced together with 11 mRNAs and 2 rRNAs from long polycistronic primary transcripts with almost no spacers. Pre-tRNAs thus require precise endonucleolytic excision. Furthermore, the CCA triplet which forms the 3' end of all tRNAs is not encoded, but must be synthesized by the CCA-adding enzyme after 3' end cleavage. Amino acid attachment to the CCA of mature tRNA is performed by aminoacyl-tRNA synthetases, which, like the preceding processing enzymes, are nuclear-encoded and imported into mitochondria. Here, we critically review the effectiveness and reliability of evidence obtained from reactions with in vitro transcripts that pathogenesis-associated mutant mitochondrial tRNAs can lead to deficiencies in tRNA 3' end metabolism (3' end cleavage, CCA addition and aminoacylation) toward an understanding of molecular mechanisms underlying human tRNA disorders. These defects probably contribute, individually and cumulatively, to the progression of human mitochondrial diseases.