Mitochondrial DNA transcription and translation: clinical syndromes.
Mitochondrial DNA transcription and translation: clinical syndromes.
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DOI：
10.1042/ebc20170103
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发表时间：
2018-07-20
影响因子：
6.4
通讯作者：
Horvath R
中科院分区：
文献类型：
--
作者：
Boczonadi V;Ricci G;Horvath R
诊断原发性线粒体疾病在临床实践中具有挑战性。虽然氧化磷酸化缺陷（OXPHOS）是常见的最终途径，但尚不清楚为什么不同的mtDNA或核突变会导致很大程度上异质性和组织特异性的临床表现。线粒体tRNA （mt-tRNA）突变是儿童和成人线粒体疾病的常见原因。然而，据报道，许多涉及线粒体蛋白合成的核突变影响了无处不在的表达基因，并与非常组织特异性的临床表现相关，这表明迄今为止仍有未知因素决定线粒体翻译的组织特异性。这些基因缺陷大多导致组织学异常和受影响器官的多重呼吸链缺陷。临床表型通常是早发的，严重的，往往是致命的，这意味着线粒体翻译的重要性从出生开始。然而，一些罕见的、可逆性的婴儿线粒体疾病是由非常特殊的线粒体翻译缺陷引起的。无偏见的遗传方法（全外显子组测序，RNA测序）结合蛋白质组学和功能研究揭示了线粒体翻译的新因素，这些因素有助于这些罕见的可逆线粒体疾病的临床表现和恢复。
Diagnosing primary mitochondrial diseases is challenging in clinical practice. Although, defective oxidative phosphorylation (OXPHOS) is the common final pathway, it is unknown why different mtDNA or nuclear mutations result in largely heterogeneous and often tissue -specific clinical presentations. Mitochondrial tRNA (mt-tRNA) mutations are frequent causes of mitochondrial diseases both in children and adults. However numerous nuclear mutations involved in mitochondrial protein synthesis affecting ubiquitously expressed genes have been reported in association with very tissue specific clinical manifestations suggesting that there are so far unknown factors determining the tissue specificity in mitochondrial translation. Most of these gene defects result in histological abnormalities and multiple respiratory chain defects in the affected organs. The clinical phenotypes are usually early-onset, severe, and often fatal, implying the importance of mitochondrial translation from birth. However, some rare, reversible infantile mitochondrial diseases are caused by very specific defects of mitochondrial translation. An unbiased genetic approach (whole exome sequencing, RNA sequencing) combined with proteomics and functional studies revealed novel factors involved in mitochondrial translation which contribute to the clinical manifestation and recovery in these rare reversible mitochondrial conditions.