Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
PLoS Genet. 2011 Apr;7(4):e1001379. doi: 10.1371/journal.pgen.1001379. Epub 2011 Apr 21.
About half of the mitochondrial DNA (mtDNA) mutations causing diseases in humans occur in tRNA genes. Particularly intriguing are those pathogenic tRNA mutations than can reach homoplasmy and yet show very different penetrance among patients. These mutations are scarce and, in addition to their obvious interest for understanding human pathology, they can be excellent experimental examples to model evolution and fixation of mitochondrial tRNA mutations. To date, the only source of this type of mutations is human patients. We report here the generation and characterization of the first mitochondrial tRNA pathological mutation in mouse cells, an m.3739G>A transition in the mitochondrial mt-Ti gene. This mutation recapitulates the molecular hallmarks of a disease-causing mutation described in humans, an m.4290T>C transition affecting also the human mt-Ti gene. We could determine that the pathogenic molecular mechanism, induced by both the mouse and the human mutations, is a high frequency of abnormal folding of the tRNA(Ile) that cannot be charged with isoleucine. We demonstrate that the cells harboring the mouse or human mutant tRNA have exacerbated mitochondrial biogenesis triggered by an increase in mitochondrial ROS production as a compensatory response. We propose that both the nature of the pathogenic mechanism combined with the existence of a compensatory mechanism can explain the penetrance pattern of this mutation. This particular behavior can allow a scenario for the evolution of mitochondrial tRNAs in which the fixation of two alleles that are individually deleterious can proceed in two steps and not require the simultaneous mutation of both.
约有一半导致人类疾病的线粒体 DNA（mtDNA）突变发生在 tRNA 基因中。特别有趣的是那些能够达到同质的致病性 tRNA 突变，但在患者中表现出非常不同的外显率。这些突变很少见，除了对理解人类病理学的明显兴趣外，它们还可以成为很好的实验范例，用于模拟线粒体 tRNA 突变的进化和固定。迄今为止，这种类型的突变的唯一来源是人类患者。我们在这里报告了第一个在小鼠细胞中产生和表征的线粒体 tRNA 病理性突变，即线粒体 mt-Ti 基因中的 m.3739G>A 转换。该突变重现了在人类中描述的致病突变的分子特征，即 m.4290T>C 转换也影响了人类 mt-Ti 基因。我们可以确定，由小鼠和人类突变引起的致病分子机制是 tRNA（Ile）异常折叠的高频，无法用异亮氨酸进行充电。我们证明，携带小鼠或人类突变 tRNA 的细胞具有加剧的线粒体生物发生，这是由线粒体 ROS 产生增加作为补偿性反应引起的。我们提出，致病机制的性质与存在补偿机制可以解释这种突变的外显率模式。这种特殊的行为可以为线粒体 tRNAs 的进化提供一种情景，其中两个单独有害的等位基因的固定可以分两步进行，而不需要同时突变两个等位基因。
