Telethon Kids Institute, Northern Entrance, Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA 6009, Australia.
Harry Perkins Institute of Medical Research, 6 Verdun Street, Nedlands, WA 6009, Australia.
Hum Mol Genet. 2024 May 22;33(R1):R61-R79. doi: 10.1093/hmg/ddae020.
Mitochondria are hubs of metabolic activity with a major role in ATP conversion by oxidative phosphorylation (OXPHOS). The mammalian mitochondrial genome encodes 11 mRNAs encoding 13 OXPHOS proteins along with 2 rRNAs and 22 tRNAs, that facilitate their translation on mitoribosomes. Maintaining the internal production of core OXPHOS subunits requires modulation of the mitochondrial capacity to match the cellular requirements and correct insertion of particularly hydrophobic proteins into the inner mitochondrial membrane. The mitochondrial translation system is essential for energy production and defects result in severe, phenotypically diverse diseases, including mitochondrial diseases that typically affect postmitotic tissues with high metabolic demands. Understanding the complex mechanisms that underlie the pathologies of diseases involving impaired mitochondrial translation is key to tailoring specific treatments and effectively targeting the affected organs. Disease mutations have provided a fundamental, yet limited, understanding of mitochondrial protein synthesis, since effective modification of the mitochondrial genome has proven challenging. However, advances in next generation sequencing, cryoelectron microscopy, and multi-omic technologies have revealed unexpected and unusual features of the mitochondrial protein synthesis machinery in the last decade. Genome editing tools have generated unique models that have accelerated our mechanistic understanding of mitochondrial translation and its physiological importance. Here we review the most recent mouse models of disease pathogenesis caused by defects in mitochondrial protein synthesis and discuss their value for preclinical research and therapeutic development.
线粒体是代谢活动的中心，在氧化磷酸化（OXPHOS）中起着将 ATP 转化的主要作用。哺乳动物的线粒体基因组编码 11 种 mRNA，编码 13 种 OXPHOS 蛋白，以及 2 种 rRNA 和 22 种 tRNA，这些 RNA 有助于在线粒体核糖体上翻译。维持核心 OXPHOS 亚基的内部产生需要调节线粒体的能力，以匹配细胞的需求，并将特别疏水性的蛋白质正确插入线粒体内膜。线粒体翻译系统对于能量产生是必不可少的，缺陷会导致严重的、表型多样的疾病，包括通常影响有高代谢需求的有丝分裂后组织的线粒体疾病。了解导致线粒体翻译受损的疾病的病理学的复杂机制是制定特定治疗方法和有效靶向受影响器官的关键。疾病突变为线粒体蛋白合成的病理学提供了基本但有限的理解，因为有效修饰线粒体基因组已被证明具有挑战性。然而，下一代测序、冷冻电子显微镜和多组学技术的进步在过去十年中揭示了线粒体蛋白合成机制的意想不到和不寻常的特征。基因组编辑工具已经产生了独特的模型，这些模型加速了我们对线粒体翻译及其生理重要性的机制理解。在这里，我们回顾了由线粒体蛋白合成缺陷引起的疾病发病机制的最新小鼠模型，并讨论了它们在临床前研究和治疗开发中的价值。
