International Institute of Molecular and Cell Biology, Warsaw, Poland.
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
PLoS Genet. 2018 Nov 20;14(11):e1007743. doi: 10.1371/journal.pgen.1007743. eCollection 2018 Nov.
Development and function of tissues and organs are powered by the activity of mitochondria. In humans, inherited genetic mutations that lead to progressive mitochondrial pathology often manifest during infancy and can lead to death, reflecting the indispensable nature of mitochondrial biogenesis and function. Here, we describe a zebrafish mutant for the gene mia40a (chchd4a), the life-essential homologue of the evolutionarily conserved Mia40 oxidoreductase which drives the biogenesis of cysteine-rich mitochondrial proteins. We report that mia40a mutant animals undergo progressive cellular respiration defects and develop enlarged mitochondria in skeletal muscles before their ultimate death at the larval stage. We generated a deep transcriptomic and proteomic resource that allowed us to identify abnormalities in the development and physiology of endodermal organs, in particular the liver and pancreas. We identify the acinar cells of the exocrine pancreas to be severely affected by mutations in the MIA pathway. Our data contribute to a better understanding of the molecular, cellular and organismal effects of mitochondrial deficiency, important for the accurate diagnosis and future treatment strategies of mitochondrial diseases.
组织和器官的发育和功能是由线粒体的活动提供动力的。在人类中，导致进行性线粒体病变的遗传基因突变通常在婴儿期表现出来，并可能导致死亡，这反映了线粒体生物发生和功能的不可或缺性。在这里，我们描述了一种斑马鱼 mia40a（chchd4a）基因的突变体，mia40a 是进化上保守的 Mia40 氧化还原酶的必需同源物，该酶驱动富含半胱氨酸的线粒体蛋白的生物发生。我们报告说，mia40a 突变体动物在幼虫期最终死亡之前经历进行性细胞呼吸缺陷，并在骨骼肌中发育出增大的线粒体。我们生成了一个深度转录组和蛋白质组资源，使我们能够识别内胚层器官（特别是肝脏和胰腺）发育和生理学的异常。我们发现，外分泌胰腺的腺泡细胞受到 MIA 途径突变的严重影响。我们的数据有助于更好地理解线粒体缺陷的分子、细胞和机体效应，这对于线粒体疾病的准确诊断和未来的治疗策略非常重要。
