Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Research Programs Unit-Molecular Neurology, University of Helsinki, Helsinki, Finland.
Life Sci Alliance. 2019 Jan 25;2(1). doi: 10.26508/lsa.201800219. Print 2019 Feb.
Mitochondria have a compartmentalized gene expression system dedicated to the synthesis of membrane proteins essential for oxidative phosphorylation. Responsive quality control mechanisms are needed to ensure that aberrant protein synthesis does not disrupt mitochondrial function. Pathogenic mutations that impede the function of the mitochondrial matrix quality control protease complex composed of AFG3L2 and paraplegin cause a multifaceted clinical syndrome. At the cell and molecular level, defects to this quality control complex are defined by impairment to mitochondrial form and function. Here, we establish the etiology of these phenotypes. We show how disruptions to the quality control of mitochondrial protein synthesis trigger a sequential stress response characterized first by OMA1 activation followed by loss of mitochondrial ribosomes and by remodelling of mitochondrial inner membrane ultrastructure. Inhibiting mitochondrial protein synthesis with chloramphenicol completely blocks this stress response. Together, our data establish a mechanism linking major cell biological phenotypes of AFG3L2 pathogenesis and show how modulation of mitochondrial protein synthesis can exert a beneficial effect on organelle homeostasis.
线粒体具有一个分隔的基因表达系统，专门用于合成氧化磷酸化所必需的膜蛋白。需要有响应性的质量控制机制来确保异常的蛋白质合成不会破坏线粒体功能。妨碍由 AFG3L2 和 paraplegin 组成的线粒体基质质量控制蛋白酶复合物功能的致病性突变会导致多种临床表现综合征。在细胞和分子水平上，该质量控制复合物的缺陷表现为线粒体形态和功能的损伤。在这里，我们确定了这些表型的病因。我们展示了线粒体蛋白质合成的质量控制如何受到干扰，引发了一系列应激反应，其特征首先是 OMA1 的激活，随后是线粒体核糖体的丧失，以及线粒体内膜超微结构的重塑。用氯霉素抑制线粒体蛋白质合成可以完全阻断这种应激反应。总之，我们的数据建立了一种机制，将 AFG3L2 发病的主要细胞生物学表型联系起来，并展示了如何调节线粒体蛋白质合成可以对细胞器稳态产生有益的影响。
