MRC Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building Hills Road, Cambridge CB2 0XY, UK.
Istituto Neurologico "Casimiro Mondino," via Mondino 2, Pavia 27100, Italy.
Mol Cell. 2017 Jul 6;67(1):96-105.e4. doi: 10.1016/j.molcel.2017.06.001. Epub 2017 Jun 29.
Loss-of-function mutations in TTC19 (tetra-tricopeptide repeat domain 19) have been associated with severe neurological phenotypes and mitochondrial respiratory chain complex III deficiency. We previously demonstrated the mitochondrial localization of TTC19 and its link with complex III biogenesis. Here we provide detailed insight into the mechanistic role of TTC19, by investigating a Ttc19 mouse model that shows progressive neurological and metabolic decline, decreased complex III activity, and increased production of reactive oxygen species. By using both the Ttc19 mouse model and a range of human cell lines, we demonstrate that TTC19 binds to the fully assembled complex III dimer, i.e., after the incorporation of the iron-sulfur Rieske protein (UQCRFS1). The in situ maturation of UQCRFS1 produces N-terminal polypeptides, which remain bound to holocomplex III. We show that, in normal conditions, these UQCRFS1 fragments are rapidly removed, but when TTC19 is absent they accumulate within complex III, causing its structural and functional impairment.
TTC19（四聚体重复结构域 19）功能丧失突变与严重的神经表型和线粒体呼吸链复合物 III 缺陷有关。我们之前证明了 TTC19 的线粒体定位及其与复合物 III 生物发生的联系。在这里，我们通过研究一种表现出进行性神经和代谢衰退、复合物 III 活性降低以及活性氧产生增加的 Ttc19 小鼠模型，详细研究了 TTC19 的作用机制。通过使用 Ttc19 小鼠模型和一系列人类细胞系，我们证明 TTC19 与完全组装的复合物 III 二聚体结合，即在铁硫 Rieske 蛋白（UQCRFS1）掺入之后。UQCRFS1 的原位成熟产生与全酶复合物 III 结合的 N 端多肽。我们表明，在正常条件下，这些 UQCRFS1 片段会迅速被去除，但当 TTC19 缺失时，它们会在复合物 III 内积累，导致其结构和功能受损。
