PDF(Pubmed)
Abstract：
Autosomal dominant tubulointerstitial kidney disease (ADTKD), a rare genetic disorder characterised by progressive chronic kidney disease, is caused by mutations in different genes, including REN, encoding renin. Renin is a secreted protease composed of three domains: the leader peptide that allows insertion in the endoplasmic reticulum (ER), a pro-segment regulating its activity, and the mature part of the protein. Mutations in mature renin lead to ER retention of the mutant protein and to late-onset disease, whereas mutations in the leader peptide, associated with defective ER translocation, and mutations in the pro-segment, leading to accumulation in the ER-to-Golgi compartment, lead to a more severe, early-onset disease. In this study, we demonstrate a common, unprecedented effect of mutations in the leader peptide and pro-segment as they lead to full or partial mistargeting of the mutated proteins to mitochondria. The mutated pre-pro-sequence of renin is necessary and sufficient to drive mitochondrial rerouting, mitochondrial import defect and fragmentation. Mitochondrial localisation and fragmentation were also observed for wild-type renin when ER translocation was affected. These results expand the spectrum of cellular phenotypes associated with ADTKD-associated REN mutations, providing new insight into the molecular pathogenesis of the disease.
摘要：
常染色体显性肾小管间质性肾病(ADTKD),一种罕见的遗传性疾病，以进行性慢性肾病为特征，是由不同基因的突变引起的，包括REN,编码肾素。肾素是由三个结构域组成的分泌蛋白酶：允许插入内质网（ER）的前导肽，调节其活动的亲部门，和蛋白质的成熟部分。成熟肾素的突变导致突变蛋白的ER保留和迟发性疾病，而前导肽的突变，与有缺陷的ER易位相关，和pro-segment中的突变，导致内质网到高尔基间的积累，导致更严重的，早发性疾病。在这项研究中,我们展示了一个共同的，前导肽和pro-segment中的突变产生了前所未有的影响，因为它们导致突变蛋白全部或部分误定到线粒体。肾素的突变前原序列是必要的，足以驱动线粒体重新路由，线粒体进口缺陷和碎片化。当ER易位受到影响时，野生型肾素也观察到线粒体定位和片段化。这些结果扩展了与ADTKD相关的REN突变相关的细胞表型谱，为该疾病的分子发病机制提供了新的见解。
