Mitochondrial membrane potential decrease caused by loss of PINK1 is not due to proton leak, but to respiratory chain defects
Mitochondrial membrane potential decrease caused by loss of PINK1 is not due to proton leak, but to respiratory chain defects
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DOI：
10.1016/j.nbd.2010.08.027
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发表时间：
2011-01-01
影响因子：
6.1
通讯作者：
Hattori, Nobutaka
中科院分区：
文献类型：
--
作者：
Amo, Taku;Sato, Shigeto;Hattori, Nobutaka
pten诱导的推定激酶1 （PINK1）突变导致隐性帕金森病（PD）。PINK1与线粒体质量控制有关，其部分敲除可诱导线粒体功能障碍，包括膜电位下降和对线粒体毒素的易感性增加，但PINK1在线粒体中的确切功能尚未在PINK1零表达的细胞中进行研究。在这里，我们证明PINK1的丢失导致线粒体！功能障碍。PINK1缺陷（PINK1(-/-)）小鼠胚胎成纤维细胞（mef）与野生型mef相比，线粒体膜电位和细胞ATP水平降低。然而，在没有ATP合成的情况下，线粒体质子泄漏会降低膜电位，而PINK1的缺失并未改变线粒体质子泄漏。相反，通过氧气氧化底物而产生膜电位的呼吸链活性下降。由于耗氧速率降低，PINK1（-/-）线粒体的H2O2产率低于PINK1（+/+）线粒体，而H2O2产率比PINK1（+/+）线粒体高。这些结果表明，帕金森病的线粒体功能障碍不是由质子泄漏引起的，而是由呼吸链缺陷引起的。(C) 2010爱思唯尔公司版权所有。
Mutations in PTEN-induced putative kinase 1 (PINK1) cause a recessive format Parkinson's disease (PD). PINK1 is associated with mitochondrial quality control and its partial knock-down induces mitochondrial dysfunction including decreased membrane potential and increased vulnerability against mitochondrial toxins, but the exact function of PINK1 in mitochondria has not been investigated using cells with null expression of PINK1. Here, we show that loss of PINK1 caused mitochondria! dysfunction. In PINK1-deficient (PINK1(-/-)) mouse embryonic fibroblasts (MEFs), mitochondrial membrane potential and cellular ATP levels were decreased compared with those in littermate wild-type MEFs. However, mitochondrial proton leak, which reduces membrane potential in the absence of ATP synthesis, was not altered by loss of PINK1. Instead, activity of the respiratory chain, which produces the membrane potential by oxidizing substrates using oxygen, declined. H2O2 production rate by PINK1(-/-) mitochondria was lower than PINK1(+/+) mitochondria as a consequence of decreased oxygen consumption rate, while the proportion (H2O2 production rate per oxygen consumption rate) was higher. These results suggest that mitochondrial dysfunctions in PD pathogenesis are caused not by proton leak, but by respiratory chain defects. (C) 2010 Elsevier Inc. All rights reserved.