Loss of DJ-1 does not affect mitochondrial respiration but increases ROS production and mitochondrial permeability transition pore opening.
Loss of DJ-1 does not affect mitochondrial respiration but increases ROS production and mitochondrial permeability transition pore opening.
复制标题
DOI：
10.1371/journal.pone.0040501
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Shen J
中科院分区：
文献类型：
--
作者：
Giaime E;Yamaguchi H;Gautier CA;Kitada T;Shen J
DJ-1 基因的功能缺失突变与隐性遗传的帕金森症有关。线粒体功能障碍和氧化应激增加被认为是帕金森病发病机制中的关键事件。尽管有报道称 DJ-1 通过氧化其半胱氨酸残基而充当活性氧化物质 (ROS) 的清除剂，但 DJ-1 的缺失如何影响线粒体功能尚不清楚。使用原代小鼠胚胎成纤维细胞（MEF）或 DJ-1−/− 小鼠的大脑，我们发现 DJ-1 的缺失不会影响线粒体呼吸。具体而言，在完整的 DJ-1−/− MEF 中，内源性呼吸活动以及基础和最大呼吸是正常的，并且在透化的 DJ-1−/− MEF 中以及从 3 个月或 2 岁的 DJ-1−/− 小鼠大脑皮层分离的线粒体中，底物特异性状态 3 和状态 4 线粒体呼吸也不受影响。组成电子传递系统的所有单个复合物的表达水平和活性均未改变，但 DJ-1−/− MEF 中 ATP 的产生减少。在没有 DJ-1 的情况下，线粒体跨膜电位会降低。此外，DJ-1−/− 细胞中线粒体通透性过渡孔开放增加，而线粒体钙水平未改变。与之前的报道一致，活性氧（ROS）的产生增加，但抗氧化酶的水平没有改变。有趣的是，DJ-1−/− MEF 中线粒体跨膜电位降低和线粒体通透性过渡孔开放增加可以通过抗氧化处理来恢复，而氧化应激诱导剂对线粒体跨膜电位和线粒体通透性过渡孔开放具有相反的影响。我们的研究表明，DJ-1 的缺失不会影响线粒体呼吸或线粒体钙水平，但会增加 ROS 的产生，导致线粒体通透性过渡孔开放升高并降低线粒体跨膜电位。
Loss of function mutations in the DJ-1 gene have been linked to recessively inherited forms of Parkinsonism. Mitochondrial dysfunction and increased oxidative stress are thought to be key events in the pathogenesis of Parkinson’s disease. Although it has been reported that DJ-1 serves as scavenger for reactive oxidative species (ROS) by oxidation on its cysteine residues, how loss of DJ-1 affects mitochondrial function is less clear. Using primary mouse embryonic fibroblasts (MEFs) or brains from DJ-1−/− mice, we found that loss of DJ-1 does not affect mitochondrial respiration. Specifically, endogenous respiratory activity as well as basal and maximal respiration are normal in intact DJ-1−/− MEFs, and substrate-specific state 3 and state 4 mitochondrial respiration are also unaffected in permeabilized DJ-1−/− MEFs and in isolated mitochondria from the cerebral cortex of DJ-1−/− mice at 3 months or 2 years of age. Expression levels and activities of all individual complexes composing the electron transport system are unchanged, but ATP production is reduced in DJ-1−/− MEFs. Mitochondrial transmembrane potential is decreased in the absence of DJ-1. Furthermore, mitochondrial permeability transition pore opening is increased, whereas mitochondrial calcium levels are unchanged in DJ-1−/− cells. Consistent with earlier reports, production of reactive oxygen species (ROS) is increased, though levels of antioxidative enzymes are unaltered. Interestingly, the decreased mitochondrial transmembrane potential and the increased mitochondrial permeability transition pore opening in DJ-1−/− MEFs can be restored by antioxidant treatment, whereas oxidative stress inducers have the opposite effects on mitochondrial transmembrane potential and mitochondrial permeability transition pore opening. Our study shows that loss of DJ-1 does not affect mitochondrial respiration or mitochondrial calcium levels but increases ROS production, leading to elevated mitochondrial permeability transition pore opening and reduced mitochondrial transmembrane potential.
登录
查看更多内容
DOI：
10.1073/pnas.0911175107
发表时间：
2010-05-25
影响因子：
11.1
作者：
Hao, Ling-Yang;Giasson, Benoit I.;Bonini, Nancy M.
通讯作者：
Bonini, Nancy M.
影响因子：
56.9
作者：
Bonifati, V;Rizzu, P;Heutink, P
通讯作者：
Heutink, P
DOI：
10.1073/pnas.0607260103
发表时间：
2006-10-10
影响因子：
11.1
作者：
Clements, Casey M.;McNally, Richard S.;Ting, Jenny P-Y.
通讯作者：
Ting, Jenny P-Y.
DOI：
10.1007/978-1-59745-365-3_29
发表时间：
2007-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Frezza, Christian;Cipolat, Sara;Scorrano, Luca
通讯作者：
Scorrano, Luca
影响因子：
8.6
作者：
Cookson, Mark R.
通讯作者：
Cookson, Mark R.