ATP13A2 regulates mitochondrial bioenergetics through macroautophagy.
ATP13A2 regulates mitochondrial bioenergetics through macroautophagy.
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DOI：
10.1016/j.nbd.2011.12.015
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发表时间：
2012-03
影响因子：
6.1
通讯作者：
Chu, Charleen T.
中科院分区：
文献类型：
--
作者：
Gusdon, Aaron M.;Zhu, Jianhui;Van Houten, Bennett;Chu, Charleen T.
关键词：
线粒体功能障碍和自噬是帕金森病（PD）的中心环节。ATP 13 A2编码一种功能未知的溶酶体P型ATP酶，其突变可引起一种罕见的常染色体隐性帕金森综合征。溶酶体对于自噬是必不可少的，并且功能障碍的线粒体的自噬清除代表线粒体质量控制的重要元素。在这项研究中，我们验证了ATP 13 A2功能丧失会影响线粒体功能的假设。敲除ATP 13 A2导致原代小鼠皮质神经元和SH-SY 5 Y细胞中线粒体质量增加，迫使其进入线粒体依赖性。ATP 13 A2缺陷细胞表现出增加的耗氧量，而ATP的稳态水平没有显着变化。敲除细胞中的线粒体表现出增加的碎片化和增加的活性氧（ROS）的产生。自噬体标志物LC 3-II的基础水平没有显著变化，然而，ATP 13 A2敲低细胞表现出自噬通量降低，与磷酸化mTOR水平增加相关，并且对雷帕霉素诱导的自噬具有抗性。ATP 13 A2 siRNA对耗氧量、线粒体质量和ROS产生的影响可以通过使用针对Atg 7的siRNA抑制自噬诱导来模拟。我们认为ATP 13 A2缺乏导致的自噬减少会影响线粒体的质量控制，导致ROS产生增加。这些数据是第一个涉及线粒体维持和氧化应激中ATP 13 A2功能丧失的数据，进一步支持了PD发病机制中线粒体失调的遗传和环境证据。
Mitochondrial dysfunction and autophagy are centrally implicated in Parkinson’s disease (PD). Mutations in ATP13A2, which encodes a lysosomal P-type ATPase of unknown function, cause a rare, autosomal recessive parkinsonian syndrome. Lysosomes are essential for autophagy, and autophagic clearance of dysfunctional mitochondria represents an important element of mitochondrial quality control. In this study, we tested the hypothesis that loss of ATP13A2 function will affect mitochondrial function. Knockdown of ATP13A2 led to an increase in mitochondrial mass in primary mouse cortical neurons and SH-SY5Y cells forced into mitochondrial dependence. ATP13A2-deficient cells exhibited increased oxygen consumption without a significant change in steady-state levels of ATP. Mitochondria in knockdown cells exhibited increased fragmentation and increased production of reactive oxygen species (ROS). Basal levels of the autophagosome marker LC3-II were not significantly changed, however, ATP13A2 knockdown cells exhibited decreased autophagic flux, associated with increased levels of phospho-mTOR, and resistance to autophagy induction by rapamycin. The effects of ATP13A2 siRNA on oxygen consumption, mitochondrial mass and ROS production could be mimicked by inhibiting autophagy induction using siRNA to Atg7. We propose that decreased autophagy associated with ATP13A2 deficiency affects mitochondrial quality control, resulting in increased ROS production. These data are the first to implicate loss of ATP13A2 function in mitochondrial maintenance and oxidative stress, lending further support to converging genetic and environmental evidence for mitochondrial dysregulation in PD pathogenesis.
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影响因子：
56.9
作者：
Dennis, PB;Jaeschke, A;Thomas, G
通讯作者：
Thomas, G
DOI：
10.1083/jcb.201002108
发表时间：
2010-08-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cherra SJ 3rd;Kulich SM;Uechi G;Balasubramani M;Mountzouris J;Day BW;Chu CT
通讯作者：
Chu CT
影响因子：
5
作者：
Cherra SJ 3rd;Dagda RK;Chu CT
通讯作者：
Chu CT
影响因子：
12.4
作者：
通讯作者：
--
影响因子：
3.9
作者：
Axelsen, KB;Palmgren, MG
通讯作者：
Palmgren, MG