Enhanced parkin levels favor ER-mitochondria crosstalk and guarantee Ca2+ transfer to sustain cell bioenergetics
Enhanced parkin levels favor ER-mitochondria crosstalk and guarantee Ca2+ transfer to sustain cell bioenergetics
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DOI：
10.1016/j.bbadis.2013.01.004
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发表时间：
2013-04-01
影响因子：
6.2
通讯作者：
Brini, Marisa
中科院分区：
文献类型：
--
作者：
Cali, Tito;Ottolini, Denis;Brini, Marisa
PINK 1或parkin基因的功能缺失突变与帕金森病的青少年发病常染色体隐性形式相关许多研究已经确定PINK 1和parkin参与共同的细胞质量控制途径，通过线粒体自噬促进功能障碍的线粒体的选择性降解。parkin mRNA和蛋白水平的上调已被提出作为对抗线粒体和内质网（ER）应激的保护机制。为了更好地理解parkin如何发挥保护功能，我们考虑了它可以调节ER-线粒体细胞器间串扰的可能性。为了验证这一假设，我们研究了parkin过表达对ER-线粒体串扰的影响，涉及两个关键细胞参数的调节：Ca 2+稳态和ATP产生。我们的研究结果表明，parkin在模型细胞中的过表达在物理上和功能上增强了ER-线粒体偶联，有利于在用1，4，5-三磷酸肌醇（InsP（3））产生激动剂刺激细胞后Ca 2+从ER转移到线粒体，并增加激动剂诱导的ATP产生。缺乏前79个残基的parkin突变体（Delta Ubl）的过表达未能增强线粒体Ca 2+瞬变，从而突出了N-末端泛素样结构域对于所观察到的表型的重要性。siRNA介导的parkin沉默导致线粒体片段化，损害线粒体Ca 2+处理并减少ER-线粒体束缚。这些数据支持帕金在生理条件下调节线粒体稳态、Ca 2+信号和能量代谢中的新作用。(C)2013爱思唯尔有限公司版权所有。
Loss-of-function mutations in PINK1 or parkin genes are associated with juvenile-onset autosomal recessive forms of Parkinson disease. Numerous studies have established that PINK1 and parkin participate in a common mitochondrial-quality control pathway, promoting the selective degradation of dysfunctional mitochondria by mitophagy. Upregulation of parkin mRNA and protein levels has been proposed as protective mechanism against mitochondrial and endoplasmic reticulum (ER) stress. To better understand how parkin could exert protective function we considered the possibility that it could modulate the ER-mitochondria inter-organelles cross talk. To verify this hypothesis we investigated the effects of parkin overexpression on ER-mitochondria crosstalk with respect to the regulation of two key cellular parameters: Ca2+ homeostasis and ATP production. Our results indicate that parkin overexpression in model cells physically and functionally enhanced ER-mitochondria coupling, favored Ca2+ transfer from the ER to the mitochondria following cells stimulation with an 1,4,5 inositol trisphosphate (InsP(3)) generating agonist and increased the agonist-induced ATP production. The overexpression of a parkin mutant lacking the first 79 residues (Delta Ubl) failed to enhance the mitochondrial Ca2+ transients, thus highlighting the importance of the N-terminal ubiquitin like domain for the observed phenotype. siRNA-mediated parkin silencing caused mitochondrial fragmentation, impaired mitochondrial Ca2+ handling and reduced the ER-mitochondria tethering. These data support a novel role for parkin in the regulation of mitochondrial homeostasis, Ca2+ signaling and energy metabolism under physiological conditions. (C) 2013 Elsevier B.V. All rights reserved.