A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter.
A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter.
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内膜的四十千克蛋白是线粒体钙Uniporter。
DOI：
10.1038/nature10230
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发表时间：
2011-06-19
期刊：
影响因子：
64.8
通讯作者：
Rizzuto, Rosario
中科院分区：
文献类型：
--
作者：
De Stefani, Diego;Raffaello, Anna;Teardo, Enrico;Szabo, Ildiko;Rizzuto, Rosario
线粒体钙稳态在有氧代谢和细胞存活的调节中起着关键作用，但钙通道（线粒体钙单向转运体）的分子身份仍然未知。我们已经通过计算机识别出一种蛋白质（命名为MCU），其与MICU1（一种最近表征的单向转运蛋白调节剂）共享组织分布，与单转运蛋白活性共存于胚胎发育中，并且在序列中包括两个跨膜结构域。siRNA沉默HeLa细胞中MCU显著降低线粒体Ca2+摄取。MCU过表达使IP3产生激动剂引起的[Ca2+]mt升高加倍，从而显著缓冲了胞质升高。纯化的MCU蛋白在平面脂质双层中具有通道活性，具有电生理特性和单向转运体的抑制剂敏感性。突变MCU，其中两个带负电荷的残基的推定孔形成区域被替换，没有通道活性和减少激动剂依赖的[Ca2+]mt瞬变时，在HeLa细胞中过表达。总之，这些数据表明，所鉴定的40 kDa蛋白是负责钌红敏感性线粒体Ca2+摄取的通道，从而为该过程提供了最大生理和病理相关性的分子基础。
Mitochondrial Ca2+ homeostasis plays a key role in the regulation of aerobic metabolism and cell survival, but the molecular identity of the Ca2+ channel, the mitochondrial calcium uniporter, was still unknown. We have identified in silico a protein (denominated MCU) that shares tissue distribution with MICU1, a recently characterized uniporter regulator, coexists with uniporter activity in phylogeny and includes two trasmembrane domains in the sequence. siRNA silencing of MCU in HeLa cells drastically reduced mitochondrial Ca2+ uptake. MCU overexpression doubled the [Ca2+]mt rise evoked by IP3-generating agonists, thus significantly buffering the cytosolic elevation. The purified MCU protein exhibited channel activity in planar lipid bilayers, with electrophysiological properties and inhibitor sensitivity of the uniporter. A mutant MCU, in which two negatively-charged residues of the putative pore forming region were replaced, had no channel activity and reduced agonist-dependent [Ca2+]mt transients when overexpressed in HeLa cells. Overall, these data demonstrate that the identified 40 kDa protein is the channel responsible for Ruthenium Red-sensitive mitochondrial Ca2+ uptake, thus providing molecular basis for this process of utmost physiological and pathological relevance.
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影响因子：
11.4
作者：
Csordás, G;Thomas, AP;Hajnóczky, G
通讯作者：
Hajnóczky, G
DOI：
10.1083/jcb.145.4.795
发表时间：
1999-05-17
期刊：
The Journal of cell biology
影响因子：
--
作者：
Boitier E;Rea R;Duchen MR
通讯作者：
Duchen MR
影响因子：
11.4
作者：
Pacher, P;Hajnóczky, G
通讯作者：
Hajnóczky, G
影响因子：
12.4
作者：
Szabo, I.;Soddemann, M.;Gulbins, E.
通讯作者：
Gulbins, E.
影响因子：
11.4
作者：
Tinel, H;Cancela, JM;Petersen, OH
通讯作者：
Petersen, OH