Mitochondria suppress local feedback activation of inositol 1,4,5-trisphosphate receptors by Ca2+
Mitochondria suppress local feedback activation of inositol 1,4,5-trisphosphate receptors by Ca2+
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DOI：
10.1074/jbc.274.20.14157
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发表时间：
1999-05-14
影响因子：
4.8
通讯作者：
Thomas, AP
中科院分区：
文献类型：
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作者：
Hajnóczky, G;Hager, R;Thomas, AP
1，4，5-三磷酸肌醇（IP 3）和Ca 2+对IP 3受体Ca 2+释放通道（IP 3R）的协同作用是产生胞浆Ca 2+振荡和波的基本步骤，这是许多细胞中Ca 2+信号传导的基础。线粒体似乎与富含IP 3R的内质网（ER）区域密切相关，并且特别响应于IP 3诱导的胞质Ca 2+增加（[Ca 2 +]（c））。为了确定通过释放的Ca 2+对IP 3R的反馈调节是否受到线粒体Ca 2+摄取的调节，通过透化肝细胞中区室化Ca 2+指示剂的荧光成像来检查ER和线粒体Ca 2+池之间的相互作用，IP 3降低管腔ER Ca 2+。（[Ca 2 +]（ER）），并通过线粒体基质Ca 2+（[Ca 2 +]（m））的增加和Ca 2+敏感的线粒体代谢的激活来抑制。值得注意的是，当用钌红或解偶联剂阻断线粒体Ca 2+摄取时，亚最大IP 3诱发的[Ca 2 +]（ER）降低增强。此外，线粒体相对缺乏的亚细胞区域比线粒体密度高的细胞区域对IP 3表现出更大的敏感性。这些数据表明，由线粒体的Ca 2+摄取抑制局部正反馈作用的Ca 2+的IP 3R，引起亚细胞异质性的IP 3敏感性和IP 3R兴奋性。因此，线粒体可以在设定激活阈值和建立IP 3依赖性[Ca 2 +]（c）信号传导的亚细胞模式中发挥重要作用。
The concerted action of inositol 1,4,5-trisphosphate (IP3) and Ca2+ on the IP3 receptor Ca2+ release channel (IP3R) is a fundamental step in the generation of cytosolic Ca2+ oscillations and waves, which underlie Ca2+ signaling in many cells. Mitochondria appear in close association with regions of endoplasmic reticulum (ER) enriched in IP3R and are particularly responsive to IP3-induced increases of cytosolic Ca2+ ([Ca2+](c)). To determine whether feedback regulation of the IP3R by released Ca2+ is modulated by mitochondrial Ca2+ uptake, the interactions between ER and mitochondrial Ca2+ pools were examined by fluorescence imaging of compartmentalized Ca2+ indicators in permeabilized hepatocytes, IP3 decreased luminal ER Ca2+ ([Ca2+](ER)), and this was paralleled by an increase in mitochondrial matrix Ca2+ ([Ca2+](m)) and activation of Ca2+-sensitive mitochondrial metabolism. Remarkably, the decrease in [Ca2+](ER) evoked by submaximal IP3 was enhanced when mitochondrial Ca2+ uptake was blocked with ruthenium red or uncoupler. Moreover, subcellular regions that were relatively deficient in mitochondria demonstrated greater sensitivity to IP3 than regions of the cell with a high density of mitochondria. These data demonstrate that Ca2+ uptake by the mitochondria suppresses the local positive feedback effects of Ca2+ on the IP3R, giving rise to subcellular heterogeneity in IP3 sensitivity and IP3R excitability. Thus, mitochondria can play an important role in setting the threshold for activation and establishing the subcellular pattern of IP3-dependent [Ca2+](c) signaling.