Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU.
Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU.
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DOI：
10.1126/scisignal.2005673
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发表时间：
2015-03-03
影响因子：
7.3
通讯作者：
Madesh M
中科院分区：
文献类型：
--
作者：
Shanmughapriya S;Rajan S;Hoffman NE;Zhang X;Guo S;Kolesar JE;Hines KJ;Ragheb J;Jog NR;Caricchio R;Baba Y;Zhou Y;Kaufman BA;Cheung JY;Kurosaki T;Gill DL;Madesh M
胞内钙信号通过钙离子跨质膜(PM)和内质网(ER)膜的协调转运而产生，介导不同的细胞反应。线粒体Ca~(2+)对线粒体的功能很重要，当细胞内的Ca~(2+)浓度过高时，线粒体就会随着细胞内的Ca~(2+)下沉而发挥作用。通过测量线粒体钙电流，我们发现，缺乏内质网定位的三磷酸肌醇受体(IP3R)和PM定位的钙通透通道复合体Orai1或STIM1的鸡DT40 B淋巴细胞线粒体钙摄取减少。IP3R可以从内质网释放钙离子，Orai1或STIM1是PM定位的钙通透通道复合体的组成部分，在内质网钙库耗尽时，Orai1或STIM1介导存储操作的钙内流(SOCE)。在缺乏IP3R、STIM1或Orai1的细胞中，线粒体钙单一转运体的造孔亚单位MCU的丰度降低。染色质免疫沉淀和启动子报告分析表明，钙离子调控的转录因子CREB直接与MCU启动子结合并刺激表达。缺乏IP3R、STIM1或Orai1的淋巴细胞表现出线粒体代谢的改变，表明从内质网和SOCE介导的信号中释放的钙离子调节线粒体的功能。因此，我们的结果表明，涉及钙依赖的CREB激活的转录调控电路控制着线粒体对钙的摄取能力，从而调节线粒体的代谢。
Cytosolic Ca2+ signals, generated through the coordinated translocation of Ca2+ across the plasma membrane (PM) and endoplasmic reticulum (ER) membrane, mediate diverse cellular responses. Mitochondrial Ca2+ is important for mitochondrial function and, when cytosolic Ca2+ concentrations become too high, mitochondria function as cellular Ca2+ sinks. By measuring mitochondrial Ca2+ currents, we found that mitochondrial Ca2+ uptake was reduced in chicken DT40 B lymphocytes lacking either the ER-localized inositol trisphosphate receptor (IP3R), which releases Ca2+ from the ER, or Orai1 or STIM1, components of the PM-localized Ca2+-permeable channel complex that mediates store-operated calcium entry (SOCE) in response to depletion of ER Ca2+ stores. The abundance of MCU, the pore-forming subunit of the mitochondrial Ca2+ uniporter, was reduced in cells deficient in IP3R, STIM1, or Orai1. Chromatin immunoprecipitation and promoter reporter analyses revealed that the Ca2+-regulated transcription factor CREB directly bound the mcu promoter and stimulated expression. Lymphocytes deficient in IP3R, STIM1, or Orai1 exhibited altered mitochondrial metabolism, indicating that Ca2+ released from the ER and SOCE-mediated signals modulate mitochondrial function. Thus, our results showed that a transcriptional regulatory circuit involving Ca2+-dependent activation of CREB controls the Ca2+-uptake capability of mitochondria and hence regulates mitochondrial metabolism.