Mitochondrial Ca2+ uptake contributes to buffering cytoplasmic Ca2+ peaks in cardiomyocytes
Mitochondrial Ca2+ uptake contributes to buffering cytoplasmic Ca2+ peaks in cardiomyocytes
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DOI：
10.1073/pnas.1210718109
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发表时间：
2012-08-07
影响因子：
11.1
通讯作者：
Pozzan, Tullio
中科院分区：
文献类型：
--
作者：
Drago, Ilaria;De Stefani, Diego;Pozzan, Tullio
线粒体塑造Ca 2+信号的能力已在大量细胞类型中得到证实，但在心脏细胞中仍有争议。在这里，我们利用线粒体Ca 2+单向转运体（MCU）和独特的靶向Ca 2+探针的分子鉴定直接解决这个问题。我们证明，在自发的钙离子起搏，Ca 2+峰值上的外线粒体膜（OMM）是远远大于在细胞质中，因为大量的Ca 2+热点上产生的OMM表面。细胞质Ca 2+峰分别通过MCU过表达和siRNA沉默降低或增强;相反的情况发生在线粒体基质内。因此，收缩的程度通过MCU的过表达而降低，并通过其下调而增强。MCU水平的调节不影响心肌细胞的ATP含量。因此，在新生心肌细胞中，线粒体显著有助于缓冲收缩期Ca 2+升高的幅度。
Mitochondrial ability of shaping Ca2+ signals has been demonstrated in a large number of cell types, but it is still debated in heart cells. Here, we take advantage of the molecular identification of the mitochondrial Ca2+ uniporter (MCU) and of unique targeted Ca2+ probes to directly address this issue. We demonstrate that, during spontaneous Ca2+ pacing, Ca2+ peaks on the outer mitochondrial membrane (OMM) are much greater than in the cytoplasm because of a large number of Ca2+ hot spots generated on the OMM surface. Cytoplasmic Ca2+ peaks are reduced or enhanced by MCU overexpression and siRNA silencing, respectively; the opposite occurs within the mitochondrial matrix. Accordingly, the extent of contraction is reduced by overexpression of MCU and augmented by its down-regulation. Modulation of MCU levels does not affect the ATP content of the cardiomyocytes. Thus, in neonatal cardiac myocytes, mitochondria significantly contribute to buffering the amplitude of systolic Ca2+ rises.