Polycystin 2 regulates mitochondrial Ca2+ signaling, bioenergetics, and dynamics through mitofusin 2
Polycystin 2 regulates mitochondrial Ca2+ signaling, bioenergetics, and dynamics through mitofusin 2
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DOI：
10.1126/scisignal.aat7397
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发表时间：
2019-05-07
影响因子：
7.3
通讯作者：
Ehrlich, Barbara E.
中科院分区：
文献类型：
--
作者：
Kuo, Ivana Y.;Brill, Allison L.;Ehrlich, Barbara E.
线粒体和内质网（ER）有密切的功能关系，这是由于拴系蛋白使它们的膜接近（类似于30纳米）。这种细胞器间连接的一个功能是增加Ca2+转移到线粒体的效率，从而刺激线粒体呼吸。在这里，我们发现内质网阳离子渗透通道多囊蛋白2 （PC2）具有减少线粒体-内质网接触的功能。在细胞培养模型中，PC2敲低导致线粒体外膜GTPase - mitofusin 2 （MFN2）表达增加50%。活细胞超分辨率和电镜分析显示，PC2敲低细胞内质网和线粒体之间的mfn2依赖性系链增强。PC2敲低也导致er介导的线粒体Ca2+信号、生物能量激活和线粒体密度增加。编码PC2的基因突变或缺失会导致常染色体显性多囊肾病（ADPKD），这种疾病以大量充满液体的囊肿为特征。在细胞培养模型和肾特异性PC2敲除小鼠中，敲除MFN2可挽救肾囊肿中有缺陷的线粒体Ca2+转移和减少细胞增殖。与这些结果一致，来自人类ADPKD肾脏的囊壁上皮细胞的线粒体和MFN2表达增加了两倍。我们的数据表明，PC2通常在er -线粒体界面限制关键的线粒体蛋白，并作为线粒体生物发生和生物能量学的检查点。这种调节的缺失可能导致ADPKD肾囊肿典型的氧化代谢增加和异常细胞增殖。
Mitochondria and the endoplasmic reticulum (ER) have an intimate functional relationship due to tethering proteins that bring their membranes in close (similar to 30 nm) apposition. One function of this interorganellar junction is to increase the efficiency of Ca2+ transfer into mitochondria, thus stimulating mitochondrial respiration. Here, we showed that the ER cation-permeant channel polycystin 2 (PC2) functions to reduce mitochondria-ER contacts. In cell culture models, PC2 knockdown led to a 50% increase in mitofusin 2 (MFN2) expression, an outer mitochondrial membrane GTPase. Live-cell super-resolution and electron microscopy analyses revealed enhanced MFN2-dependent tethering between the ER and mitochondria in PC2 knockdown cells. PC2 knockdown also led to increased ER-mediated mitochondrial Ca2+ signaling, bioenergetic activation, and mitochondrial density. Mutation or deletion of the gene encoding for PC2 results in autosomal dominant polycystic kidney disease (ADPKD), a condition characterized by numerous fluid-filled cysts. In cell culture models and mice with kidney-specific PC2 knockout, knockdown of MFN2 rescued defective mitochondrial Ca2+ transfer and diminished cell proliferation in kidney cysts. Consistent with these results, cyst-lining epithelial cells from human ADPKD kidneys had a twofold increase in mitochondria and MFN2 expression. Our data suggest that PC2 normally serves to limit key mitochondrial proteins at the ER-mitochondrial interface and acts as a checkpoint for mitochondrial biogenesis and bioenergetics. Loss of this regulation may contribute to the increased oxidative metabolism and aberrant cell proliferation typical of kidney cysts in ADPKD.