线粒体膜通透性转换孔在重编程中的作用和机理研究

Mitochondrial permeability transition pore (mPTP) is a protein pore that is formed through the inner and outer membrane of the mitochondria. It has been reported to play important roles not only in cell survival and apoptosis but also in cancer, aging and neurodegeneration. mPTP has also been shown to be involved in cardiomyocyte differentiation, but its role in cell fate determination is far from clear. Our previous studies found that activation of mPTP opening could improve the reprogramming (Cell Metabolism, 2016). We hypothesize that mPTP enhances reprogramming via the Ca2+, ROS signal or mitochondrial metabolism. In this project, we will investigate the methylation of histone, Calcineurin signaling pathway and mitochondrial oxidative metabolism to study the mechanism of mPTP improved reprogramming. The research includes: (1) the regulation of histone methylation by mPTP; (2) the mechanism of Calcineurin signaling pathway regulated by mPTP; (3) the mechanism of mitochondrial oxidative metabolism regulated by mPTP. Our research will reveal the molecular and subcellular mechanism of mPTP in reprogramming, which clearly describes the novel function of mPTP.

线粒体膜通透性转换孔道（mPTP）是存在于线粒体的内外膜之间的由蛋白复合体组成的非特异性通道。mPTP在细胞的生存、凋亡等细胞活动中扮演着重要角色，它在肿瘤、衰老、神经变性等多个领域中的功能已经有详细的报道，但它在细胞命运转变中的功能除了有报道它能促进心肌分化外其它的机制研究未见报道。在前期的研究中我们发现线粒体mPTP能促进重编程（Cell Metabolism, 2016），我们推测mPTP可能会调控钙氧信号和线粒体代谢从而促进重编程，在本研究中我们将从组蛋白的甲基化修饰，Calcineurin信号通路和线粒体代谢方面进一步研究mPTP促进重编程的机制，包括（1）mPTP促进重编程的组蛋白甲基化调控；（2）mPTP促进重编程的Calcineurin信号通路机制；（3）mPTP促进重编程的线粒体代谢机制。本研究将揭示mPTP促进重编程的调控机制，从而阐述mPTP在细胞命运中的新功能。

线粒体膜通透性转换孔道（mPTP）是存在于线粒体的内外膜之间的由蛋白复合体组成的非特异性通道。mPTP在细胞的生存、凋亡等细胞活动中扮演着重要角色。在前期的研究中我们发现线粒体mPTP能促进重编程，我们分别检测了mPTP开放后线粒体相关通路的激活，细胞核内组蛋白的甲基化和组蛋白甲基化相关酶的表达，我们发现mPTP能通过促进组蛋白H3K9me2和H3K27me3的去甲基化促进重编程，进一步的机制研究发现mPTP的开放能通过线粒体活性氧（ROS）信号促进组蛋白甲基化相关酶PHF8的表达。由于H3K9me2和H3K27me3是重编程的阻碍，降低它们的水平能促进重编程，所以我们的项目揭示了线粒体通透性孔道开放能通过调控表观遗传学促进重编程。