Mitochondrial Omi/HtrA2 Promotes Caspase Activation Through Cleavage of HAX-1 in Aging Heart
Mitochondrial Omi/HtrA2 Promotes Caspase Activation Through Cleavage of HAX-1 in Aging Heart
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线粒体 Omi/HtrA2 通过切割老化心脏中的 HAX-1 促进 Caspase 激活
DOI：
10.1089/rej.2016.1861
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发表时间：
2017-06-01
影响因子：
2.6
通讯作者：
Liu, Huirong
中科院分区：
文献类型：
--
作者：
Liu, Xin;Lei, Jinghui;Liu, Huirong
线粒体稳态是细胞命运和器官功能的关键过程。当线粒体状态异常时，它就会成为一个“死亡马达”。受损的线粒体会导致细胞色素c的释放，然后触发caspase诱导的caspase激活。Omi/HtrA 2是一种丝氨酸蛋白酶，位于线粒体中，参与线粒体稳态。在衰老的心脏组织中观察到Omi/HtrA 2增加，并且这是否对线粒体状态有影响尚未报道。在本研究中，使用天然Sprague-Dawley大鼠（22个月）。心肌细胞Omi/HtrA 2蛋白水解活性明显增强，caspase-9和caspase-3活性明显激活。构建稳定转染线粒体的Omi/HtrA 2细胞，用JC-1（线粒体探针）和四甲基罗丹明甲酯（TMRM）染色检测线粒体膜电位的降低，分离线粒体组分和胞浆组分后观察到细胞色素c的显著释放。Omi/HtrA 2特异性抑制剂ucf-101和HAX-1 siRNA可改善上述现象。总之，线粒体中过量的Omi/HtrA 2通过其蛋白水解活性诱导线粒体膜电位降低，随后细胞色素c从线粒体释放到细胞质中，其中细胞色素c促进caspase活化。Omi/HtrA 2-HAX-1链在线粒体内环境稳定中起重要作用。
Mitochondrial homeostasis is a key process involved in cellular destiny and organic function. When mitochondrial status is abnormal, it will become a "death motor.'' Impaired mitochondria lead to the release of cytochrome c, and then trigger mitochondria-induced caspase activation. Omi/HtrA2, a serine protease, locates in mitochondria and involves in mitochondrial homeostasis. Increased Omi/HtrA2 is observed in aging cardiac tissues, and whether this has effects on mitochondrial status has not been reported. In this study, natural Sprague-Dawley rats (22 months) were used. We detected markedly increased proteolytic activity of Omi/HtrA2 and obvious activation of caspase-9 and caspase-3 in their myocardium. Then, we constructed stably transfected mitochondrial Omi/HtrA2 cells, and decreased mitochondrial membrane potential was detected by JC-1 (a probe for mitochondria) and tetramethylrhodamine methyl ester (TMRM) dyeing and significant release of cytochrome c was observed after separation of mitochondrial fraction and cytosolic fraction. Furthermore, ucf-101 (a special inhibitor of Omi/HtrA2) and HAX-1 siRNA could ameliorate those phenomena above. In conclusion, excessive Omi/HtrA2 in mitochondria induced decreased mitochondrial membrane potential by its proteolytic activity, followed by cytochrome c released from mitochondria into cytosol where cytochrome c promoted caspase activation. Also, Omi/HtrA2-HAX-1 chain played a significant role in mitochondrial homeostasis.