Mitochondrial Omi/HtrA2 Promotes Caspase Activation Through Cleavage of HAX-1 in Aging Heart

作者：Liu, Xin; Lei, Jinghui; Wang, Ke; Ma, Lu; Liu, Dan; Du, Yunhui; Wu, Ye; Zhang, Suli; Wang, Wen; Ma, Xinliang^*; Liu, Huirong^*

来源：Rejuvenation Research, 2017, 20(3): 183-192.

DOI：10.1089/rej.2016.1861

• Omi/HtrA2
• mitochondria
• cytochrome c
• HAX-1

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.

• 出版日期2017-6
• 单位首都医科大学