title: Mitochondrial Omi/HtrA2 Promotes Caspase Activation Through Cleavage of HAX-1 in Aging Heart.
abstract: 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.
authors.affiliation: 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University , Beijing, China .
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University , Beijing, China .
authors.forename: Jinghui
authors.initials: J
authors.lastname: Lei
authors.affiliation: 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University , Beijing, China .
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University , Beijing, China .
authors.forename: Lu
authors.initials: L
authors.lastname: Ma
authors.affiliation: 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University , Beijing, China .
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University , Beijing, China .
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Du
authors.affiliation: 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University , Beijing, China .|2 Beijing Key Laboratory of Metabolic Disturbance Related Cardiovascular Disease , Beijing, China .
authors.forename: Ye
authors.initials: Y
authors.lastname: Wu
authors.affiliation: 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University , Beijing, China .|2 Beijing Key Laboratory of Metabolic Disturbance Related Cardiovascular Disease , Beijing, China .
authors.forename: Suli
authors.initials: S
authors.lastname: Zhang
authors.affiliation: 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University , Beijing, China .
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.affiliation: 2 Beijing Key Laboratory of Metabolic Disturbance Related Cardiovascular Disease , Beijing, China .|3 Department of Emergency Medicine, Thomas Jefferson University , Philadelphia, Pennsylvania.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Ma
authors.affiliation: 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University , Beijing, China .|2 Beijing Key Laboratory of Metabolic Disturbance Related Cardiovascular Disease , Beijing, China .
authors.forename: Huirong
authors.initials: H
authors.lastname: Liu
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism*; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D000074923:High-Temperature Requirement A Serine Peptidase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology*; D011506:Proteins / Q000378:metabolism*; D011744:Pyrimidinones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013871:Thiones / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; C491295:Hs1bp1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011744:Pyrimidinones; D034741:RNA, Small Interfering; D013871:Thiones; C501517:UCF 101; D045304:Cytochromes c; D000074923:High-Temperature Requirement A Serine Peptidase 2; D053148:Caspase 3; D053453:Caspase 9
keywords: HAX-1; Omi/HtrA2; cytochrome c; mitochondria