Translocation of Heme Oxygenase-1 to Mitochondria Is a Novel Cytoprotective Mechanism against Non-steroidal Anti-inflammatory Drug-induced Mitochondrial Oxidative Stress, Apoptosis, and Gastric Mucosal Injury
Translocation of Heme Oxygenase-1 to Mitochondria Is a Novel Cytoprotective Mechanism against Non-steroidal Anti-inflammatory Drug-induced Mitochondrial Oxidative Stress, Apoptosis, and Gastric Mucosal Injury
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DOI：
10.1074/jbc.m111.279893
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发表时间：
2011-11-11
影响因子：
4.8
通讯作者：
Bandyopadhyay, Uday
中科院分区：
文献类型：
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作者：
Bindu, Samik;Pal, Chinmay;Bandyopadhyay, Uday
探讨血红素氧合酶-1（HO-1）在线粒体氧化应激（MOS）介导的凋亡性组织损伤中的作用机制。非甾体类抗炎药吲哚美辛可诱导大鼠胃粘膜MOS介导的凋亡和损伤。在这里，我们报告，HO-1不仅诱导，而且还易位到线粒体在胃粘膜损伤，有利于修复机制。此外，HO-1的线粒体易位导致MOS和线粒体病理学的预防，这从复合物I驱动的线粒体呼吸控制比率和跨膜电位的恢复中显而易见。HO-1的线粒体易位也导致了时间依赖性的细胞凋亡抑制。我们寻找可能的机制负责HO-1的诱导和线粒体定位。胃损伤时线粒体内HO-1底物游离血红素增加，HO-1进入线粒体内降低线粒体内游离血红素含量，提示HO-1线粒体转位的目的之一是解毒积累的血红素。血红素可能通过激活NF-E2相关因子2的核转位，通过活性氧的产生诱导HO-1的产生。电泳迁移率改变分析和染色质免疫沉淀研究表明，NF-E2相关因子2的核转位和结合HO-1启动子诱导HO-1表达在胃损伤。锌原卟啉抑制HO-1可加重粘膜损伤，延迟愈合。锌原卟啉进一步降低呼吸控制率和跨膜电位，增强MOS和细胞凋亡。相比之下，钴原卟啉诱导HO-1减少MOS，纠正线粒体功能障碍，并防止细胞凋亡和胃损伤。因此，HO-1的诱导和线粒体定位是针对MOS介导的凋亡组织损伤的新的细胞保护机制。
The mechanism of action of heme oxygenase-1 (HO-1) in mitochondrial oxidative stress (MOS)-mediated apoptotic tissue injury was investigated. MOS-mediated gastric mucosal apoptosis and injury were introduced in rat by indomethacin, a non-steroidal anti-inflammatory drug. Here, we report that HO-1 was not only induced but also translocated to mitochondria during gastric mucosal injury to favor repair mechanisms. Furthermore, mitochondrial translocation of HO-1 resulted in the prevention of MOS and mitochondrial pathology as evident from the restoration of the complex I-driven mitochondrial respiratory control ratio and transmembrane potential. Mitochondrial translocation of HO-1 also resulted in time-dependent inhibition of apoptosis. We searched for the plausible mechanisms responsible for HO-1 induction and mitochondrial localization. Free heme, the substrate for HO-1, was increased inside mitochondria during gastric injury, and mitochondrial entry of HO-1 decreased intramitochondrial free heme content, suggesting that a purpose of mitochondrial translocation of HO-1 is to detoxify accumulated heme. Heme may activate nuclear translocation of NF-E2-related factor 2 to induce HO-1 through reactive oxygen species generation. Electrophoretic mobility shift assay and chromatin immunoprecipitation studies indicated nuclear translocation of NF-E2-related factor 2 and its binding to HO-1 promoter to induce HO-1 expression during gastric injury. Inhibition of HO-1 by zinc protoporphyrin aggravated the mucosal injury and delayed healing. Zinc protoporphyrin further reduced the respiratory control ratio and transmembrane potential and enhanced MOS and apoptosis. In contrast, induction of HO-1 by cobalt protoporphyrin reduced MOS, corrected mitochondrial dysfunctions, and prevented apoptosis and gastric injury. Thus, induction and mitochondrial localization of HO-1 are a novel cytoprotective mechanism against MOS-mediated apoptotic tissue injury.