Activation of Mitochondrial Biogenesis by Heme Oxygenase-1-mediated NF-E2-related Factor-2 Induction Rescues Mice from Lethal Staphylococcus aureus Sepsis
Activation of Mitochondrial Biogenesis by Heme Oxygenase-1-mediated NF-E2-related Factor-2 Induction Rescues Mice from Lethal Staphylococcus aureus Sepsis
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DOI：
10.1164/rccm.201106-1152oc
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发表时间：
2012-04-15
影响因子：
24.7
通讯作者：
Piantadosi, Claude A.
中科院分区：
文献类型：
--
作者：
MacGarvey, Nancy Chou;Suliman, Hagir B.;Piantadosi, Claude A.
基本原理：线粒体损伤是多器官衰竭综合征的重要组成部分，多器官衰竭综合征是严重脓毒症的高致死性并发症，缺乏特异性治疗。线粒体质量控制部分由血红素加氧酶-1调节（HO-1; Hmox 1）系统通过氧化还原调节的NF-E2相关因子-2（Nrf 2）转录因子，但其在金黄色葡萄球菌脓毒症线粒体生物合成中的作用尚不清楚。为了检验HO-1/一氧化碳（CO）的Nrf 2依赖性上调系统将保护线粒体生物发生并拯救小鼠免受致命的S.方法：采用对照小鼠S.金黄色葡萄球菌腹膜炎模型与和没有吸入CO检查HO-1和Nrf 2调节线粒体生物合成和分辨率的肝线粒体damage. Measures和主要结果：败血症生存率显着提高使用吸入CO（250 ppm，每天一次，1小时），并连接机械Hmox 1诱导和线粒体！通过Nrf 2转录和Akt激酶活性的HO活性。HO-1/CO刺激Nrf 2依赖性基因表达和核呼吸因子-1，2 α（Gabpa）和过氧化物酶体增殖物激活受体γ共激活因子-1 α的核积累;增加线粒体转录因子A和柠檬酸合酶蛋白水平;并增加mtDNA拷贝数。一氧化碳可增强IL-10的表达，减少促炎性肿瘤坏死因子-a的产生。相比之下，Nrf 2（-/-）和Akt 1（-/-）小鼠缺乏Hmox 1和线粒体生物合成的CO诱导，CO也不能从S.结论：我们确定了一个诱导型Nrf 2/HO-1调节周期的线粒体生物合成，是促生存和抗炎败血症，并描述了有针对性的诱导线粒体生物合成作为一个潜在的多器官衰竭治疗。
Rationale: Mitochondrial damage is an important component of multiple organ failure syndrome, a highly lethal complication of severe sepsis that lacks specific therapy. Mitochondrial quality control is regulated in part by the heme oxygenase-1 (HO-1; Hmox1) system through the redox-regulated NF-E2-related factor-2 (Nrf2) transcription factor, but its role in mitochondrial biogenesis in Staphylococcus aureus sepsis is unknown.Objectives: To test the hypothesis that Nrf2-dependent up-regulation of the HO-1/carbon monoxide (CO) system would preserve mitochondrial biogenesis and rescue mice from lethal S. aureus sepsis.Methods: A controlled murine S. aureus peritonitis model with and without inhaled CO was examined for HO-1 and Nrf2 regulation of mitochondrial biogenesis and the resolution of hepatic mitochondrial damage.Measurements and Main Results: Sepsis survival was significantly enhanced using inhaled CO (250 ppm once-daily for 1 h), and linked mechanistically to Hmox1 induction and mitochondria! HO activity through Nrf2 transcriptional and Akt kinase activity. HO-1/CO stimulated Nrf2-dependent gene expression and nuclear accumulation of nuclear respiratory factor-1, -2 alpha (Gabpa), and peroxisome proliferator-activated receptor gamma coactivator-1 alpha; increased mitochondrial transcription factor-A and citrate synthase protein levels; and augmented mtDNA copy number. CO enhanced antiinflammatory IL-10 and reduced proinflammatory tumor necrosis factor-a production. By contrast, Nrf2(-/-) and Akt1(-/-) mice lacked CO induction of Hmox1 and mitochondrial biogenesis, and CO rescued neither strain from S. aureus sepsis.Conclusions: We identify an inducible Nrf2/HO-1 regulatory cycle for mitochondrial biogenesis that is prosurvival and counter-inflammatory in sepsis, and describe targeted induction of mitochondrial biogenesis as a potential multiple organ failure therapy.