School of Pharmacy, Sungkyunkwan University, Suwon, Gyonggi-do, Republic of Korea.
Shock. 2018 Aug;50(2):209-218. doi: 10.1097/SHK.0000000000001020.
Mitochondrial dysfunction is involved in the pathogenesis of sepsis-induced multiple organ dysfunction syndrome (MODS). Mitochondrial quality control (QC) is characterized by self-recovering mitochondrial damage through mitochondrial biogenesis, mitophagy, and fission/fusion. Heme oxygenase (HO)-1 acts as a signaling molecule to modulate inflammation. The present study elucidated the cytoprotective mechanisms of HO-1 in sepsis, particularly focusing on toll-like receptor (TLR)4-mediated mitochondrial QC. Mice were subjected to sepsis by cecal ligation and puncture (CLP). The mice were injected intraperitoneally with hemin (10 mg/kg) at 12 h before CLP or zinc protoporphyrin IX (ZnPP; 30 mg/kg) at 2 h before CLP. The serum and tissues were collected 6 h after CLP. Mortality, MODS, and proinflammatory cytokines increased in septic mice. These increases were augmented by ZnPP but attenuated by hemin. Hemin decreased mitochondrial lipid peroxidation and mitochondrial dysfunction. Hemin enhanced mitochondrial biogenesis, as indicated by increased levels of peroxisome proliferator-activated receptor-γ coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor A (TFAM). Hemin also enhanced mitophagy, as indicated by decreased PTEN-induced putative kinase 1 (PINK1) level and increased Parkin level. Hemin decreased fission-related protein, dynamin-related protein 1 (DRP1), and increased fusion-related protein, mitofusin 2. Hemin attenuated the increased TLR4 expression. TAK-242, a TLR4 antagonist, attenuated mortality, inflammatory response, and impaired mitochondrial QC. Our findings suggest that HO-1 attenuates septic injury by modulating TLR4-mediated mitochondrial QC.
线粒体功能障碍与脓毒症诱导的多器官功能障碍综合征（MODS）的发病机制有关。线粒体质量控制（QC）的特征是通过线粒体生物发生、线粒体自噬、分裂/融合来自我修复线粒体损伤。血红素加氧酶（HO）-1 作为一种信号分子，调节炎症反应。本研究阐明了 HO-1 在脓毒症中的细胞保护机制，特别是聚焦于 Toll 样受体（TLR）4 介导的线粒体 QC。通过盲肠结扎和穿孔（CLP）使小鼠发生脓毒症。在 CLP 前 12 小时，小鼠腹腔内注射血红素（10mg/kg），或在 CLP 前 2 小时，注射锌原卟啉 IX（ZnPP；30mg/kg）。CLP 后 6 小时收集血清和组织。脓毒症小鼠的死亡率、MODS 和促炎细胞因子增加。这些增加被 ZnPP 增强，被血红素减弱。血红素降低了线粒体脂质过氧化和线粒体功能障碍。血红素增强了线粒体生物发生，表现为过氧化物酶体增殖物激活受体-γ共激活因子 1α、核呼吸因子 1 和线粒体转录因子 A（TFAM）水平升高。血红素还增强了线粒体自噬，表现为 PTEN 诱导的假定激酶 1（PINK1）水平降低和 Parkin 水平升高。血红素降低了分裂相关蛋白，如 dynamin-related protein 1（DRP1），并增加了融合相关蛋白，如 mitofusin 2。血红素减弱了 TLR4 表达的增加。TLR4 拮抗剂 TAK-242 减轻了死亡率、炎症反应和受损的线粒体 QC。我们的研究结果表明，HO-1 通过调节 TLR4 介导的线粒体 QC 来减轻脓毒症损伤。
