Mitochondrial Cu,Zn-Superoxide Dismutase Mediates Pulmonary Fibrosis by Augmenting H2O2 Generation
Mitochondrial Cu,Zn-Superoxide Dismutase Mediates Pulmonary Fibrosis by Augmenting H2O2 Generation
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DOI：
10.1074/jbc.m110.187377
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发表时间：
2011-04-29
影响因子：
4.8
通讯作者：
Carter, A. Brent
中科院分区：
文献类型：
--
作者：
He, Chao;Murthy, Shubha;Carter, A. Brent
肺泡巨噬细胞释放H_2O_2与肺纤维化的发生发展有关，但对其来源或产生机制知之甚少。我们发现石棉肺患者的肺泡巨噬细胞自发产生高水平的H_2O_2，并高表达铜锌超氧化物歧化酶(SOD)。由于线粒体膜间间隙存在铜锌超氧化物歧化酶，我们推测线粒体铜锌超氧化物歧化酶介导的过氧化氢生成参与了肺纤维化的发生。石棉诱导的铜，锌-超氧化物歧化酶向IMS的移位是巨噬细胞特有的，依赖于功能性线粒体呼吸和至少一个形成二硫键所需的保守半胱氨酸的存在。这些保守的半胱氨酸残基也是酶激活和过氧化氢产生所必需的。铜，锌-超氧化物歧化酶介导的H_2O_2的产生可被络合物III中的铁-硫蛋白Rieske抑制。铜，锌-超氧化物歧化酶的作用具有生物学意义，因为铜，锌-超氧化物歧化酶-/-小鼠产生的H_2O_2显著减少，且小鼠肺泡灌洗液和肺组织中的氧化应激程度较小。此外，铜，锌-超氧化物歧化酶-/-小鼠没有发生肺纤维化，单核细胞中铜，锌-超氧化物歧化酶的基因敲除可减少肺成纤维细胞的I型胶原沉积。我们的发现为肺纤维化的发病机制提供了一种新的机制，即抗氧化酶铜，锌-超氧化物歧化酶移位到线粒体IMS，增加肺泡巨噬细胞中过氧化氢的产生。
The release of H2O2 from alveolar macrophages has been linked to the development of pulmonary fibrosis, but little is known about its source or mechanism of production. We found that alveolar macrophages from asbestosis patients spontaneously produce high levels of H2O2 and have high expression of Cu,Zn-superoxide dismutase (SOD). Because Cu,Zn-SOD is found in the mitochondrial intermembrane space (IMS), we hypothesized that mitochondrial Cu,Zn-SOD-mediated H2O2 generation contributed to pulmonary fibrosis. Asbestos-induced translocation of Cu,Zn-SOD to the IMS was unique to macrophages and dependent on functional mitochondrial respiration and the presence of at least one of the conserved cysteines required for disulfide bond formation. These conserved cysteine residues were also necessary for enzyme activation and H2O2 generation. Cu,Zn-SOD-mediated H2O2 generation was inhibited by knockdown of the iron-sulfur protein, Rieske, in complex III. The role of Cu,Zn-SOD was biologically relevant in that Cu,Zn-SOD-/- mice generated significantly less H2O2 and had less oxidant stress in bronchoalveolar lavage fluid and lung parenchyma. Furthermore, Cu,Zn-SOD-/- mice did not develop pulmonary fibrosis, and knockdown of Cu,Zn-SOD in monocytes attenuated collagen I deposition by lung fibroblasts. Our findings demonstrate a novel mechanism for the pathogenesis of pulmonary fibrosis where the antioxidant enzyme Cu,Zn-SOD translocates to the mitochondrial IMS to increase H2O2 generation in alveolar macrophages.