Journal article
Mitochondrial Cu,Zn-Superoxide Dismutase Mediates Pulmonary Fibrosis by Augmenting H2O2 Generation
The Journal of biological chemistry, Vol.286(17), pp.15597-15607
04/29/2011
DOI: 10.1074/jbc.M110.187377
PMCID: PMC3083152
PMID: 21393238
Abstract
The release of H
2
O
2
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 H
2
O
2
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 H
2
O
2
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 H
2
O
2
generation. Cu,Zn-SOD-mediated H
2
O
2
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 H
2
O
2
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 H
2
O
2
generation in alveolar macrophages.
Details
- Title: Subtitle
- Mitochondrial Cu,Zn-Superoxide Dismutase Mediates Pulmonary Fibrosis by Augmenting H2O2 Generation
- Creators
- Chao He - Radiation Oncology and the Graduate Program in Free Radical and Radiation Biology, Carver College of Medicine, andShubha Murthy - From the Departments ofMichael L McCormick - Radiation Oncology and the Graduate Program in Free Radical and Radiation Biology, Carver College of Medicine, andDouglas R Spitz - Radiation Oncology and the Graduate Program in Free Radical and Radiation Biology, Carver College of Medicine, andAlan J Ryan - From the Departments ofA. Brent Carter - From the Departments of
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.286(17), pp.15597-15607
- DOI
- 10.1074/jbc.M110.187377
- PMID
- 21393238
- PMCID
- PMC3083152
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- Grant note
- ES015981; ES014871; P30 CA086862 / National Institutes of Health
- Alternative title
- Cu,Zn-SOD−/− Mice Are Protected from Pulmonary Fibrosis
- Language
- English
- Date published
- 04/29/2011
- Academic Unit
- Pathology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984047654302771
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