Journal article
Mitochondrial Rac1 GTPase Import and Electron Transfer from Cytochrome c Are Required for Pulmonary Fibrosis
The Journal of biological chemistry, Vol.287(5), pp.3301-3312
01/27/2012
DOI: 10.1074/jbc.M111.308387
PMCID: PMC3270985
PMID: 22157762
Abstract
Background:
Rac1 activation is linked to H
2
O
2
generation in macrophages.
Results:
Two cysteine residues in Rac1 modulate mitochondrial H
2
O
2
generation via import and electron transfer from cytochrome
c
.
Conclusion:
Mitochondrial Rac1 activity in alveolar macrophages is associated with oxidative stress.
Significance:
Rac1 directly mediates mitochondrial H
2
O
2
production in alveolar macrophages, which is linked to pulmonary fibrosis.
The generation of reactive oxygen species, particularly H
2
O
2
, from alveolar macrophages is causally related to the development of pulmonary fibrosis. Rac1, a small GTPase, is known to increase mitochondrial H
2
O
2
generation in macrophages; however, the mechanism by which this occurs is not known. This study shows that Rac1 is localized in the mitochondria of alveolar macrophages from asbestosis patients, and mitochondrial import requires the C-terminal cysteine of Rac1 (Cys-189), which is post-translationally modified by geranylgeranylation. Furthermore, H
2
O
2
generation mediated by mitochondrial Rac1 requires electron transfer from cytochrome
c
to a cysteine residue on Rac1 (Cys-178). Asbestos-exposed mice harboring a conditional deletion of Rac1 in macrophages demonstrated decreased oxidative stress and were significantly protected from developing pulmonary fibrosis. These observations demonstrate that mitochondrial import and direct electron transfer from cytochrome
c
to Rac1 modulates mitochondrial H
2
O
2
production in alveolar macrophages pulmonary fibrosis.
Details
- Title: Subtitle
- Mitochondrial Rac1 GTPase Import and Electron Transfer from Cytochrome c Are Required for Pulmonary Fibrosis
- Creators
- Heather L Osborn-Heaford - From the Departments ofAlan J Ryan - From the Departments ofShubha Murthy - From the Departments ofAna-Monica Racila - From the Departments ofChao He - Radiation Oncology, Free Radical and Radiation Biology Program, andJessica C Sieren - Department of Radiology, University of Iowa Carver College of Medicine, andDouglas R Spitz - Radiation Oncology, Free Radical and Radiation Biology Program, andA. Brent Carter - From the Departments of
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.287(5), pp.3301-3312
- DOI
- 10.1074/jbc.M111.308387
- PMID
- 22157762
- PMCID
- PMC3270985
- 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; CA133114; P30 CA086862; UL1RR024979 / National Institutes of Health
- Alternative title
- Mitochondrial Rac1 Mediates Pulmonary Fibrosis
- Language
- English
- Date published
- 01/27/2012
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Pathology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984047610902771
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