Mitochondrial Rac1 GTPase Import and Electron Transfer from Cytochrome c Are Required for Pulmonary Fibrosis
Year: 2011
Type: article
Abstract: 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.
Source: Journal of Biological Chemistry
Institutions: University of Iowa, University of Iowa Health Care
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Awards: The Use of 2-Deoxyglucose in Head and Neck Cancer Therapy, G3169336615, G4159529714, Hydrogen Peroxide and Asbestosis, University of Iowa Clinical and Translational Science Program (UL1), Lung Macrophage Metabolic Reprogramming in Asbestos-Induced Toxicity, G8825412911, Cancer Center Support Grant
OpenAlex ID: W2003766096