title: Mitochondrial Rac1 GTPase import and electron transfer from cytochrome c are required for pulmonary fibrosis.
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.
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Osborn-Heaford
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Ryan
authors.forename: Shubha
authors.initials: S
authors.lastname: Murthy
authors.forename: Ana-Monica
authors.initials: AM
authors.lastname: Racila
authors.forename: Chao
authors.initials: C
authors.lastname: He
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Sieren
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
authors.forename: A Brent
authors.initials: AB
authors.lastname: Carter
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001194:Asbestos / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism*; D004579:Electron Transport / Q000187:drug effects / Q000235:genetics; D004583:Electrons; D005260:Female; D006801:Humans; D016676:Macrophages, Alveolar / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D017368:Protein Prenylation / Q000187:drug effects / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D024101:Mitochondrial Proteins; D009479:Neuropeptides; C107953:RAC1 protein, human; C484602:Rac1 protein, mouse; D001194:Asbestos; D045304:Cytochromes c; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein