Mitochondrial Rac1 GTPase Import and Electron Transfer from Cytochrome c Are Required for Pulmonary Fibrosis

作者：O**orn Heaford Heather L; Ryan Alan J; Murthy Shubha; Racila Ana Monica; He Chao; Sieren Jessica C; Spitz Douglas R; Carter A Brent^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287(5): 3301-3312.

DOI：10.1074/jbc.M111.308387

The generation of reactive oxygen species, particularly H2O2, from alveolar macrophages is causally related to the development of pulmonary fibrosis. Rac1, a small GTPase, is known to increase mitochondrial H2O2 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, H2O2 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 H2O2 production in alveolar macrophages pulmonary fibrosis.

• 出版日期2012-1-27