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Mitochondrial Rac1 GTPase import and electron transfer from cytochrome c are required for pulmonary fibrosis

Heather L Osborn-Heaford1, Alan J Ryan, Shubha Murthy

  • 1Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.

The Journal of Biological Chemistry
|December 14, 2011
PubMed

Insights

Mitochondrial Rac1 drives reactive oxygen species (ROS) production in macrophages, contributing to pulmonary fibrosis. Inhibiting this pathway protects against asbestos-induced lung disease.

Area of Science:

  • Cell Biology
  • Pulmonary Medicine
  • Biochemistry

Background:

  • Alveolar macrophages generate reactive oxygen species (ROS), including hydrogen peroxide (H2O2), which are implicated in pulmonary fibrosis development.
  • The small GTPase Rac1 is known to enhance mitochondrial H2O2 generation in macrophages, but the underlying mechanism remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which Rac1 contributes to mitochondrial H2O2 production in alveolar macrophages.
  • To investigate the role of Rac1 in asbestos-induced pulmonary fibrosis.

Main Methods:

  • Immunofluorescence to determine Rac1 localization in alveolar macrophages from asbestosis patients.
  • Biochemical assays to study the role of Rac1’s C-terminal cysteine (Cys-189) and geranylgeranylation in mitochondrial import.
  • Analysis of electron transfer from cytochrome c to Rac1 (Cys-178) in H2O2 generation.
  • Assessment of pulmonary fibrosis and oxidative stress in Rac1-deficient mice exposed to asbestos.

Main Results:

  • Rac1 localizes to mitochondria in alveolar macrophages from asbestosis patients.
  • Mitochondrial import of Rac1 requires Cys-189 and geranylgeranylation.
  • Mitochondrial Rac1-mediated H2O2 generation depends on electron transfer from cytochrome c to Cys-178.
  • Mice with macrophage-specific Rac1 deletion showed reduced oxidative stress and protection from pulmonary fibrosis.

Conclusions:

  • Mitochondrial import of Rac1, facilitated by geranylgeranylation of Cys-189, is crucial for its function in macrophages.
  • Direct electron transfer from cytochrome c to Rac1 (Cys-178) modulates mitochondrial H2O2 production.
  • Targeting Rac1 in macrophages offers a potential therapeutic strategy for preventing or treating pulmonary fibrosis.

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