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

@article{OsbornHeaford2011MitochondrialRG,
  title={Mitochondrial Rac1 GTPase Import and Electron Transfer from Cytochrome c Are Required for Pulmonary Fibrosis*},
  author={Heather L Osborn-Heaford and A. Ryan and S. Murthy and A-M. Racila and Chao He and J. Sieren and D. Spitz and A. Carter},
  journal={The Journal of Biological Chemistry},
  year={2011},
  volume={287},
  pages={3301 - 3312}
}
Background: Rac1 activation is linked to H2O2 generation in macrophages. Results: Two cysteine residues in Rac1 modulate mitochondrial H2O2 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 H2O2 production in alveolar macrophages, which is linked to pulmonary fibrosis. The generation of reactive oxygen species, particularly H2O2… Expand
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References

SHOWING 1-10 OF 52 REFERENCES
Mitochondrial Cu,Zn-Superoxide Dismutase Mediates Pulmonary Fibrosis by Augmenting H2O2 Generation*
TLDR
A novel mechanism for the pathogenesis of pulmonary fibrosis where the antioxidant enzyme Cu,Zn-SOD translocates to the mitochondrial IMS to increase H2O2 generation in alveolar macrophages is demonstrated. Expand
Electron Transfer between Cytochrome c and p66Shc Generates Reactive Oxygen Species that Trigger Mitochondrial Apoptosis
TLDR
P66Shc is a redox enzyme that generates mitochondrial ROS (hydrogen peroxide) as signaling molecules for apoptosis and the existence of alternative redox reactions of the mitochondrial electron transfer chain is demonstrated, which evolved to generate proapoptotic ROS in response to specific stress signals. Expand
Constitutive NADPH oxidase and increased mitochondrial respiratory chain activity regulate chemokine gene expression.
  • L. Tephly, A. Carter
  • Biology, Medicine
  • American journal of physiology. Lung cellular and molecular physiology
  • 2007
TLDR
Results suggest that in alveolar macrophages, O(2)(*-) generation mediates chemokine expression after TNF-alpha stimulation in an ERK-dependent manner. Expand
Modulation of reactive oxygen species by Rac1 or catalase prevents asbestos-induced pulmonary fibrosis.
TLDR
It is demonstrated that Rac1 null mice are protected from asbestos-induced pulmonary fibrosis, as determined by histological and biochemical analysis and suggests that a simple intervention may be useful to prevent progression of the disease. Expand
Effect of Cytochrome c on the Generation and Elimination of O 2 ⨪ and H2O2 in Mitochondria*
TLDR
Evidence is presented showing that cytochrome c plays an antioxidative role by acting on the generation and elimination of O 2 ⨪ and H2O2 in mitochondria, which should have some role in the early stage of cell apoptosis. Expand
Rac1-mediated Mitochondrial H2O2 Generation Regulates MMP-9 Gene Expression in Macrophages via Inhibition of SP-1 and AP-1*
TLDR
Rac1 regulates MMP-9 transcription via mitochondrial H2O2 generation, providing a potential mechanism by which Rac1 null mice fail to develop pulmonary fibrosis. Expand
Integrins engage mitochondrial function for signal transduction by a mechanism dependent on Rho GTPases
TLDR
A new molecular mechanism of signal transduction triggered by integrin engagement where a global mitochondrial metabolic response leads to gene expression rather than apoptosis is unveiled. Expand
Constitutive Activation of rac 1 Results in Mitochondrial Oxidative Stress and Induces Premature Endothelial Cell Senescence
TLDR
Findings paint a picture in which the constitutive activation of rac 1, via the generation of ceramide, results in mitochondrial oxidative stress and premature endothelial cell senescence, however, they speak against a role for endogenous rac1 activation in the induction of mitochondrial oxidative Stress associated with replicative senescences of endothelial cells. Expand
A Disulfide Relay System in the Intermembrane Space of Mitochondria that Mediates Protein Import
TLDR
It is suggested that the existence of a disulfide exchange system in the IMS is unexpected in view of the free exchange of metabolites between IMS and cytosol via porin channels, and reflects the evolutionary origin of the I MS from the periplasmic space of the prokaryotic ancestors of mitochondria. Expand
SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model.
TLDR
It is demonstrated that SOD1 is not just a catabolic enzyme, but can also directly regulate NADPH oxidase-dependent (Nox-dependent) O(2)(*-) production by binding Rac1 and inhibiting its GTPase activity. Expand
...
1
2
3
4
5
...