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Akt is required for Rac1 mediated mitochondrial oxidative stress and pulmonary fibrosis
Author(s) -
Casey Jennifer,
Murthy Shubha,
Ryan Alan J,
Carter A. Brent
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb185
Subject(s) - protein kinase b , rac1 , mitochondrion , microbiology and biotechnology , oxidative stress , chemistry , reactive oxygen species , downregulation and upregulation , mitochondrial ros , biology , cancer research , biochemistry , signal transduction , gene
The production of reactive oxygen species, especially hydrogen peroxide (H 2 O 2 ) from alveolar macrophages, has been linked to the development of pulmonary fibrosis. We have shown that Rac1 is imported into the mitochondria and modulates H 2 O 2 production in macrophages. In this study upstream regulators of Rac1 mitochondria import were investigated. Rac1 and Akt have been shown to positively and negatively modulate each other. We hypothesized that Akt activity was required for Rac1 activation and mitochondrial import. We found that macrophages exposed to chrysotile asbestos had increased Akt activity. Rac1 mitochondrial import was enhanced by the over‐expression of constitutively active Akt and conversely the knockdown of Akt was shown to abrogate Rac1 mitochondrial translocation, as Rac1 remained in the cytoplasm of macrophages expressing Akt siRNA. In contrast to the cytoplasm, Rac1 activity was significantly upregulated in the mitochondria of macrophages expressing constitutively active Akt, which consequently resulted in increased H 2 O 2 production in these cells. These observations suggest that Akt plays a vital role in the development and progression of pulmonary fibrosis, as it is necessary for mitochondrial Rac1 import and regulating mitochondrial oxidative stress. (Supported by 2R01ES015981–06, R01ES014871, VA Merit Review 1BX001135 (to A.B.C.) and NIH T32 CA078586).