Glutathione peroxidase-1 regulates mitochondrial function to modulate redox-dependent cellular responses.
Glutathione peroxidase-1 (GPx-1) is a selenocysteine-containing enzyme that plays a major role in the reductive detoxification of peroxides in cells. In permanently transfected cells with approximate 2-fold overexpression of GPx-1, we found that intracellular accumulation of oxidants in response to exogenous hydrogen peroxide was diminished, as was epidermal growth factor receptor (EGFR)-mediated Akt activation in response to hydrogen peroxide or EGF stimulation. Knockdown of GPx-1 augmented EGFR-mediated Akt activation, whereas overexpression of catalase decreased Akt activation, suggesting that EGFR signaling is regulated by redox mechanisms. To determine whether mitochondrial oxidants played a role in these processes, cells were pretreated with a mitochondrial uncoupler prior to EGF stimulation. Inhibition of mitochondrial function attenuated EGF-mediated activation of Akt in control cells but had no additional effect in GPx-1-overexpressing cells, suggesting that GPx-1 overexpression decreased EGFR signaling by decreasing mitochondrial oxidants. Consistent with this finding, GPx-1 overexpression decreased global protein disulfide bond formation, which is dependent on mitochondrially produced oxidants. GPx-1 overexpression, in permanently transfected or adenovirus-treated cells, also caused overall mitochondrial dysfunction with a decrease in mitochondrial potential and a decrease in ATP production. GPx-1 overexpression also decreased EGF- and serum-mediated [(3)H]thymidine incorporation, indicating that alterations in GPx-1 can attenuate cell proliferation. Taken together, these data suggest that GPx-1 can modulate redox-dependent cellular responses by regulating mitochondrial function.
Handy
Diane E
DE
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. dhandy@rics.bwh.harvard.edu
Lubos
Edith
E
Yang
Yi
Y
Galbraith
John D
JD
Kelly
Neil
N
Zhang
Ying-Yi
YY
Leopold
Jane A
JA
Loscalzo
Joseph
J
D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000235:genetics; D000256:Adenoviridae; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004220:Disulfides / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017279:Selenocysteine / Q000235:genetics / Q000378:metabolism; D051140:Selenoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014161:Transduction, Genetic / Q000379:methods; D014475:Uncoupling Agents / Q000494:pharmacology; D000094765:Glutathione Peroxidase GPX1
D004220:Disulfides; D016877:Oxidants; D051140:Selenoproteins; D014475:Uncoupling Agents; D017279:Selenocysteine; D004815:Epidermal Growth Factor; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D002374:Catalase; D005979:Glutathione Peroxidase; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000094765:Glutathione Peroxidase GPX1