The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index.
Glutathione Peroxidase-1 Regulates Mitochondrial Function to Modulate Redox-dependent Cellular Responses
Open accessAbstract
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.
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“Furthermore, this suppression of mitochondrial function contributes to diminished responses in growth factor-mediated Akt activation and cellular proliferation (169).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [169]
In the citing paper
“GPx-1 plays an essential role in modulating intracellular hydrogen peroxide with consequences for growth factor-mediated signaling and mitochondrial ATP production (169).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [169]
In the citing paper
“Furthermore, GPx-1 modulates mitochondrial function as its overexpression decreases mitochondrial electrochemical potential (decreases ΔΨ), ROS generation, and ATP synthesis (169).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [169]
In the citing paper
“Our more recent study showed that decreasing cellular ROS through the overexpression of the antioxidant GPx-1 disrupts normal cellular disulfide formation with consequences for mitochondrial function (169).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [169]
In the citing paper
“Thus, excess GPx-1, in both the cytosol and the mitochondria, decreases mitochondrial potential and ATP production.”
From Redox regulation of mitochondrial function (2012) · cites this paper as [169]
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Self-citation
Metadata
- Authors
- Handy, D. E., Lubos, E., Yang, Y., Galbraith, J. D., Kelly, N., Zhang, Y.-Y., Leopold, J. A., & Loscalzo, J.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Handy, Diane E.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 284
- Issue
- 18
- Pages
- 11913-11921
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2673260
- OpenAlex
- W2020272282
- Cited by
- 187
- References
- 64
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 5 · 2023: 6 · 2022: 18 · 2021: 8 · 2020: 17 · 2019: 11 · 2018: 14 · 2017: 16 · 2016: 9 · 2015: 11 · 2014: 7 · 2013: 13 · 2012: 8
- FWCI
- 4.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Heart, Lung, and Blood Institute (HL81587, HL61795, HL58976, R01HL058976, P01HL081587, R01HL061795)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Physical Sciences › Chemistry › Organic Chemistry › Organoselenium and organotellurium chemistry
- Keywords
- glutathione peroxidase 1, redox signaling, EGFR signaling, Akt activation, hydrogen peroxide, protein disulfide bond formation, mitochondrial dysfunction, mitochondrial membrane potential, ATP production, cell proliferation, catalase, oxidative stress
- MeSH terms
- Glutathione Peroxidase GPX1, Adenosine Triphosphate, Adenoviridae, Catalase, Cell Line, Disulfides, Enzyme Activation, Epidermal Growth Factor, Glutathione Peroxidase, Humans, Hydrogen Peroxide, Mitochondria, Liver, Oxidation-Reduction, Transduction, Genetic, Uncoupling Agents, Signal Transduction, Oxidants, Selenocysteine, Cell Proliferation, Proto-Oncogene Proteins c-akt, Selenoproteins, Gene Knockdown Techniques, ErbB Receptors
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