Respiration-dependent H2O2 removal in brain mitochondria via the thioredoxin/peroxiredoxin system
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Mitochondrial reactive oxygen species (ROS) play an important role in both physiological cell signaling processes and numerous pathological states, including neurodegenerative disorders such as Parkinson disease. While mitochondria are considered the major cellular source of ROS, their role in ROS removal remains largely unknown. Using polarographic methods for real-time detection of steady-state H(2)O(2) levels, we were able to quantitatively measure the contributions of potential systems toward H(2)O(2) removal by brain mitochondria. Isolated rat brain mitochondria showed significant rates of exogenous H(2)O(2) removal (9-12 nmol/min/mg of protein) in the presence of substrates, indicating a respiration-dependent process. Glutathione systems showed only minimal contributions: 25% decrease with glutathione reductase inhibition and no effect by glutathione peroxidase inhibition. In contrast, inhibitors of thioredoxin reductase, including auranofin and 1-chloro-2,4-dinitrobenzene, attenuated H(2)O(2) removal rates in mitochondria by 80%. Furthermore, a 50% decrease in H(2)O(2) removal was observed following oxidation of peroxiredoxin. Differential oxidation of glutathione or thioredoxin proteins by copper (II) or arsenite, respectively, provided further support for the thioredoxin/peroxiredoxin system as the major contributor to mitochondrial H(2)O(2) removal. Inhibition of the thioredoxin system exacerbated mitochondrial H(2)O(2) production by the redox cycling agent, paraquat. Additionally, decreases in H(2)O(2) removal were observed in intact dopaminergic neurons with thioredoxin reductase inhibition, implicating this mechanism in whole cell systems. Therefore, in addition to their recognized role in ROS production, mitochondria also remove ROS. These findings implicate respiration- and thioredoxin-dependent ROS removal as a potentially important mitochondrial function that may contribute to physiological and pathological processes in the brain.
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H2O2 scavenger activities of isolated mitochondria are lower with succinate as the sole substrate than with NADH-generating substrates like malate/glutamate or malate/pyruvate.
“In this context, it is important to note that the H 2 O 2 scavenger activities of isolated mitochondria are lower with succinate as the sole substrate than with NADH-generating substrates like malate/glutamate or malate/pyruvate [111,112].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [112]
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- Authors
- Drechsel, D. A., & Patel, M.
- Affiliations
- University of Colorado Denver (US)
- Corresponding author
- Patel, Manisha
- ORCID
- Patel, Manisha
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 285
- Issue
- 36
- Pages
- 27850-27858
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2934652
- OpenAlex
- W2090005130
- Cited by
- 199
- References
- 46
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 6 · 2023: 3 · 2022: 10 · 2021: 13 · 2020: 11 · 2019: 9 · 2018: 13 · 2017: 15 · 2016: 10 · 2015: 20 · 2014: 18 · 2013: 17 · 2012: 20
- FWCI
- 7.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Foundation for Pharmaceutical Education
- National Institutes of Health (RO1NS04748, 1f31ns061438-01a1, RO1NS039587)
- National Institute of Neurological Disorders and Stroke (1F31NS061438, R01NS039587, R01NS045748, R01NS04748, F31 NS061438, RO1NS039587)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- hydrogen peroxide removal, brain mitochondria, thioredoxin system, peroxiredoxin, thioredoxin reductase, mitochondrial reactive oxygen species, oxidative stress, Parkinson's disease, dopaminergic neurons, glutathione, paraquat, auranofin, arsenite, mitochondrial respiration
- MeSH terms
- Animals, Brain, Cell Line, Cell Membrane Permeability, Dopamine, Enzyme Inhibitors, Hydrogen Peroxide, Liver, Male, Metals, Mitochondria, Polarography, Thioredoxins, Thioredoxin-Disulfide Reductase, Rats, Sprague-Dawley, Cell Respiration, Rats, Peroxiredoxins
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