Respiration-dependent Removal of Exogenous H2O2 in Brain Mitochondria
Open accessAbstract
In brain mitochondria, state 4 respiration supported by the NAD-linked substrates glutamate/malate in the presence of EGTA promotes a high rate of exogenous H2O2 removal. Omitting EGTA decreases the H2O2 removal rate by almost 80%. The decrease depends on the influx of contaminating Ca2+, being prevented by the Ca2+ uniporter inhibitor ruthenium red. Arsenite is also an inhibitor (maximal effect approximately 40%, IC50, 12 microm). The H2O2 removal rate (EGTA present) is decreased by 20% during state 3 respiration and by 60-70% in fully uncoupled conditions. H2O2 removal in mitochondria is largely dependent on glutathione peroxidase and glutathione reductase. Both enzyme activities, as studied in disrupted mitochondria, are inhibited by Ca2+. Glutathione reductase is decreased by 70% with an IC50 of about 0.9 microm, and glutathione peroxidase is decreased by 38% with a similar IC50. The highest Ca2+ effect with glutathione reductase is observed in the presence of low concentrations of H2O2. With succinate as substrate, the removal is 50% less than with glutamate/malate. This appears to depend on succinate-supported production of H2O2 by reverse electron flow at NADH dehydrogenase competing with exogenous H2O2 for removal. Succinate-dependent H2O2 is inhibited by rotenone, decreased DeltaPsi, as described previously, and by ruthenium red and glutamate/malate. These agents also increase the measured rate of exogenous H2O2 removal with succinate. Succinate-dependent H2O2 generation is also inhibited by contaminating Ca2+. Therefore, Ca2+ acts as an inhibitor of both H2O2 removal and the succinate-supported H2O2 production. It is concluded that mitochondria function as intracellular Ca2+-modulated peroxide sinks.
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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 [111]
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- Authors
- Zoccarato, F., Cavallini, L., & Alexandre, A.
- Affiliations
- University of Padua (IT)
- Corresponding author
- Zoccarato, Franco
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-02
- Volume
- 279
- Issue
- 6
- Pages
- 4166-4174
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2093485207
- Cited by
- 130
- References
- 36
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 5 · 2020: 2 · 2019: 3 · 2018: 8 · 2017: 5 · 2016: 3 · 2015: 3 · 2014: 6 · 2013: 8 · 2012: 7
- FWCI
- 3.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- hydrogen peroxide removal, brain mitochondria, state 4 respiration, glutamate-malate, succinic acid, calcium, glutathione peroxidase, glutathione reductase, reverse electron flow, NADH dehydrogenase, rotenone, ruthenium red, calcium uniporter, uncoupled respiration
- MeSH terms
- Animals, Brain, Calcium, Egtazic Acid, Electron Transport, Glutathione Peroxidase, Glutathione Reductase, Hydrogen Peroxide, Kinetics, Mitochondria, NADP, Oxidation-Reduction, Arsenites, Succinic Acid, Rats, In Vitro Techniques
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