Sources of Reactive Oxygen Species in Normoxic and Hypoxic Naked Mole-Rat Brain
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Abstract
Oxygen availability dictates the rate of reactive oxygen species production from various cellular sources; excessive ROS accumulation can be cytotoxic. Mitochondria are usually the primary contributors to basal reactive oxygen species generation in the brain; however, xanthine oxidoreductase and nicotinamide adenine dinucleotide phosphate oxidase can also produce considerable reactive oxygen species during hypoxia/reoxygenation. In the brains of most mammals, cellular death accompanies hypoxia-mediated surges in reactive oxygen species production, but this is avoided in the cortex of hypoxia-tolerant naked mole-rats (Heterocephalus glaber). However, the contributions of various reactive oxygen species generators towards total reactive oxygen species homeostasis in naked mole-rat brain is unknown. We hypothesized that mitochondria remain the primary reactive oxygen species generators in naked mole-rat cortex and predicted that pharmacological inhibition of mitochondrial complex I would induce greater fluctuations in superoxide (O2•-) and hydrogen peroxide (H2O2) than inhibition of xanthine oxidoreductase or nicotinamide adenine dinucleotide phosphate oxidase. To test this, we used fluorescence microscopy to measure H2O2 and O2•- production from cortical slices during normoxia and hypoxia while pharmacologically inhibiting mitochondrial complex I, xanthine oxidoreductase, or nicotinamide adenine dinucleotide phosphate oxidase. Unexpectedly, we found xanthine oxidoreductase inhibition induced the greatest increase in O2•- during normoxia and hypoxia (~100% and 70%, respectively). Hypoxic inhibition of nicotinamide adenine dinucleotide phosphate oxidase induced the greatest decrease in H2O2 by ~35% below baseline. Finally, although inhibition of mitochondrial complex I during hypoxia yielded significant fluctuations in O2•- and H2O2, these changes were considerably smaller than fluctuations induced by inhibiting xanthine oxidoreductase or nicotinamide adenine dinucleotide phosphate oxidase. Together, and unlike in other rodent brain, our results suggest that xanthine oxidoreductase is the primary contributor to reactive oxygen species production in naked mole-rat cortex.
Keywords:
NADPH oxidase, mitochondria, electron transport system, xanthine oxidoreductase, superoxide, hydrogen peroxide, reactive oxygen species, hypoxia
Article Details
How to Cite
EATON, Liam et al.
Sources of Reactive Oxygen Species in Normoxic and Hypoxic Naked Mole-Rat Brain.
Medical Research Archives, [S.l.], v. 12, n. 1, jan. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4857>. Date accessed: 27 apr. 2024.
doi: https://doi.org/10.18103/mra.v12i1.4857.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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2. West AP, Shadel GS, Ghosh S. Mitochondria in innate immune responses. Nat Rev Immunol. Jun 2011;11(6):389-402. doi:10.1038/nri2975
3. Finkel T. Signal transduction by mitochondrial oxidants. J Biol Chem. Feb 10 2012;287(7):4434-40. doi:10.1074/jbc.R111.271999
4. Kiselyov K, Muallem S. ROS and intracellular ion channels. Cell Calcium. Aug 2016;60(2):108-14. doi:10.1016/j.ceca.2016.03.004
5. Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. Apr 4 2007;26(7):1749-60. doi:10.1038/sj.emboj.7601623
6. Starkov AA, Andreyev AY, Zhang SF, et al. Scavenging of H2O2 by mouse brain mitochondria. J Bioenerg Biomembr. Dec 2014;46(6):471-7. doi:10.1007/s10863-014-9581-9
7. Munro D, Banh S, Sotiri E, Tamanna N, Treberg JR. The thioredoxin and glutathione-dependent H2O2 consumption pathways in muscle mitochondria: Involvement in H2O2 metabolism and consequence to H2O2 efflux assays. Free Radic Biol Med. Jul 2016;96:334-46. doi:10.1016/j.freeradbiomed.2016.04.014
8. Drechsel DA, Patel M. Respiration-dependent H2O2 removal in brain mitochondria via the thioredoxin/peroxiredoxin system. J Biol Chem. Sep 3 2010;285(36):27850-8. doi:10.1074/jbc.M110.101196
9. Guzy RD, Hoyos B, Robin E, et al. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab. Jun 2005;1(6):401-8. doi:10.1016/j.cmet.2005.05.001
10. Panov A, Dikalov S, Shalbuyeva N, Hemendinger R, Greenamyre JT, Rosenfeld J. Species- and tissue-specific relationships between mitochondrial permeability transition and generation of ROS in brain and liver mitochondria of rats and mice. Am J Physiol Cell Physiol. Feb 2007;292(2):C708-18. doi:10.1152/ajpcell.00202.2006
11. Wang F, Wang X, Liu Y, Zhang Z. Effects of Exercise-Induced ROS on the Pathophysiological Functions of Skeletal Muscle. Oxid Med Cell Longev. 2021;2021:3846122. doi:10.1155/2021/3846122
12. Marchi S, Giorgi C, Suski JM, et al. Mitochondria-ros crosstalk in the control of cell death and aging. J Signal Transduct. 2012;2012:329635. doi:10.1155/2012/329635
13. Apel K, Hirt H. Reactive oxygen species: metabolism, oxidative stress, and signal transduction. Annu Rev Plant Biol. 2004;55:373-99. doi:10.1146/annurev.arplant.55.031903.141701
14. Levraut J, Iwase H, Shao ZH, Vanden Hoek TL, Schumacker PT. Cell death during ischemia: relationship to mitochondrial depolarization and ROS generation. Am J Physiol Heart Circ Physiol. Feb 2003;284(2):H549-58. doi:10.1152/ajpheart.00708.2002
15. Adam-Vizi V. Production of reactive oxygen species in brain mitochondria: contribution by electron transport chain and non-electron transport chain sources. Antioxid Redox Signal. Sep-Oct 2005;7(9-10):1140-9. doi:10.1089/ars.2005.7.1140
16. Aon MA, Stanley BA, Sivakumaran V, et al. Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: an experimental-computational study. J Gen Physiol. Jun 2012;139(6):479-91. doi:10.1085/jgp.201210772
17. Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol Rev. Jul 1979;59(3):527-605. doi:10.1152/physrev.1979.59.3.527
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