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: 21 dec. 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.
References
1. Wang Y, Zang QS, Liu Z, et al. Regulation of VEGF-induced endothelial cell migration by mitochondrial reactive oxygen species. Am J Physiol Cell Physiol. Sep 2011;301(3):C695-704. doi:10.1152/ajpcell.00322.2010
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
18. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. Jul 2014;94(3):909-50. doi:10.1152/physrev.00026.2013
19. Turrens JF, Freeman BA, Levitt JG, Crapo JD. The effect of hyperoxia on superoxide production by lung submitochondrial particles. Arch Biochem Biophys. Sep 1982;217(2):401-10. doi:10.1016/0003-9861(82)90518-5
20. Wilson DF, Rumsey WL, Green TJ, Vanderkooi JM. The oxygen dependence of mitochondrial oxidative phosphorylation measured by a new optical method for measuring oxygen concentration. J Biol Chem. Feb 25 1988;263(6):2712-8.
21. Orr AL, Ashok D, Sarantos MR, Shi T, Hughes RE, Brand MD. Inhibitors of ROS production by the ubiquinone-binding site of mitochondrial complex I identified by chemical screening. Free Radic Biol Med. Dec 2013;65:1047-1059. doi:10.1016/j.freeradbiomed.2013.08.170
22. Scialo F, Fernandez-Ayala DJ, Sanz A. Role of Mitochondrial Reverse Electron Transport in ROS Signaling: Potential Roles in Health and Disease. Front Physiol. 2017;8:428. doi:10.3389/fphys.2017.00428
23. Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci U S A. Sep 29 1998;95(20):11715-20. doi:10.1073/pnas.95.20.11715
24. Paddenberg R, Ishaq B, Goldenberg A, et al. Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature. Am J Physiol Lung Cell Mol Physiol. May 2003;284(5):L710-9. doi:10.1152/ajplung.00149.2002
25. Quinlan CL, Orr AL, Perevoshchikova IV, Treberg JR, Ackrell BA, Brand MD. Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions. J Biol Chem. Aug 3 2012;287(32):27255-64. doi:10.1074/jbc.M112.374629
26. Chouchani ET, Pell VR, James AM, et al. A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury. Cell Metab. Feb 9 2016;23(2):254-63. doi:10.1016/j.cmet.2015.12.009
27. Bayir H. Reactive oxygen species. Crit Care Med. Dec 2005;33(12 Suppl):S498-501. doi:10.1097/01.ccm.0000186787.64500.12
28. Kishida KT, Klann E. Sources and targets of reactive oxygen species in synaptic plasticity and memory. Antioxid Redox Signal. Feb 2007;9(2):233-44. doi:10.1089/ars.2007.9.ft-8
29. Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol. Mar 16 2004;555(Pt 3):589-606. doi:10.1113/jphysiol.2003.055913
30. Collin F. Chemical Basis of Reactive Oxygen Species Reactivity and Involvement in Neurodegenerative Diseases. Int J Mol Sci. May 15 2019;20(10)doi:10.3390/ijms20102407
31. Hille R, Hall J, Basu P. The mononuclear molybdenum enzymes. Chem Rev. Apr 9 2014;114(7):3963-4038. doi:10.1021/cr400443z
32. Godber BL, Doel JJ, Sapkota GP, et al. Reduction of nitrite to nitric oxide catalyzed by xanthine oxidoreductase. J Biol Chem. Mar 17 2000;275(11):7757-63. doi:10.1074/jbc.275.11.7757
33. Nanduri J, Vaddi DR, Khan SA, et al. HIF-1alpha activation by intermittent hypoxia requires NADPH oxidase stimulation by xanthine oxidase. PLoS One. 2015;10(3):e0119762. doi:10.1371/journal.pone.0119762
34. Abramov AY, Scorziello A, Duchen MR. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci. Jan 31 2007;27(5):1129-38. doi:10.1523/JNEUROSCI.4468-06.2007
35. Babior BM. The respiratory burst oxidase. Adv Enzymol Relat Areas Mol Biol. 1992;65:49-95. doi:10.1002/9780470123119.ch2
36. Vignais PV. The superoxide-generating NADPH oxidase: structural aspects and activation mechanism. Cell Mol Life Sci. Sep 2002;59(9):1428-59. doi:10.1007/s00018-002-8520-9
37. Mennerich D, Kellokumpu S, Kietzmann T. Hypoxia and Reactive Oxygen Species as Modulators of Endoplasmic Reticulum and Golgi Homeostasis. Antioxid Redox Signal. Jan 1 2019;30(1):113-137. doi:10.1089/ars.2018.7523
38. Sies H, Belousov VV, Chandel NS, et al. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nat Rev Mol Cell Biol. Feb 21 2022;doi:10.1038/s41580-022-00456-z
39. Welker AF, Campos EG, Cardoso LA, Hermes-Lima M. Role of catalase on the hypoxia/reoxygenation stress in the hypoxia-tolerant Nile tilapia. Am J Physiol Regul Integr Comp Physiol. May 2012;302(9):R1111-8. doi:10.1152/ajpregu.00243.2011
40. Eaton L, Wang T, Roy M, Pamenter ME. Naked Mole-Rat Cortex Maintains Reactive Oxygen Species Homeostasis During In Vitro Hypoxia or Ischemia and Reperfusion. Curr Neuropharmacol. 2023;21(6):1450-1461. doi:10.2174/1570159X20666220327220929
41. Pamenter ME, Richards MD, Buck LT. Anoxia-induced changes in reactive oxygen species and cyclic nucleotides in the painted turtle. J Comp Physiol B. May 2007;177(4):473-81. doi:10.1007/s00360-007-0145-8
42. Hickey AJ, Renshaw GM, Speers-Roesch B, et al. A radical approach to beating hypoxia: depressed free radical release from heart fibres of the hypoxia-tolerant epaulette shark (Hemiscyllum ocellatum). J Comp Physiol B. Jan 2012;182(1):91-100. doi:10.1007/s00360-011-0599-6
43. Buffenstein R. Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J Comp Physiol B. May 2008;178(4):439-45. doi:10.1007/s00360-007-0237-5
44. Eaton L, Pamenter ME. What to do with low O2: Redox adaptations in vertebrates native to hypoxic environments. Comp Biochem Physiol A Mol Integr Physiol. Sep 2022;271:111259. doi:10.1016/j.cbpa.2022.111259
45. Munro D, Baldy C, Pamenter ME, Treberg JR. The exceptional longevity of the naked mole-rat may be explained by mitochondrial antioxidant defenses. Aging Cell. Jun 2019;18(3):e12916. doi:10.1111/acel.12916
46. Schulke S, Dreidax D, Malik A, et al. Living with stress: regulation of antioxidant defense genes in the subterranean, hypoxia-tolerant mole rat, Spalax. Gene. Jun 1 2012;500(2):199-206. doi:10.1016/j.gene.2012.03.019
47. Du SN, Mahalingam S, Borowiec BG, Scott GR. Mitochondrial physiology and reactive oxygen species production are altered by hypoxia acclimation in killifish (Fundulus heteroclitus). J Exp Biol. Apr 15 2016;219(Pt 8):1130-8. doi:10.1242/jeb.132860
48. Reiterer M, Milton SL. Induction of foxo3a protects turtle neurons against oxidative stress. Comp Biochem Physiol A Mol Integr Physiol. May 2020;243:110671. doi:10.1016/j.cbpa.2020.110671
49. Lushchak VI, Lushchak LP, Mota AA, Hermes-Lima M. Oxidative stress and antioxidant defenses in goldfish Carassius auratus during anoxia and reoxygenation. Am J Physiol Regul Integr Comp Physiol. Jan 2001;280(1):R100-7. doi:10.1152/ajpregu.2001.280.1.R100
50. Mahalingam S, McClelland GB, Scott GR. Evolved changes in the intracellular distribution and physiology of muscle mitochondria in high-altitude native deer mice. J Physiol. Jul 15 2017;595(14):4785-4801. doi:10.1113/JP274130
51. Pamenter ME. Adaptations to a hypoxic lifestyle in naked mole-rats. J Exp Biol. Feb 15 2022;225(4)doi:10.1242/jeb.196725
52. Buffenstein R, Amoroso V, Andziak B, et al. The naked truth: a comprehensive clarification and classification of current 'myths' in naked mole-rat biology. Biol Rev Camb Philos Soc. Feb 2022;97(1):115-140. doi:10.1111/brv.12791
53. Cheng H, Pamenter ME. Naked mole-rat brain mitochondria tolerate in vitro ischaemia. J Physiol. Oct 2021;599(20):4671-4685. doi:10.1113/JP281942
54. Wang TH, Eaton L, Pamenter ME. Nitric oxide homeostasis is maintained during acute in vitro hypoxia and following reoxygenation in naked mole-rat but not mouse cortical neurons. Comp Biochem Physiol A Mol Integr Physiol. Dec 2020;250:110792. doi:10.1016/j.cbpa.2020.110792
55. Hadj-Moussa H, Eaton L, Cheng H, Pamenter ME, Storey KB. Naked mole-rats resist the accumulation of hypoxia-induced oxidative damage. Comp Biochem Physiol A Mol Integr Physiol. Nov 2022;273:111282. doi:10.1016/j.cbpa.2022.111282
56. Vakharia K, Shallwani H, Beecher JS, Jowdy PK, Levy EI. 23 - Endovascular Treatment of Acute Stroke and Occlusive Cerebrovascular Disease. In: Ellenbogen RG, Sekhar LN, Kitchen ND, da Silva HB, eds. Principles of Neurological Surgery (Fourth Edition). Elsevier; 2018:343-354.e4.
57. Augsburger F, Filippova A, Rasti D, et al. Pharmacological characterization of the seven human NOX isoforms and their inhibitors. Redox Biology. 2019/09/01/ 2019;26:101272. doi:https://doi.org/10.1016/j.redox.2019.101272
58. Suzuki G, Okamoto K, Kusano T, Matsuda Y, Fuse A, Yokota H. Evaluation of neuronal protective effects of xanthine oxidoreductase inhibitors on severe whole-brain ischemia in mouse model and analysis of xanthine oxidoreductase activity in the mouse brain. Neurol Med Chir (Tokyo). 2015;55(1):77-85. doi:10.2176/nmc.oa.2013-0307
59. Feng Y, Shi W, Huang M, LeBlanc MH. Oxypurinol administration fails to prevent hypoxic-ischemic brain injury in neonatal rats. Brain Res Bull. Feb 15 2003;59(6):453-7. doi:10.1016/s0361-9230(02)00963-2
60. Garcia-Gil M, Camici M, Allegrini S, Pesi R, Petrotto E, Tozzi MG. Emerging Role of Purine Metabolizing Enzymes in Brain Function and Tumors. Int J Mol Sci. Nov 14 2018;19(11)doi:10.3390/ijms19113598
61. Mijailovic NR, Vesic K, Borovcanin MM. The Influence of Serum Uric Acid on the Brain and Cognitive Dysfunction. Front Psychiatry. 2022;13:828476. doi:10.3389/fpsyt.2022.828476
62. Yu ZF, Bruce-Keller AJ, Goodman Y, Mattson MP. Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo. J Neurosci Res. Sep 1 1998;53(5):613-25. doi:10.1002/(SICI)1097-4547(19980901)53:5<613::AID-JNR11>3.0.CO;2-1
63. Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A. Nov 1981;78(11):6858-62. doi:10.1073/pnas.78.11.6858
64. Kutzing MK, Firestein BL. Altered uric acid levels and disease states. J Pharmacol Exp Ther. Jan 2008;324(1):1-7. doi:10.1124/jpet.107.129031
65. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. Jan 2007;87(1):315-424. doi:10.1152/physrev.00029.2006
66. De Miranda BR, Rocha EM, Castro SL, Greenamyre JT. Protection from alpha-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20. NPJ Parkinsons Dis. Dec 8 2020;6(1):38. doi:10.1038/s41531-020-00139-6
67. Votyakova TV, Reynolds IJ. DeltaPsi(m)-Dependent and -independent production of reactive oxygen species by rat brain mitochondria. J Neurochem. Oct 2001;79(2):266-77. doi:10.1046/j.1471-4159.2001.00548.x
68. Ramsay RR, Singer TP. Relation of superoxide generation and lipid peroxidation to the inhibition of NADH-Q oxidoreductase by rotenone, piericidin A, and MPP+. Biochem Biophys Res Commun. Nov 30 1992;189(1):47-52. doi:10.1016/0006-291x(92)91523-s
69. Ibarra-Gutierrez MT, Serrano-Garcia N, Orozco-Ibarra M. Rotenone-Induced Model of Parkinson's Disease: Beyond Mitochondrial Complex I Inhibition. Mol Neurobiol. Apr 2023;60(4):1929-1948. doi:10.1007/s12035-022-03193-8
70. Eaton L, Welch I, Halal AK, Bengtsson J, Pamenter ME. Apocynin reduces dihydroethidium fluorescence in naked mole-rat cortex independently of NADPH oxidase. Comp Biochem Physiol A Mol Integr Physiol. Feb 2023;276:111342. doi:10.1016/j.cbpa.2022.111342
71. Moretti A, Ramirez A, Mink R. Xanthine oxidase does not contribute to apoptosis after brain hypoxia-ischemia in immature rabbits. ISRN Neurosci. 2013;2013:253093. doi:10.1155/2013/253093
72. Park TJ, Reznick J, Peterson BL, et al. Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science. Apr 21 2017;356(6335):307-311. doi:10.1126/science.aab3896
73. Russo E, Leoncini G, Esposito P, Garibotto G, Pontremoli R, Viazzi F. Fructose and Uric Acid: Major Mediators of Cardiovascular Disease Risk Starting at Pediatric Age. Int J Mol Sci. Jun 24 2020;21(12)doi:10.3390/ijms21124479
74. Ali SS, Hsiao M, Zhao HW, Dugan LL, Haddad GG, Zhou D. Hypoxia-adaptation involves mitochondrial metabolic depression and decreased ROS leakage. PLoS One. 2012;7(5):e36801. doi:10.1371/journal.pone.0036801
75. Buffenstein R, Yahav S. Is the naked mole-rat Hererocephalus glaber an endothermic yet poikilothermic mammal? Journal of Thermal Biology. 1991/07/01/ 1991;16(4):227-232. doi:https://doi.org/10.1016/0306-4565(91)90030-6
76. Saldmann F, Viltard M, Leroy C, Friedlander G. The Naked Mole Rat: A Unique Example of Positive Oxidative Stress. Oxid Med Cell Longev. 2019;2019:4502819. doi:10.1155/2019/4502819
77. Pamenter ME, Lau GY, Richards JG, Milsom WK. Naked mole rat brain mitochondria electron transport system flux and H(+) leak are reduced during acute hypoxia. J Exp Biol. Feb 20 2018;221(Pt 4)doi:10.1242/jeb.171397
78. Altenhofer S, Radermacher KA, Kleikers PW, Wingler K, Schmidt HH. Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement. Antioxid Redox Signal. Aug 10 2015;23(5):406-27. doi:10.1089/ars.2013.5814
79. Chen R, Lai UH, Zhu L, Singh A, Ahmed M, Forsyth NR. Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors. Front Cell Dev Biol. 2018;6:132. doi:10.3389/fcell.2018.00132
80. Nagel S, Genius J, Heiland S, Horstmann S, Gardner H, Wagner S. Diphenyleneiodonium and dimethylsulfoxide for treatment of reperfusion injury in cerebral ischemia of the rat. Brain Res. Feb 9 2007;1132(1):210-7. doi:10.1016/j.brainres.2006.11.023
81. Panday A, Sahoo MK, Osorio D, Batra S. NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cell Mol Immunol. Jan 2015;12(1):5-23. doi:10.1038/cmi.2014.89
82. Reis J, Massari M, Marchese S, et al. A closer look into NADPH oxidase inhibitors: Validation and insight into their mechanism of action. Redox Biology. 2020/05/01/ 2020;32:101466. doi:https://doi.org/10.1016/j.redox.2020.101466
83. Lambert AJ, Buckingham JA, Boysen HM, Brand MD. Diphenyleneiodonium acutely inhibits reactive oxygen species production by mitochondrial complex I during reverse, but not forward electron transport. Biochim Biophys Acta. May 2008;1777(5):397-403. doi:10.1016/j.bbabio.2008.03.005
84. Wang Q, Chu CH, Oyarzabal E, et al. Subpicomolar diphenyleneiodonium inhibits microglial NADPH oxidase with high specificity and shows great potential as a therapeutic agent for neurodegenerative diseases. Glia. Dec 2014;62(12):2034-43. doi:10.1002/glia.22724
85. Wind S, Beuerlein K, Eucker T, et al. Comparative pharmacology of chemically distinct NADPH oxidase inhibitors. Br J Pharmacol. Oct 2010;161(4):885-98. doi:10.1111/j.1476-5381.2010.00920.x
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
18. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. Jul 2014;94(3):909-50. doi:10.1152/physrev.00026.2013
19. Turrens JF, Freeman BA, Levitt JG, Crapo JD. The effect of hyperoxia on superoxide production by lung submitochondrial particles. Arch Biochem Biophys. Sep 1982;217(2):401-10. doi:10.1016/0003-9861(82)90518-5
20. Wilson DF, Rumsey WL, Green TJ, Vanderkooi JM. The oxygen dependence of mitochondrial oxidative phosphorylation measured by a new optical method for measuring oxygen concentration. J Biol Chem. Feb 25 1988;263(6):2712-8.
21. Orr AL, Ashok D, Sarantos MR, Shi T, Hughes RE, Brand MD. Inhibitors of ROS production by the ubiquinone-binding site of mitochondrial complex I identified by chemical screening. Free Radic Biol Med. Dec 2013;65:1047-1059. doi:10.1016/j.freeradbiomed.2013.08.170
22. Scialo F, Fernandez-Ayala DJ, Sanz A. Role of Mitochondrial Reverse Electron Transport in ROS Signaling: Potential Roles in Health and Disease. Front Physiol. 2017;8:428. doi:10.3389/fphys.2017.00428
23. Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci U S A. Sep 29 1998;95(20):11715-20. doi:10.1073/pnas.95.20.11715
24. Paddenberg R, Ishaq B, Goldenberg A, et al. Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature. Am J Physiol Lung Cell Mol Physiol. May 2003;284(5):L710-9. doi:10.1152/ajplung.00149.2002
25. Quinlan CL, Orr AL, Perevoshchikova IV, Treberg JR, Ackrell BA, Brand MD. Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions. J Biol Chem. Aug 3 2012;287(32):27255-64. doi:10.1074/jbc.M112.374629
26. Chouchani ET, Pell VR, James AM, et al. A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury. Cell Metab. Feb 9 2016;23(2):254-63. doi:10.1016/j.cmet.2015.12.009
27. Bayir H. Reactive oxygen species. Crit Care Med. Dec 2005;33(12 Suppl):S498-501. doi:10.1097/01.ccm.0000186787.64500.12
28. Kishida KT, Klann E. Sources and targets of reactive oxygen species in synaptic plasticity and memory. Antioxid Redox Signal. Feb 2007;9(2):233-44. doi:10.1089/ars.2007.9.ft-8
29. Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol. Mar 16 2004;555(Pt 3):589-606. doi:10.1113/jphysiol.2003.055913
30. Collin F. Chemical Basis of Reactive Oxygen Species Reactivity and Involvement in Neurodegenerative Diseases. Int J Mol Sci. May 15 2019;20(10)doi:10.3390/ijms20102407
31. Hille R, Hall J, Basu P. The mononuclear molybdenum enzymes. Chem Rev. Apr 9 2014;114(7):3963-4038. doi:10.1021/cr400443z
32. Godber BL, Doel JJ, Sapkota GP, et al. Reduction of nitrite to nitric oxide catalyzed by xanthine oxidoreductase. J Biol Chem. Mar 17 2000;275(11):7757-63. doi:10.1074/jbc.275.11.7757
33. Nanduri J, Vaddi DR, Khan SA, et al. HIF-1alpha activation by intermittent hypoxia requires NADPH oxidase stimulation by xanthine oxidase. PLoS One. 2015;10(3):e0119762. doi:10.1371/journal.pone.0119762
34. Abramov AY, Scorziello A, Duchen MR. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci. Jan 31 2007;27(5):1129-38. doi:10.1523/JNEUROSCI.4468-06.2007
35. Babior BM. The respiratory burst oxidase. Adv Enzymol Relat Areas Mol Biol. 1992;65:49-95. doi:10.1002/9780470123119.ch2
36. Vignais PV. The superoxide-generating NADPH oxidase: structural aspects and activation mechanism. Cell Mol Life Sci. Sep 2002;59(9):1428-59. doi:10.1007/s00018-002-8520-9
37. Mennerich D, Kellokumpu S, Kietzmann T. Hypoxia and Reactive Oxygen Species as Modulators of Endoplasmic Reticulum and Golgi Homeostasis. Antioxid Redox Signal. Jan 1 2019;30(1):113-137. doi:10.1089/ars.2018.7523
38. Sies H, Belousov VV, Chandel NS, et al. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nat Rev Mol Cell Biol. Feb 21 2022;doi:10.1038/s41580-022-00456-z
39. Welker AF, Campos EG, Cardoso LA, Hermes-Lima M. Role of catalase on the hypoxia/reoxygenation stress in the hypoxia-tolerant Nile tilapia. Am J Physiol Regul Integr Comp Physiol. May 2012;302(9):R1111-8. doi:10.1152/ajpregu.00243.2011
40. Eaton L, Wang T, Roy M, Pamenter ME. Naked Mole-Rat Cortex Maintains Reactive Oxygen Species Homeostasis During In Vitro Hypoxia or Ischemia and Reperfusion. Curr Neuropharmacol. 2023;21(6):1450-1461. doi:10.2174/1570159X20666220327220929
41. Pamenter ME, Richards MD, Buck LT. Anoxia-induced changes in reactive oxygen species and cyclic nucleotides in the painted turtle. J Comp Physiol B. May 2007;177(4):473-81. doi:10.1007/s00360-007-0145-8
42. Hickey AJ, Renshaw GM, Speers-Roesch B, et al. A radical approach to beating hypoxia: depressed free radical release from heart fibres of the hypoxia-tolerant epaulette shark (Hemiscyllum ocellatum). J Comp Physiol B. Jan 2012;182(1):91-100. doi:10.1007/s00360-011-0599-6
43. Buffenstein R. Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J Comp Physiol B. May 2008;178(4):439-45. doi:10.1007/s00360-007-0237-5
44. Eaton L, Pamenter ME. What to do with low O2: Redox adaptations in vertebrates native to hypoxic environments. Comp Biochem Physiol A Mol Integr Physiol. Sep 2022;271:111259. doi:10.1016/j.cbpa.2022.111259
45. Munro D, Baldy C, Pamenter ME, Treberg JR. The exceptional longevity of the naked mole-rat may be explained by mitochondrial antioxidant defenses. Aging Cell. Jun 2019;18(3):e12916. doi:10.1111/acel.12916
46. Schulke S, Dreidax D, Malik A, et al. Living with stress: regulation of antioxidant defense genes in the subterranean, hypoxia-tolerant mole rat, Spalax. Gene. Jun 1 2012;500(2):199-206. doi:10.1016/j.gene.2012.03.019
47. Du SN, Mahalingam S, Borowiec BG, Scott GR. Mitochondrial physiology and reactive oxygen species production are altered by hypoxia acclimation in killifish (Fundulus heteroclitus). J Exp Biol. Apr 15 2016;219(Pt 8):1130-8. doi:10.1242/jeb.132860
48. Reiterer M, Milton SL. Induction of foxo3a protects turtle neurons against oxidative stress. Comp Biochem Physiol A Mol Integr Physiol. May 2020;243:110671. doi:10.1016/j.cbpa.2020.110671
49. Lushchak VI, Lushchak LP, Mota AA, Hermes-Lima M. Oxidative stress and antioxidant defenses in goldfish Carassius auratus during anoxia and reoxygenation. Am J Physiol Regul Integr Comp Physiol. Jan 2001;280(1):R100-7. doi:10.1152/ajpregu.2001.280.1.R100
50. Mahalingam S, McClelland GB, Scott GR. Evolved changes in the intracellular distribution and physiology of muscle mitochondria in high-altitude native deer mice. J Physiol. Jul 15 2017;595(14):4785-4801. doi:10.1113/JP274130
51. Pamenter ME. Adaptations to a hypoxic lifestyle in naked mole-rats. J Exp Biol. Feb 15 2022;225(4)doi:10.1242/jeb.196725
52. Buffenstein R, Amoroso V, Andziak B, et al. The naked truth: a comprehensive clarification and classification of current 'myths' in naked mole-rat biology. Biol Rev Camb Philos Soc. Feb 2022;97(1):115-140. doi:10.1111/brv.12791
53. Cheng H, Pamenter ME. Naked mole-rat brain mitochondria tolerate in vitro ischaemia. J Physiol. Oct 2021;599(20):4671-4685. doi:10.1113/JP281942
54. Wang TH, Eaton L, Pamenter ME. Nitric oxide homeostasis is maintained during acute in vitro hypoxia and following reoxygenation in naked mole-rat but not mouse cortical neurons. Comp Biochem Physiol A Mol Integr Physiol. Dec 2020;250:110792. doi:10.1016/j.cbpa.2020.110792
55. Hadj-Moussa H, Eaton L, Cheng H, Pamenter ME, Storey KB. Naked mole-rats resist the accumulation of hypoxia-induced oxidative damage. Comp Biochem Physiol A Mol Integr Physiol. Nov 2022;273:111282. doi:10.1016/j.cbpa.2022.111282
56. Vakharia K, Shallwani H, Beecher JS, Jowdy PK, Levy EI. 23 - Endovascular Treatment of Acute Stroke and Occlusive Cerebrovascular Disease. In: Ellenbogen RG, Sekhar LN, Kitchen ND, da Silva HB, eds. Principles of Neurological Surgery (Fourth Edition). Elsevier; 2018:343-354.e4.
57. Augsburger F, Filippova A, Rasti D, et al. Pharmacological characterization of the seven human NOX isoforms and their inhibitors. Redox Biology. 2019/09/01/ 2019;26:101272. doi:https://doi.org/10.1016/j.redox.2019.101272
58. Suzuki G, Okamoto K, Kusano T, Matsuda Y, Fuse A, Yokota H. Evaluation of neuronal protective effects of xanthine oxidoreductase inhibitors on severe whole-brain ischemia in mouse model and analysis of xanthine oxidoreductase activity in the mouse brain. Neurol Med Chir (Tokyo). 2015;55(1):77-85. doi:10.2176/nmc.oa.2013-0307
59. Feng Y, Shi W, Huang M, LeBlanc MH. Oxypurinol administration fails to prevent hypoxic-ischemic brain injury in neonatal rats. Brain Res Bull. Feb 15 2003;59(6):453-7. doi:10.1016/s0361-9230(02)00963-2
60. Garcia-Gil M, Camici M, Allegrini S, Pesi R, Petrotto E, Tozzi MG. Emerging Role of Purine Metabolizing Enzymes in Brain Function and Tumors. Int J Mol Sci. Nov 14 2018;19(11)doi:10.3390/ijms19113598
61. Mijailovic NR, Vesic K, Borovcanin MM. The Influence of Serum Uric Acid on the Brain and Cognitive Dysfunction. Front Psychiatry. 2022;13:828476. doi:10.3389/fpsyt.2022.828476
62. Yu ZF, Bruce-Keller AJ, Goodman Y, Mattson MP. Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo. J Neurosci Res. Sep 1 1998;53(5):613-25. doi:10.1002/(SICI)1097-4547(19980901)53:5<613::AID-JNR11>3.0.CO;2-1
63. Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A. Nov 1981;78(11):6858-62. doi:10.1073/pnas.78.11.6858
64. Kutzing MK, Firestein BL. Altered uric acid levels and disease states. J Pharmacol Exp Ther. Jan 2008;324(1):1-7. doi:10.1124/jpet.107.129031
65. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. Jan 2007;87(1):315-424. doi:10.1152/physrev.00029.2006
66. De Miranda BR, Rocha EM, Castro SL, Greenamyre JT. Protection from alpha-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20. NPJ Parkinsons Dis. Dec 8 2020;6(1):38. doi:10.1038/s41531-020-00139-6
67. Votyakova TV, Reynolds IJ. DeltaPsi(m)-Dependent and -independent production of reactive oxygen species by rat brain mitochondria. J Neurochem. Oct 2001;79(2):266-77. doi:10.1046/j.1471-4159.2001.00548.x
68. Ramsay RR, Singer TP. Relation of superoxide generation and lipid peroxidation to the inhibition of NADH-Q oxidoreductase by rotenone, piericidin A, and MPP+. Biochem Biophys Res Commun. Nov 30 1992;189(1):47-52. doi:10.1016/0006-291x(92)91523-s
69. Ibarra-Gutierrez MT, Serrano-Garcia N, Orozco-Ibarra M. Rotenone-Induced Model of Parkinson's Disease: Beyond Mitochondrial Complex I Inhibition. Mol Neurobiol. Apr 2023;60(4):1929-1948. doi:10.1007/s12035-022-03193-8
70. Eaton L, Welch I, Halal AK, Bengtsson J, Pamenter ME. Apocynin reduces dihydroethidium fluorescence in naked mole-rat cortex independently of NADPH oxidase. Comp Biochem Physiol A Mol Integr Physiol. Feb 2023;276:111342. doi:10.1016/j.cbpa.2022.111342
71. Moretti A, Ramirez A, Mink R. Xanthine oxidase does not contribute to apoptosis after brain hypoxia-ischemia in immature rabbits. ISRN Neurosci. 2013;2013:253093. doi:10.1155/2013/253093
72. Park TJ, Reznick J, Peterson BL, et al. Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science. Apr 21 2017;356(6335):307-311. doi:10.1126/science.aab3896
73. Russo E, Leoncini G, Esposito P, Garibotto G, Pontremoli R, Viazzi F. Fructose and Uric Acid: Major Mediators of Cardiovascular Disease Risk Starting at Pediatric Age. Int J Mol Sci. Jun 24 2020;21(12)doi:10.3390/ijms21124479
74. Ali SS, Hsiao M, Zhao HW, Dugan LL, Haddad GG, Zhou D. Hypoxia-adaptation involves mitochondrial metabolic depression and decreased ROS leakage. PLoS One. 2012;7(5):e36801. doi:10.1371/journal.pone.0036801
75. Buffenstein R, Yahav S. Is the naked mole-rat Hererocephalus glaber an endothermic yet poikilothermic mammal? Journal of Thermal Biology. 1991/07/01/ 1991;16(4):227-232. doi:https://doi.org/10.1016/0306-4565(91)90030-6
76. Saldmann F, Viltard M, Leroy C, Friedlander G. The Naked Mole Rat: A Unique Example of Positive Oxidative Stress. Oxid Med Cell Longev. 2019;2019:4502819. doi:10.1155/2019/4502819
77. Pamenter ME, Lau GY, Richards JG, Milsom WK. Naked mole rat brain mitochondria electron transport system flux and H(+) leak are reduced during acute hypoxia. J Exp Biol. Feb 20 2018;221(Pt 4)doi:10.1242/jeb.171397
78. Altenhofer S, Radermacher KA, Kleikers PW, Wingler K, Schmidt HH. Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement. Antioxid Redox Signal. Aug 10 2015;23(5):406-27. doi:10.1089/ars.2013.5814
79. Chen R, Lai UH, Zhu L, Singh A, Ahmed M, Forsyth NR. Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors. Front Cell Dev Biol. 2018;6:132. doi:10.3389/fcell.2018.00132
80. Nagel S, Genius J, Heiland S, Horstmann S, Gardner H, Wagner S. Diphenyleneiodonium and dimethylsulfoxide for treatment of reperfusion injury in cerebral ischemia of the rat. Brain Res. Feb 9 2007;1132(1):210-7. doi:10.1016/j.brainres.2006.11.023
81. Panday A, Sahoo MK, Osorio D, Batra S. NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cell Mol Immunol. Jan 2015;12(1):5-23. doi:10.1038/cmi.2014.89
82. Reis J, Massari M, Marchese S, et al. A closer look into NADPH oxidase inhibitors: Validation and insight into their mechanism of action. Redox Biology. 2020/05/01/ 2020;32:101466. doi:https://doi.org/10.1016/j.redox.2020.101466
83. Lambert AJ, Buckingham JA, Boysen HM, Brand MD. Diphenyleneiodonium acutely inhibits reactive oxygen species production by mitochondrial complex I during reverse, but not forward electron transport. Biochim Biophys Acta. May 2008;1777(5):397-403. doi:10.1016/j.bbabio.2008.03.005
84. Wang Q, Chu CH, Oyarzabal E, et al. Subpicomolar diphenyleneiodonium inhibits microglial NADPH oxidase with high specificity and shows great potential as a therapeutic agent for neurodegenerative diseases. Glia. Dec 2014;62(12):2034-43. doi:10.1002/glia.22724
85. Wind S, Beuerlein K, Eucker T, et al. Comparative pharmacology of chemically distinct NADPH oxidase inhibitors. Br J Pharmacol. Oct 2010;161(4):885-98. doi:10.1111/j.1476-5381.2010.00920.x