Nitrite reductase activity is a novel function of mammalian mitochondria
Open accessAbstract
Nitrite, which is the major stable degradation product of nitric oxide, exists in all tissues capable of nitric oxide synthesis from L‐arginine. The present study provides experimental evidence that nitrite in contact with respiring mitochondria accepts reducing equivalents from the ubiquinone cycle of the respiratory chain. Univalent reduction of nitrite was totally inhibited by myxothiazol. We therefore conclude on the involvement of redox cycling that ubisemiquinone is associated with the bc 1 complex. Recycling of nitric oxide degradation products via these electron carriers may become a threat to energy‐linked respiration since nitric oxide in direct contact with mitochondria was shown to slow the energy‐linked respiration down and to trigger a mitochondrial source for superoxide radicals. Until now, the existence of nitrite reductase activity was only demonstrated in plants and bacteria. In addition, the present observation elucidates the existence of a nitric oxide synthase‐independent nitric oxide source.
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Under hypoxic conditions, when oxygen-dependent NO synthases may malfunction, nitrite reduction is greatly increased.
“In situations of hypoxia, when the oxygen-dependent NO synthases may become dysfunctional, nitrite reduction is instead greatly enhanced.”
From Nitrate and nitrite in biology, nutrition and therapeutics (2009) · cites this paper as [9]
The Results (section 3; page unavailable) show nitrite-to-NO conversion under anaerobic conditions, and the Discussion (section 4; page unavailable) links this pathway to the lack of oxygen during ischemia. The paper does not establish that nitrite reduction is greatly increased relative to oxygenated conditions or state that NO synthases become dysfunctional under hypoxia. (LLM, conf=0.84)
Experimental — accuracy not yet measuredComponents of the respiratory chain can reduce nitrite to NO.
“Sruti Shiva (University of Pittsburgh) reviewed a number of studies demonstrating that components of the respiratory chain can reduce nitrite to NO (refs. 4,9)”
From Nitrate and nitrite in biology, nutrition and therapeutics (2009) · cites this paper as [9]
Cytochrome c oxidase is an important regulator of nitrite reduction to NO in the mitochondria.
“This was later confirmed by Kozlov’s group who illustrated that cytochrome c oxidase was an important regulator of nitrite reduction to NO in the mitochondria [120, 121].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [120]
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Dietary Nitrate, Nitric Oxide, and Cardiovascular Health
Bondonno, C. P., Croft, K. D., & Hodgson, J. M. (2016) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2013.811212 · Cited by 141 · see citing works
“…et al., 1997), hemoglobin (Cosby et al., 2003), myoglobin (Shiva et al., 2007a), neuroglobin (Petersen et al., 2008), respiratory chain enzymes (Kozlov et al., 1999), cytochrome P 450 (Kozlov et al., 2003), aldehyde oxidase (Li et al., 2008), carbonic anhydrase (Aamand et al., 2009), and NO…”
BackgroundNitrite–nitric oxide control of mitochondrial respiration at the frontier of anoxia
Benamar, A., Rolletschek, H., Borisjuk, L., Avelange‐Macherel, M., Curien, G., Mostefai, H. A., Andriantsitohaina, R., & Macherel, D. (2008) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2008.06.002 · Cited by 140 · see citing works
“Briefly, at low O2 content, nitrite is reduced into NO by the electron transfer chain, likely at the external Q site of complex III [24,25].”
BackgroundResultInfluentialMechanisms involved in the pro- and anti-apoptotic role of NO in human leukemia
Kolb, J. P. (2000) · Leukemia · doi:10.1038/sj.leu.2401896 · Cited by 139 · see citing works
Penna, C. R. R., Cappello, S., Mancardi, D., Raimondo, S., Rastaldo, R., Gattullo, D., Losano, G., & Pagliaro, P. (2005) · Basic Research in Cardiology · doi:10.1007/s00395-005-0543-6 · Cited by 137 · see citing works
Mechanisms of nitrite reduction to nitric oxide in the heart and vessel wall
Zweier, J. L., Li, H., Samouilov, A., & Liu, X. (2010) · Nitric Oxide · doi:10.1016/j.niox.2009.12.004 · Cited by 132 · see citing works
“studies have demonstrated that nitrite can be an important source rather than simply a product of NO in mammalian cells and tissues [8-24].”
BackgroundThe Key Role of Nitric Oxide in Hypoxia: Hypoxic Vasodilation and Energy Supply–Demand Matching
Umbrello, M., Dyson, A., Feelisch, M., & Singer, M. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4979 · Cited by 131 · see citing works
“…significant NO 2 - reductase activity, as do heme protein-containing enzymes such as the mitochondrial electron transport chain cytochromes (17, 49, 138), the cytochrome P450 family of microsomal heme proteins (151), and aldehyde dehydrogenase (ALDH2), a mitochondrial enzyme involved in ethanol…”
Nitric oxide and hydrogen sulfide crosstalk during heavy metal stress in plants
Shivaraj, S. M., Vats, S., Bhat, J. A., Dhakte, P., Goyal, V., Khatri, P., Kumawat, S., Singh, A. K., Prasad, M., Sonah, H., et al. (2019) · Physiologia Plantarum · doi:10.1111/ppl.13028 · Cited by 129 · see citing works
Production and Scavenging of Nitric Oxide by Barley Root Mitochondria
Gupta, K. J., & Kaiser, W. M. (2010) · Plant and Cell Physiology · doi:10.1093/pcp/pcq022 · Cited by 128 · see citing works
Nitroglycerin as a comparative experimental model of migraine pain: From animal to human and back
Demartini, C., Greco, R., Zanaboni, A. M., Sances, G., Icco, R. D., Borsook, D., & Tassorelli, C. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.02.002 · Cited by 125 · see citing works
Mitochondrial NO and reactive nitrogen species production: Does mtNOS exist?
Lacza, Z., Pankotai, E., Csordás, A., Gerő, D., Kiss, L., Horvath, E. M., Kollai, M., Busija, D. W., & Szabó, C. (2005) · Nitric Oxide · doi:10.1016/j.niox.2005.05.011 · Cited by 126 · see citing works
The enigma of nitroglycerin bioactivation and nitrate tolerance: news, views and troubles
Mayer, B., & Beretta, M. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.263 · Cited by 123 · see citing works
“On the basis of accumulation of nitroso-haemoglobin in isolated rat liver mitochondria incubated with respiratory substrates in the presence of nitrite, Kozlov et al. (1999) proposed that complex III catalyses nitrite reduction under anaerobic”
BackgroundPlant mitochondrial function during anaerobiosis
Igamberdiev, A. U., & Hill, R. D. (2008) · Annals of Botany · doi:10.1093/aob/mcn100 · Cited by 124 · see citing works
“Nitrite reduction by the mammalian (Kozlov et al., 1999), algal (Tischner et al., 2004) and plant (Planchet et al., 2005) mitochondria is strongly anaerobic and it is likely that it does not involve additional enzymes associated with the mitochondrial electron transport chain.”
BackgroundNitrite Reduction and Cardiovascular Protection
Omar, S. A., & Webb, A. J. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.01.012 · Cited by 121 · see citing works
Nitric oxide and its derivatives in the cancer battlefield
Kamm, A., Przychodzen, P., Kuban-Jankowska, A., Jacewicz, D., Dabrowska, A. M., Nussberger, S., Wozniak, M., & Gorska-Ponikowska, M. (2019) · Nitric Oxide · doi:10.1016/j.niox.2019.09.005 · Cited by 120 · see citing works
Nitrosylation of Cytochrome c during Apoptosis
Schonhoff, C. M., Gaston, B. M., & Mannick, J. B. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212459200 · Cited by 120 · see citing works
The emerging roles of nitric oxide (NO) in plant mitochondria
Gupta, K. J., Igamberdiev, A. U., Manjunatha, G., Segu, S., Morán, J. F., Neelawarne, B., Bauwe, H., & Kaiser, W. M. (2011) · Plant Science · doi:10.1016/j.plantsci.2011.03.018 · Cited by 119 · see citing works
Ball, K. A., Castello, P. R., & Poyton, R. Ο. (2010) · Journal of Photochemistry and Photobiology B Biology · doi:10.1016/j.jphotobiol.2010.12.002 · Cited by 119 · see citing works
“This, together with the observation that cyanide inhibits NO production, supports the conclusion that NO synthesis in these solubilized mitochondria is produced by Cco and not cytochrome c or ubiquinone/cyt bc1 (Complex III) which have been proposed to have NO 2 reductase activity [42,43].”
BackgroundBioactivation of Nitroglycerin by the Mitochondrial Aldehyde Dehydrogenase
Chen, Z., & Stamler, J. S. (2006) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2006.05.001 · Cited by 117 · see citing works
Association of Dietary Nitrate Intake With Primary Open-Angle Glaucoma
Kang, J. H., Willett, W. C., ROSNER, B. A., Buys, E. S., Wiggs, J. L., & Pasquale, L. R. (2016) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2015.5601 · Cited by 116 · see citing works
Nitric Oxide Signaling and Regulation in the Cardiovascular System: Recent Advances
Carlström, M., Weitzberg, E., & Lundberg, J. O. (2024) · Pharmacological Reviews · doi:10.1124/pharmrev.124.001060 · Cited by 103 · see citing works
Inorganic nitrite therapy: historical perspective and future directions
Kevil, C. G., Kolluru, G. K., Pattillo, C. B., & Giordano, T. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.04.042 · Cited by 113 · see citing works
Human skeletal muscle nitrate store: Influence of dietary nitrate supplementation and exercise
Wylie, L. J., Park, J. W., Vanhatalo, A., Kadach, S., Black, M. I., Stoyanov, Z., Schechter, A. N., Jones, A. M., & Piknova, B. (2019) · The Journal of Physiology · doi:10.1113/jp278076 · Cited by 116 · see citing works
“2007), mitochondrial enzymes (Kozlov et al. 1999) and XOR (Piknova et al.”
BackgroundInfluentialThe role of nitrite in nitric oxide homeostasis: A comparative perspective
Jensen, F. B. (2009) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2009.02.010 · Cited by 112 · see citing works
Novel Aspects of Endothelium-Dependent Regulation of Vascular Tone
Villar, I. C., Francis, S., Webb, A., Hobbs, A. J., & Ahluwalia, A. (2006) · Kidney International · doi:10.1038/sj.ki.5001680 · Cited by 112 · see citing works
Dalsgaard, T., Simonsen, U., & Fago, A. (2007) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01298.2006 · Cited by 110 · see citing works
Heme proteins mediate the conversion of nitrite to nitric oxide in the vascular wall
Alzawahra, W. F., Talukder, M. A. H., Liu, X., Samouilov, A., & Zweier, J. L. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00374.2008 · Cited by 111 · see citing works
Pignatelli, P., Fabietti, G., Ricci, A., Piattelli, A., & Curia, M. C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207538 · Cited by 110 · see citing works
Anoxic nitric oxide cycling in plants: participating reactions and possible mechanisms
Igamberdiev, A. U., Bykova, N. V., Shah, J. K., & Hill, R. D. (2009) · Physiologia Plantarum · doi:10.1111/j.1399-3054.2009.01314.x · Cited by 110 · see citing works
“2006, 2008), the bc1 complex (Kozlov et al. 1999), and cytochrome c itself (Basu et al.”
BackgroundMitochondrial nitric oxide synthase: current concepts and controversies
Lacza, Z. (2009) · Frontiers in bioscience · doi:10.2741/3539 · Cited by 106 · see citing works
“The first reports that initiated the hypothesis that the mitochondrial respiratory chain is a source of NO were performed by Kozlov and colleagues (12, 13).”
BackgroundHypocitrullinemia in patients with MELAS: an insight into the “MELAS paradox”
Naini, A., Kaufmann, P., Shanske, S., Engelstad, K., Vivo, D. C. D., & Schon, E. A. (2004) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2004.11.026 · Cited by 103 · see citing works
Increase in gastric pH reduces hypotensive effect of oral sodium nitrite in rats
Pinheiro, L. C., Montenegro, M. F., Amaral, J. H., Ferreira, G. C., Oliveira, A. M., & Tanus-Santos, J. E. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.06.001 · Cited by 101 · see citing works
Nitrosative stress in Parkinson’s disease
Stykel, M. G., & Ryan, S. D. (2022) · npj Parkinson s Disease · doi:10.1038/s41531-022-00370-3 · Cited by 97 · see citing works
Kollau, A., HOFER, A., Russwurm, M., Koesling, D., Keung, W. M., Schmidt, K., Brünner, F., & Mayer, B. (2005) · Biochemical Journal · doi:10.1042/bj20041354 · Cited by 97 · see citing works
The nitrate‐nitrite‐nitric oxide pathway: Its role in human exercise physiology
Bailey, S. J., Vanhatalo, A., Winyard, P. G., & JONES, A. M. (2011) · European Journal of Sport Science · doi:10.1080/17461391.2011.635705 · Cited by 96 · see citing works
“increased plasma [NO2 ] and reduced the O2 cost of submaximal cycle exercise in humans (Larsen et al., 2007; Table I). Blood [lactate], heart rate and minute ventilation ( _ VE) were not significantly impacted by NaNO3 supplementation; however, the underlying mechanisms for the action of NaNO3 and how NaNO3 administra…”
ResultRedox signaling: Bioinorganic chemistry at its best
Ullrich, V., & Kissner, R. (2006) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2006.09.019 · Cited by 93 · see citing works
Effects of NO on mitochondrial function in cardiomyocytes: Pathophysiological relevance
Davidson, S. M., & Duchen, M. R. (2006) · Cardiovascular Research · doi:10.1016/j.cardiores.2006.01.019 · Cited by 91 · see citing works
“For example, respiring mitochondria readily reduce added nitrite to NO [47,48] and NO may be produced nonenzymatically from the conversion of nitrite or nitrate [49], or by the reductase activity of xanthine oxidoreductase [50,51].”
Background
- Authors
- Kozlov, A. V., Staniek, K., & Nohl, H.
- Affiliations
- University of Veterinary Medicine Vienna (AT)
- Corresponding author
- Nohl, Hans
- ORCID
- Kozlov, Andrey V
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 1999-07-02
- Volume
- 454
- Issue
- 1-2
- Pages
- 127-130
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- OpenAlex
- W2149980494
- Cited by
- 342
- References
- 14
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 4 · 2020: 9 · 2019: 15 · 2018: 11 · 2017: 16 · 2016: 14 · 2015: 22 · 2014: 15 · 2013: 9 · 2012: 17
- FWCI
- 2.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- FEBS Letters (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Keywords
- nitrite reductase, mitochondria, nitric oxide degradation, nitrite, bc1 complex, ubisemiquinone, myxothiazol, redox cycling, superoxide, electron transport chain
- MeSH terms
- Animals, Electron Spin Resonance Spectroscopy, Electron Transport, Liver, Mitochondria, Models, Biological, Nitric Oxide, Nitrite Reductases, Cell Respiration, Rats
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