Cited by 207Nitric Oxide and Endothelin EffectsRedox biology and oxidative stressMitochondrial Function and Pathology

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Nitrite: A physiological store of nitric oxide and modulator of mitochondrial function

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Shiva, Sruti·2013·Redox Biology

DOI 10.1016/j.redox.2012.11.005PMC PMC3661298

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Abstract

Nitrite, long considered a biologically inert metabolite of nitric oxide (NO) oxidation, is now accepted as a physiological storage pool of NO that can be reduced to bioactive NO in hypoxic conditions to mediate a spectrum of physiological responses in blood and tissue. This graphical review will provide a broad overview of the role of nitrite in physiology, focusing on its formation and reduction to NO as well as its regulation of the mitochondrion- an emerging subcellular target for its biological actions in tissues.

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Andring, J. T., Lomelino, C. L., Tu, C., Silverman, D. N., McKENNA, R. V., & Swenson, E. R. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.01.015 · Cited by 27
Nitrosative stress and cytokines are linked with the severity of sepsis and organ dysfunction
Kumar, S., Gupta, E., Srivastava, V. K., Kaushik, S., Saxena, J., Goyal, L., Mehta, S. K., & Jyoti, A. (2018) · British Journal of Biomedical Science · doi:10.1080/09674845.2018.1543160 · Cited by 27
“Nitrite is a stable and inert metabolite of NO that mediates a range of physiological responses in blood and tissue [16,20].”
Background
Alterations in platelet bioenergetics in Group 2 PH-HFpEF patients
Nguyen, Q. L., Wang, Y., Helbling, N. L., Simon, M. A. M., & Shiva, S. (2019) · PLoS ONE · doi:10.1371/journal.pone.0220490 · Cited by 26
“However, acute nitrite or pure NO during hypoxia are known to inhibit mitochondrial respiration through its binding to complex IV (cytochrome c oxidase) [26, 54].”
BackgroundSelf-citation
Hepatoprotective effect of Thymus vulgaris extract on sodium nitrite-induced changes in oxidative stress, antioxidant and inflammatory marker expression
Soliman, M. M., Aldhahrani, A., & Metwally, M. M. M. (2021) · Scientific Reports · doi:10.1038/s41598-021-85264-9 · Cited by 28
“96 Ethyl 7-(4-hydroxy-3-methoxy-5-nitrophenyl)-5-methyl-4,7-dihydro-[1,2,4]triazolo[1,5-a] pyrimidine-6-carboxylate 375 C16H17N5O6”
Nitric Oxide Signalling in Yeast
Astuti, R. I., Nasuno, R., & Takagi, H. (2018) · Advances in microbial physiology/Advances in Microbial Physiology · doi:10.1016/bs.ampbs.2018.01.003 · Cited by 26
Biological Assessment of the NO-Dependent Endothelial Function
Boughaleb, H., Lobysheva, I. I., Zotti, F. D., Balligand, J., & Montiel, V. (2022) · Molecules · doi:10.3390/molecules27227921 · Cited by 25
Effects of Extended-Release 7-Nitroindazole Gel Formulation Treatment on the Behavior of Shank3 Mouse Model of Autism
Abdel-Haq, M., Ojha, S. K., Hamoudi, W., Kumar, A., Tripathi, M. K., Khaliulin, I., Domb, A. J., & Amal, H. (2023) · Nitric Oxide · doi:10.1016/j.niox.2023.09.003 · Cited by 24
Daily NO rhythms in peripheral clocks in aging male Wistar rats: protective effects of exogenous melatonin
Vinod, C., & Jagota, A. (2016) · Biogerontology · doi:10.1007/s10522-016-9656-6 · Cited by 25
“The non-enzymatic production of NO involves the reduction of its metabolite nitrite (Shiva 2013; Sindler et al. 2014; Zhao et al. 2015).”
Background
Anxiety-like behavioural effects of extremely low-frequency electromagnetic field in rats
Djordjević, N. Z., Paunović, M. G., & Peulić, A. S. (2017) · Environmental Science and Pollution Research · doi:10.1007/s11356-017-9710-1 · Cited by 24
“Nitrites formed by decomposition of ONOO- in neural tissues could be reduced to NO by the neuroglobin (Shiva 2013), which leads to NO accumulation in hypothalamus.”
Background
Recent insights into nitrite signaling processes in blood
Helms, C. C., Liu, X., & Kim‐Shapiro, D. B. (2016) · Biological Chemistry · doi:10.1515/hsz-2016-0263 · Cited by 23
“The auto-oxidation of NO to nitrite proceeds slowly (k = 2 × 106 m−2 s−1) compared to oxidation of nitric oxide to nitrate by hemoglobin (k = 8 × 107 m−1 s−1) (Shiva, 2012).”
Background
Real-Time High-Sensitivity Reaction Monitoring of Important Nitrogen-Cycle Synthons by 15N Hyperpolarized Nuclear Magnetic Resonance
Rayner, P. J., Fekete, M., Gater, C. A., Ahwal, F., Turner, N., Kennerley, A. J., & Duckett, S. B. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c02619 · Cited by 23
Proteome Profiling of RNF213 Depleted Cells Reveals Nitric Oxide Regulator DDAH1 Antilisterial Activity
Martina, L., Asselman, C., Théry, F., Boucher, K. L., Delhaye, L., Maia, T. M., Dermaut, B., Eyckerman, S., & Impens, F. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.735416 · Cited by 23
“DDAH1 has not directly been linked to infection, but as an important regulator of nitric oxide (NO) generation, the protein is an interesting target since NO plays an important role in immune defence as well as vascular regulation (Shiva, 2013; Hulin et al., 2020).”
Background
Preferential nitrite inhibition of the mitochondrial F1FO-ATPase activities when activated by Ca2+ in replacement of the natural cofactor Mg2+
Nesci, S., Ventrella, V., Trombetti, F., Pirini, M., & Pagliarani, A. (2015) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2015.11.004 · Cited by 22
High‐performance liquid chromatographic cartridge with gradient elution capability coupled with UV absorbance detector and mass spectrometer for peptide and protein analysis
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“It has been shown that myoglobin, as an oxygen carrier, plays a vital role in preventing the heart from injury [19, 20].”
Binding of Erythrocyte Hemoglobin to the Membrane to Realize Signal-Regulatory Function (Review)
Kosmachevskaya, O. V., Nasybullina, E. I., Blindar, V. N., & Topunov, A. F. (2019) · Applied Biochemistry and Microbiology · doi:10.1134/s0003683819020091 · Cited by 22
New Single-Layered Paper-Based Microfluidic Devices for the Analysis of Nitrite and Glucose Built via Deposition of Adhesive Tape
Yu, P., Deng, M., & Yang, Y. (2019) · Sensors · doi:10.3390/s19194082 · Cited by 22
“Nitrite is an important intermediate in biological systems and it can be used as food additives [31].”
Background
Nitrite Confers Preconditioning and Cytoprotection After Ischemia/Reperfusion Injury Through the Modulation of Mitochondrial Function
Portella, R. D. L., Bickta, J., & Shiva, S. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2015.6260 · Cited by 21
“- ), the stable oxidation product of NO, is now accepted as an endocrine reservoir of NO, which represents an alternative mechanism to generate bioactive NO, particularly in situations such as hypoxia when NO production by nitric oxide synthase (NOS) enzymes becomes oxygen limited (132, 134, 191).”
Self-citation
Human Indoleamine 2,3-Dioxygenase 1 Is an Efficient Mammalian Nitrite Reductase
Lim, Y. J., Foo, T. C., Yeung, A. W. S., Tu, X., Ma, Y., Hawkins, C. L., Witting, P. K., Jameson, G. N. L., Terentis, A. C., & Thomas, S. R. (2018) · Biochemistry · doi:10.1021/acs.biochem.8b01231 · Cited by 21
Differential mitochondrial dinitrosyliron complex formation by nitrite and nitric oxide
Thomas, D. D., Corey, C. G., Hickok, J. R., Wang, Y., & Shiva, S. (2017) · Redox Biology · doi:10.1016/j.redox.2017.12.007 · Cited by 21
Self-citation
Nitrite Reductases in Biomedicine: From Natural Enzymes to Artificial Mimics
Zhu, S., Liu, Z., Hu, B., Feng, Y., & Pan, G. (2025) · Research · doi:10.34133/research.0710 · Cited by 20
“…downstream signaling that induces various biological responses, including hypoxic vasodilation, promotion of angiogenesis, modulation of glucose metabolism, enhanced exercise efficiency, regulation of mitochondrial function, and increased tolerance to ischemia/reperfusion (I/R) injury [ 100 ].”
Effect of long term chilled (up to 5 weeks) then frozen (up to 12 months) storage at two different sub-zero holding temperatures on beef: 3. Protein structure degradation and a marker of protein oxidation
Holman, B. W. B., Coombs, C. E. O., Morris, S., Kerr, M. J., & Hopkins, D. L. (2018) · Meat Science · doi:10.1016/j.meatsci.2018.01.028 · Cited by 20
Nitric oxide generation from heme/copper assembly mediated nitrite reductase activity
Hematian, S., Siegler, M. A., & Karlin, K. D. (2014) · JBIC Journal of Biological Inorganic Chemistry · doi:10.1007/s00775-013-1081-6 · Cited by 20
Magnetite-Based Resistor for Nitric Oxide Detection
Daniel, T. T., Majumder, S., Yadav, V. K. S., & Paily, R. P. (2020) · IEEE Sensors Journal · doi:10.1109/jsen.2020.3005398 · Cited by 20
Visualization of NO3−/NO2− Dynamics in Living Cells by Fluorescence Resonance Energy Transfer (FRET) Imaging Employing a Rhizobial Two-component Regulatory System
Hidaka, M., Gotoh, A., Shimizu, T., Minamisawa, K., Imamura, H., & Uchida, T. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.687632 · Cited by 20
A comprehensive time course study of tissue nitric oxide metabolites concentrations after oral nitrite administration
Pinheiro, L. C., Ferreira, G. C., de Angelis, C. D., Toledo, J. C., & Tanus-Santos, J. E. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.03.006 · Cited by 20
Aluminium-Induced Behavioral Changes and Oxidative Stress in Developing Rat Brain and the Possible Ameliorating Role of Omega-6/Omega-3 Ratio
Benyettou, I., Kharoubı, O., Hallal, N., Benyettou, H. A., Taïr, K., Belmokhtar, M., Aoues, A., & Özaslan, M. (2017) · Journal of Biological Sciences · doi:10.3923/jbs.2017.106.117 · Cited by 19
Alcohol exacerbates post-traumatic stress psychiatric behavior and its neuropathological sequalae in experimental mice: preventive effects of morin
Ben‐Azu, B., Toloyai, P.-E. Y., Adebesin, A., Ojiokor, V. O., Adebayo, O. G., Fokoua, A. R., Moke, G. E., Ejukolemu, E. J., Akpojevughe, I.-O. O., Abdulkadir, A. M., et al. (2024) · Alcohol · doi:10.1016/j.alcohol.2024.07.009 · Cited by 18
The assessment of inflammatory activity and toxicity of treated sewage using RAW 264.7 cells
Makene, V. W., & Pool, E. J. (2015) · Water and Environment Journal · doi:10.1111/wej.12127 · Cited by 17
“Unfortunately, NO has a very short half-life, hence excess is instantly converted and stored in the form of nitrite (Shiva 2013).”
Background
Flipping Off and On the Redox Switch in the Microcirculation
Katona, M., Gladwin, M. T., & Straub, A. C. (2023) · Annual Review of Physiology · doi:10.1146/annurev-physiol-031522-021457 · Cited by 17
“…from the reaction of nitrite with deoxyhemoglobin or deoxygenated erythrocytes has been shown to activate platelet-soluble guanylate cyclase, increase cGMP levels, inhibit platelet activation (137), and inhibit mitochondrial respiration via NO-dependent inhibition of complex IV (137, 143).”
Background
Sodium nitrite attenuates MMP-9 production by endothelial cells and may explain similar effects of atorvastatin
Meschiari, C. A., Pinheiro, L. C., Guimarães, D. A., Gerlach, R. F., & Tanus-Santos, J. E. (2015) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-015-1192-4 · Cited by 16
Borate Ameliorates Sodium Nitrite-Induced Oxidative Stress Through Regulation of Oxidant/Antioxidant Status: Involvement of the Nrf2/HO-1 and NF-κB Pathways
Soliman, M. M., Aldhahrani, A., El-Shazly, S. A., Shukry, M., & Abouzed, T. K. (2021) · Biological Trace Element Research · doi:10.1007/s12011-021-02613-5 · Cited by 15
The emerging theme of redox bioenergetics in health and disease
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Hyperpolarized [15N]nitrate as a potential long lived hyperpolarized contrast agent for MRI
Gamliel, A., Uppala, S., Sapir, G., Harris, T., Nardi‐Schreiber, A., Shaul, D., Sosna, J., Gomori, J. M., & Katz‐Brull, R. (2019) · Journal of Magnetic Resonance · doi:10.1016/j.jmr.2019.01.001 · Cited by 16
A Double-Blind Placebo-Controlled Crossover Study of the Effect of Beetroot Juice Containing Dietary Nitrate on Aortic and Brachial Blood Pressure Over 24 h
Kukadia, S., Dehbi, H., Tillin, T., Coady, E., Chaturvedi, N., & Hughes, A. D. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00047 · Cited by 15
“Tissue and blood nitrite, derived either from oxidation of nitric oxide or dietary sources of nitrite/nitrate, serves as a reservoir from which nitric oxide can be produced through acidification or via proteins, including hemoglobin, that possess nitrite-reductase activity (Shiva, 2013).”
Background
Augmentation of Whole-Body Metabolic Status by Mind-Body Training: Synchronous Integration of Tissue- and Organ-Specific Mitochondrial Function
Stefano, G. B., Esch, T., & Kream, R. M. (2019) · Medical science monitor basic research/Medical science monitor. Basic research · doi:10.12659/msmbr.913264 · Cited by 14
“Conversely, enzymatic reduction of nitrite to NO within the reduced COX heme a3/CuB active site provides a significant physiological advantage during hypoxic/anoxic environmental conditions due to its O2-sparing effects [45].”
Background
Behaviorally-Mediated Entrainment of Whole-Body Metabolic Processes: Conservation and Evolutionary Development of Mitochondrial Respiratory Complexes
Stefano, G. B., Esch, T., & Kream, R. M. (2019) · Medical Science Monitor · doi:10.12659/msm.920174 · Cited by 14
“Conversely, enzymatic reduction of nitrite to NO within the reduced COX heme a3/CuB active site provides physiologically significant O2-sparing effects under hypoxic/anoxic environmental conditions [20].”
Background
In vitro and in vivo antiplasmodial activity of hydroethanolic bark extract of Bridelia atroviridis müll. Arg. (Euphorbiaceae) and lc-ms-based phytochemical analysis
Djouwoug, C. N., Gounoue, R. K., Ngueguim, F. T., NankapTsakem, J. M., Gouni, C. D., Kandeda, A. K., Ngouela, S. A., Lenta, B. N., Sewald, N., Boyom, F. F., et al. (2020) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2020.113424 · Cited by 14
Molecular mechanisms of non-thermal atmospheric pressure plasma-induced cellular responses
Hara, H., & Adachi, T. (2020) · Japanese Journal of Applied Physics · doi:10.35848/1347-4065/abd496 · Cited by 14
Carbonic anhydrase II does not regulate nitrite‐dependent nitric oxide formation and vasodilation
Wang, L., Sparacino-Watkins, C. E., Wang, J., Wajih, N., Varano, P., Xu, Q., Cecco, E., Tejero, J., Soleimani, M., Kim‐Shapiro, D. B., et al. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14887 · Cited by 14
“This physiological and hypoxic nitritedependent NO pathway complements the traditional normoxic L-arginine–NOS–NO pathway, which relies on oxygen and L-arginine as substrates (Lundberg et al., 2009; Shiva, 2013).”
Background

Authors: Shiva, S.
Affiliations: University of Pittsburgh (US)
Corresponding author: Shiva, Sruti
ORCID: Shiva, Sruti
Venue: Redox Biology
Publisher: Elsevier BV
Published: 2013
Volume: 1
Issue: 1
Pages: 40-44
ISSN: 2213-2317 (ISSN-L)
DOI: 10.1016/j.redox.2012.11.005
PMC: PMC3661298
OpenAlex: W2059688150
Cited by: 207
References: 38
Citations by year: 2026: 10 · 2025: 17 · 2024: 18 · 2023: 7 · 2022: 20 · 2021: 18 · 2020: 16 · 2019: 14 · 2018: 18 · 2017: 17 · 2016: 21 · 2015: 20 · 2014: 8 · 2013: 3
FWCI: 12.07
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/3.0/ (vor, 196 d)
Locations: Redox Biology (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders: NIH (1R01HL096973)
AHA (09SDG2150066)
Institution of Transfusion Medicine
Hemophilia Center of Western Pennsylvania
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
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
Keywords: nitrite, nitric oxide, nitric oxide storage, hypoxia, mitochondrial function, nitrite reduction, nitric oxide signaling, redox regulation

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Nitrite: A physiological store of nitric oxide and modulator of mitochondrial function

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