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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The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics
Lundberg, J. O., Weitzberg, E., & Gladwin, M. T. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2466 · Cited by 2,739 · cited 2×
“Nitrite reduction by these enzymes with differing oxygen affinities, tissue distribution and rates of reduction, ensures NO generation and nitrosative modification of target proteins over a wide range of physiological hypoxia in the cell [1].”
Background
Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation
Cosby, K., Partovi, K. S., Crawford, J. H., Patel, R. P., Reiter, C. D., Martyr, S., Yang, B. K., Waclawiw, M. A., Zalos, G., Xu, X., et al. (2003) · Nature Medicine · doi:10.1038/nm954 · Cited by 1,807
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Background
Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide: Implications for neurodegenerative diseases
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“Further, the authors reported a NO3 -induced decrease in the expression of uncoupling protein 3 (UCP-3) and the adenine nucleotide translocase (ANT), two proteins which facilitate proton leak [25].”
Background
Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver
Duranski, M. R., Greer, J. J. M., Dejam, A., Jaganmohan, S., Hogg, N., Langston, W., Patel, R. P., Yet, S.-F., Wang, X., Kevil, C. G., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci22493 · Cited by 674
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Effects of dietary nitrate on oxygen cost during exercise
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Background
Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia–reperfusion damage
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Deoxymyoglobin Is a Nitrite Reductase That Generates Nitric Oxide and Regulates Mitochondrial Respiration
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“It also removes nitrite ðNO2 Þ by reducing it to nitric oxide (NO) and lowers the energy status of heart cells, which subsequently prevents heat injury from hypoxic conditions [16,17].”
Background
Dietary Sodium Nitrate Activates Antioxidant and Mitochondrial Dynamics Genes after Moderate Intensity Acute Exercise in Metabolic Syndrome Patients
Ferrer, M. D., Capó, X., Reynés, C., Quetglas‐Llabrés, M. M., Salaberry, E., Tonolo, F., Suau, R., Marí, B., Tur, J. A., Sureda, A., et al. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10122618 · Cited by 12
“In fact, the mitochondrial respiratory chain produces nitric oxide from nitrite through the acceptance of electrons in the complexes I and III [51].”
BackgroundInfluential
Nitrite reductase activity of heme and copper bound Aβ peptides
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“In addition, NO can be produced via the reduction of nitrite under hypoxia conditions to regulate a spectrum of physiological responses in the blood and tissues [43].”
Background
RETRACTED: Nitric oxide sensing by chlorophyll a
Bhattacharya, A., Biswas, P., Kar, P., Roychoudhury, P., Basu, S., Ganguly, S., Ghosh, S., Panda, K., Pal, R., & Dasgupta, A. K. (2017) · Analytica Chimica Acta · doi:10.1016/j.aca.2017.07.026 · Cited by 11
Retracted
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“Since these enzymes can also operate as mammalian nitrite reductases [48], this would also reduce oxygen consumption during exercise.”
Background
Nitrite-Dependent Nitric Oxide Production Pathway: Diversity of NO Production Systems
Yamasaki, H., Watanabe, N. S., Fukuto, J., & Cohen, M. F. (2014) · Oxidative Stress in Applied Basic Research and Clinical Practice · doi:10.1007/978-1-4939-0679-6_3 · Cited by 10
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“, complex I to attenuate ROS production and cytochrome c release and with complex IV to reduce the respiratory rate and conserve oxygen, in the well-established NO2 2 cytoprotective pathways.(61)”
Background
Materialien mit Selektivität für oxidative Molekülspezies für die Diagnostik und Therapie
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Aqueous extract of bay leaf (Laurus nobilis) ameliorates testicular toxicity induced by aluminum chloride in rats
Falade, A. O., Adewole, K. E., Adekola, A.-R. O., Ikokoh, H. A., Okaiyeto, K., & Oguntibeju, O. O. (2022) · Veterinary World · doi:10.14202/vetworld.2022.2525-2534 · Cited by 9
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Oral Nitrate Increases Microvascular Reactivity and the Number of Visible Perfused Microvessels in Healthy Volunteers
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Myoglobin deficiency impairs maximal oxygen uptake and exercise performance: a lesson from Mb −/− mice
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“…opened new space for the investigation of other functions of Mb, such as myocardial and muscle nitric oxide (NO (cid:129) ) homeostasis (Clanton, 2019; Gladwin et al., 2005; Hendgen-Cotta et al., 2008; Hendgen-Cotta et al., 2014; Poole, Ferguson et al., 2022; Shiva, 2013; Shiva et al., 2007).”
BackgroundInfluential
Nitrite coordination in myoglobin
Ioannou, A., Lambrou, A., Daskalakis, V., & Pinakoulaki, E. (2016) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2016.10.002 · Cited by 8
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Carnosine and N‐acetyl cysteine protect against sodium nitrite‐induced oxidative stress in rat blood
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“Being a ready source of NO, it plays important roles in mediating cellular respiration, innate immunity, cell signaling, activation of regulatory proteins and the a form of the estrogen receptor (Bogdan, 2001; Lundberg et al., 2008; Veselik et al., 2008; Shiva, 2013).”
Background
Impact of Thymus vulgaris extract on sodium nitrite‐induced alteration of renal redox and oxidative stress: Biochemical, molecular, and immunohistochemical study
Soliman, M. M., Aldhahrani, A., Alghamdi, Y. S., & Said, A. M. (2021) · Journal of Food Biochemistry · doi:10.1111/jfbc.13630 · Cited by 8
Sodium Nitrite Attenuates Reduced Activity of Vascular Matrix Metalloproteinase-2 and Vascular Hyper-Reactivity and Increased Systolic Blood Pressure Induced by the Placental Ischemia Model of Preeclampsia in Anesthetized Rats
Martins, L. Z., da Silva, M. L. S., Rodrigues, S. D., Gomes, S. E. B., Molezini, L., Rizzi, É., Montenegro, M. F., & Dias-Junior, C. A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612818 · Cited by 6
“Importantly, endogenous NO formation from endothelium is impaired in preeclamptic RUPP rats [5,41] and in women with preeclampsia [42,43].”
Background
Chemiluminescence-based Assays for Detection of Nitric Oxide and its Derivatives from Autoxidation and Nitrosated Compounds
Fenza, R. D., Yu, B., Carroll, R. W., & Berra, L. M. (2022) · Journal of Visualized Experiments · doi:10.3791/63107 · Cited by 8
Prenatal and early life factors and type 1 diabetes
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“Nitrite and NO are rapidly and efficiently absorbed via the skin and nitrite can be converted to NO [29].”
Background
Synthesis, characterization and in vitro cytotoxicity of ruthenium(II) metronidazole complexes: Cell cycle arrest at G1/S transition and apoptosis induction in MCF-7 cells
Candido, C. C., Silva, H. V. R., Zavan, B., Ionta, M., Barbosa, M. I. F., & Doriguetto, A. C. (2022) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2022.112022 · Cited by 6
NEAT HFpEF: Organic nitrates fail to deliver
Wagdy, K., & Hassan, M. S. (2016) · Global Cardiology Science and Practice · doi:10.21542/gcsp.2016.1 · Cited by 6
“Major classes of nitrite reductase (adapted from reference [12]).”
Background
GKT137831 and hydrogen peroxide increase the release of 6-nitrodopamine from the human umbilical artery, rat-isolated right atrium, and rat-isolated vas deferens
Britto‐Júnior, J., Furlaneto, R., Lima, A. T., de Oliveira, M. G., Severino, B., Frecentese, F., Fiorino, F., Caliendo, G., Muscará, M. N., & Nucci, G. D. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1348876 · Cited by 5
“One possible pathway for the nitrosation of dopamine, independent of NOS activity, would be the reduction of endogenous nitrite/nitrate since these ions are not only the products of the metabolism of NO, but they can also act as a reservoir (Shiva, 2013).”
Background
Impaired Endothelium-Dependent Vasodilation and Increased Levels of Soluble Fms-like Tyrosine Kinase-1 Induced by Reduced Uterine Perfusion Pressure in Pregnant Rats: Evidence of Protective Effects with Sodium Nitrite Treatment in Preeclampsia
da Silva, M. L. S., Gomes, S. E. B., Martins, L. Z., Rodrigues, S. D., Toghi, C. D. J., & Dias-Junior, C. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252011051 · Cited by 5
“The reduction of nitrite in NO may be enhanced in hypoxic and ischemic tissues, conductions in which oxygen (substrate to the NO synthesis by endothelial NO synthase) is impaired, thus representing an alternative pathway to generate the NO during ischemia [33].”
Background
Antioxidant pharmacology
Koltover, V. K., & Skipa, T. A. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-823679-6.00010-2 · Cited by 5
Reduction of iron porphyrin nitrate to the iron nitrosyl by H 2 S/thiol. studies in sublimed layers
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Johnson, L. C., DeVan, A. E., Justice, J. N., & Seals, D. R. (2017) · Springer eBooks · doi:10.1007/978-3-319-46189-2_18 · Cited by 5
NO: a key player in microbiome dynamics and cancer pathogenesis
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“This process is especially relevant in tissues with high metabolic activity, where NO produced by endothelial or inducible iNOS must be tightly controlled to maintain homeostasis (Shiva, 2013).”
The nitrite reductase activity of xanthine oxidoreductase sustains cardiovascular health as mice age
Dyson, N., Khambata, R. S., Parakaw, T., Massimo, G., Khuat, N. H., Noor, A. A., Gee, L. C., Lim, I., Siddique, U., Sullivan, A. J., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103923 · Cited by 6
“We suggest that this ‘storage ’ form [58] of nitrite is utilised by XOR in the setting of the physiological hypoxia invoked by the cuff inflation, and that following Xdh deletion this reaction does not take place.”
Phase dynamics of cerebral blood flow in subarachnoid haemorrhage in response to sodium nitrite infusion
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“It can safely be administered [23] and is converted to NO in hypoxic and acidic conditions [16, 17], which can be observed after SAH [6, 42].”
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“constitute an important rescuing or alternative mechanism to the classical NOS pathway under these conditions [19,40].”
Background
The Skeletal Muscle, the Heart, and the Liver Are the Major Organs of the Accumulation of Nitric Oxide Metabolites after Oral Nitrite Treatment
Lima-Silva, A. K., Rebelo, M. A., Barros, A. C., Conde-Tella, S. O., & Tanus-Santos, J. E. (2024) · Antioxidants · doi:10.3390/antiox13030255 · Cited by 5
The modulatory influence of humic acid on cognitive impairment and neurobehavioral changes induced by colitis in adult male Wistar rats
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“Nitrite is considered the inert metabolite of nitric oxide (NO) oxidation; excessive nitrite also signals an excessive NO level [48].”
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Pan, H., Ye, S., Jiang, Y., Peng, Y., Kuo, C., Ou, H., Wu, Z., & Hsu, H. (2025) · Angewandte Chemie International Edition · doi:10.1002/anie.202517592 · Cited by 3
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“Tap water includes nitrite, which is a stable reservoir that can be converted to NO* and other bioactive nitrogen species [36,37].”
Background
Mechanism of Reactive Oxygen/Nitrogen Species in Liver Ischemia-Reperfusion Injury and Preventive Effect of Chinese Medicine
Gao, L., Li, Y.-J., Zhao, J., Liao, Y., Qin, M., Li, J., Shi, H., Wong, N.-K., Lyu, Z.-P., & Shen, J. (2024) · Chinese Journal of Integrative Medicine · doi:10.1007/s11655-024-3810-9 · Cited by 3
“(55) During chronic ischemia, NO 2 attenuates IR injury by inhibiting the production of ROS through limiting electron flow through the electron transport chain (ETC) upon reperfusion.”
Nitrite enhances liver graft protection against cold ischemia reperfusion injury through a NOS independent pathway
Cherif-Sayadi, A., Tka, K. H. A., Zaoualí, M. A., Béjaoui, M., Abdallah, N. H., Bouhlel, A., & Abdennebi, H. B. (2017) · Libyan Journal of Medicine · doi:10.1080/19932820.2017.1308780 · Cited by 3
“Otherwise, it is widely valued that I/R associated with LT induces endothelial insult characterized by marked trouble in NO homeostasis [9,16,32].”
Background
The multiplicity of hemoglobin functional forms in human organism: the modern view and practical applications.
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Limb Ischemic Conditioning Induces Oxidative Stress Followed by a Correlated Increase of HIF-1α in Healthy Volunteers
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Cardioprotective effects of physical exercise on redox biology in mice exposed to hand-rolled cornhusk cigarette smoke
Camera, F. D., Pozzi, B. G., Paganini, C. S., Sorato, H. R., Tavares, F., Pereira, B. D. C., Pedroso, G. S., Roman, S. S., Silveira, P. C. L., Nesi, R. T., et al. (2018) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2018.11.003 · Cited by 3
Nitric Oxide
Donald, J. A. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-801028-0.00251-8 · Cited by 3
Binding Modes Tuning Nitrite Reduction Reactivity at Iron(III) Centers Triggered by Hydrogen Atom, Hydride, and Proton Transfers
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Sublethal Nitrite Exposure Alters Redox Status and Metabolic Functions in Adult Zebrafish
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“Nitrite serves as a storage pool and a source of NO under hypoxic and stressful conditions [4–9], and it also regulates protein function and gene expression [5,10,11].”
Influential
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“The first of these by Sruti Shiva is entitled ‘‘Nitrite: A Physiological Store of Nitric Oxide and Modulator of Mitochondrial Function’’ [1].”
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“The excess production of NO, together with an intensification of the superoxide anion formation in the mitochondria, is accompanied by the generation of peroxynitrite, damage of the components of the respiratory chain, depolarization of mitochondria, and apoptosis (López-Figueroa et al., 2000; Giulivi et al., 2006; Sh…”
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“4 Advanced Biomedical Research | 2016 between the two groups.[23,24] It was reported that chronic iron overload result in ID in the glomeruli and proximal tubules with various kidney injuries and evidence of augmentative ROS activity, increased ROS-mediated inactivation, sequestration of NO, and compensatory up-regula…”
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“It has previously been reported that nitrite can be reduced to NO through several pathways (Lundberg and Weitzberg, 2005; Shiva, 2013).”
Background
Inorganic nitrite alters mitochondrial dynamics without overt changes in cell death and mitochondrial respiration in cardiomyoblasts under hyperglycemia
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ВАСКУЛЯРНАЯ ДИСФУНКЦИЯ: ПРОЦЕССЫ, ОБУСЛОВЛЕННЫЕ СТАРЕНИЕМ, ПОДХОДЫ К ВОССТАНОВИТЕЛЬНОЙ ТЕРАПИИ И ПРОФИЛАКТИКЕ (ЧАСТЬ 1)*
Шушпанова, Т. В., Bokhan, N. A., Смирнова, И. Н., Gameeva, E. V., Степанова, А. М., Новожеева, Т. П., Казенных, Т. В., Shushpanova, O. V., Safronov, S. M., Боев, Р. Г., et al. (2025) · Успехи геронтологии · doi:10.34922/ae.2025.38.4.019
Photo-induced nitric oxide modulation in human skin: Impacts of geographic location and seasonality on health and disease
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Method for Plasma Control of Fibrosis Signaling
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“The concentrations of nitrite and hydrogen peroxide known to affect cellular physiology are generally in the range of approximately 10–100 µM [ 52, 53].”

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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