Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins
Abstract
Mitochondria are potent producers of cellular superoxide, from complexes I and III of the electron transport chain, and mitochondrial superoxide production is a major cause of the cellular oxidative damage that may underlie degradative diseases and aging. This superoxide production is very sensitive to the proton motive force, so it can be strongly decreased by mild uncoupling. Superoxide and the lipid peroxidation products it engenders, including hydroxyalkenals such as hydroxynonenal, are potent activators of proton conductance by mitochondrial uncoupling proteins such as UCP2 and UCP3, although the mechanism of activation has yet to be established. These observations suggest a hypothesis for the main, ancestral function of uncoupling proteins: to cause mild uncoupling and so diminish mitochondrial superoxide production, hence protecting against disease and oxidative damage at the expense of a small loss of energy. We review the growing evidence for this hypothesis, in mitochondria, in cells, and in vivo. More recently evolved roles of uncoupling proteins are in adaptive thermogenesis (UCP1) and perhaps as part of a signaling pathway to regulate insulin secretion in pancreatic beta cells (UCP2).
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Endogenous NO• modulates respiration by its effect to compete reversibly for the O2 binding site on cytochrome c oxidase.
“Endogenous NO• modulates respiration by its effect to compete reversibly for the O2 binding site on cytochrome c oxidase (complex IV) (45, 58, 119).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [45]
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Short-term CR decreases cardiac mitochondrial oxidant production but increases carbonyl content
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Antioxidants and atherosclerosis
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Talbot, D. A., Hanuise, N., Rey, B., Rouanet, J., Duchamp, C., & Brand, M. D. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.11.022 · Cited by 64 · see citing works
Self-citationUbiquinone is not required for proton conductance by uncoupling protein 1 in yeast mitochondria
Esteves, T. C., Echtay, K. S., Jonassen, T., Clarke, C. F., & Brand, M. D. (2004) · Biochemical Journal · doi:10.1042/bj20031682 · Cited by 57 · see citing works
Self-citationCoenzyme Q induces GDP-sensitive proton conductance in kidney mitochondria
Echtay, K. S., & Brand, M. D. (2001) · Biochemical Society Transactions · doi:10.1042/bst0290763 · Cited by 51 · see citing works
Self-citationShatrov, V. A., & Brüne, B. (2003) · Biochemical Journal · doi:10.1042/bj20030420 · Cited by 34 · see citing works
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Hong, Y. (2001) · Endocrinology · doi:10.1210/en.142.1.249 · Cited by 27 · see citing works
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Photoaffinity labeling of the uncoupling protein UCP1 with retinoic acid: ubiquinone favors binding
Tomás, P., Ledesma, A., & Rial, E. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03116-2 · Cited by 12 · see citing works
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How mitochondria produce reactive oxygen species
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The sites and topology of mitochondrial superoxide production
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Self-citationMitochondrial proton and electron leaks
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Self-citationPhysiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3
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Superoxide flashes in single mitochondria
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UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals
Andrews, Z. B., Liu, Z.-W., Walllingford, N., Erion, D. M., Borok, E., Friedman, J. M., Tschöp, M. H., Shanabrough, M., Cline, G., Shulman, G. I., et al. (2008) · Nature · doi:10.1038/nature07181 · Cited by 710 · see citing works
Mitochondrial Energetics in the Heart in Obesity-Related Diabetes
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Mitochondrial dysfunction and mitophagy in Parkinson's: from familial to sporadic disease
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Stowe, D. F., & Camara, A. K. S. (2009) · Antioxidants & Redox Signaling · doi:10.1089/ars.2008.2331 · Cited by 471 · see citing works
OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells
Kovtun, I. V., Liu, Y., Bjoras, M., Klungland, A., Wilson, S. H., & McMurray, C. T. (2007) · Nature · doi:10.1038/nature05778 · Cited by 433 · see citing works
The basal proton conductance of mitochondria depends on adenine nucleotide translocase content
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The efficiency and plasticity of mitochondrial energy transduction.
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Self-citationMitochondrial dysfunction in neurodegenerative disorders
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Generation of superoxide by the mitochondrial Complex I
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The role of the mitochondrial permeability transition pore in heart disease
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The production of reactive oxygen species by complex I
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Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress
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Kassahn, K. S., Crozier, R. H., Pörtner, H. O., & Caley, M. J. (2009) · Biological Reviews · doi:10.1111/j.1469-185x.2008.00073.x · Cited by 263 · see citing works
The on-off switches of the mitochondrial uncoupling proteins
Azzu, V., & Brand, M. D. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2009.11.001 · Cited by 239 · see citing works
Self-citationThe chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal
Forman, H. J., Fukuto, J. M., Miller, T., Zhang, H., Rinna, A., & Levy, S. (2008) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2008.06.011 · Cited by 226 · see citing works
Oxidative Stress Causes Heart Failure with Impaired Mitochondrial Respiration
Nojiri, H., Shimizu, T., Funakoshi, M., Yamaguchi, O., Zhou, H., Kawakami, S., Ohta, Y., Sami, M., Tachibana, T., Ishikawa, H., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602118200 · Cited by 230 · see citing works
The role of free radicals in the aging brain and Parkinson’s Disease: Convergence and parallelism
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Picard, M., Hepple, R. T., & Burelle, Y. (2012) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00368.2011 · Cited by 214 · see citing works
Thyroid Hormone Effects on Mitochondrial Energetics
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The physiological regulation of uncoupling proteins
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Bianchi, G., Martella, R., Ravera, S., Marini, C., Capitanio, S., Orengo, A., Emionite, L., Lavarello, C., Amaro, A., Petretto, A., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3688 · Cited by 173 · see citing works
Mitochondrial uncoupling and lifespan
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p66Shc-generated Oxidative Signal Promotes Fat Accumulation
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The regulation and turnover of mitochondrial uncoupling proteins
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The polymorphisms of UCP2 and UCP3 genes associated with fat metabolism, obesity and diabetes
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Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice
Alexopoulos, S. J., Chen, S.-Y., Brandon, A. E., Salamoun, J. M., Byrne, F. L., Garcia, C. J., Beretta, M., Olzomer, E. M., Shah, D. P., Philp, A. M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16298-2 · Cited by 137 · see citing works
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A Possible Site of Superoxide Generation in the Complex I Segment of Rat Heart Mitochondria
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The efficiency of cellular energy transduction and its implications for obesity
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Advanced glycation end-products induce injury to pancreatic beta cells through oxidative stress
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Reactive oxygen species and uncoupling protein 2 in pancreatic <i>β</i> ‐cell function
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“Interestingly, UCP2-mediated proton leak requires activation by superoxide and lipid peroxidation derivatives such as 4-hydroxynonenal and other reactive alkenals (Echtay et al, 2002; Brand et al, 2004).”
BackgroundRole of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine
Dalla Pozza, E., Fiorini, C., Dando, I., Menegazzi, M., Sgarbossa, A., Costanzo, C., Palmieri, M., & Donadelli, M. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.06.007 · Cited by 84 · see citing works
On the role of uncoupling protein-2 in pancreatic beta cells
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Self-citationStronger control of ATP/ADP by proton leak in pancreatic β-cells than skeletal muscle mitochondria
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Self-citationDecoding the Rosetta stone of mitonuclear communication
English, J., Son, J. M., Cardamone, M. D., Lee, C., & Perissi, V. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105161 · Cited by 55 · see citing works
de Cavanagh, E. M. V., Ferder, L., Toblli, J. E., Piotrkowski, B., Stella, I., Fraga, C. G., & Inserra, F. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00926.2007 · Cited by 54 · see citing works
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Self-citationThe emerging neuroprotective role of mitochondrial uncoupling protein-2 in traumatic brain injury
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Exercise Is Medicine for Nonalcoholic Fatty Liver Disease: Exploration of Putative Mechanisms
Heinle, J. W., DiJoseph, K., Sabag, A., Oh, S., Kimball, S. R., Keating, S., & Stine, J. G. (2023) · Nutrients · doi:10.3390/nu15112452 · Cited by 26 · see citing works
- Authors
- Brand, M. D., Affourtit, C., Esteves, T. C., Green, K., Lambert, A. J., Miwa, S., Pakay, J. L., & Parker, N.
- Affiliations
- MRC Mitochondrial Biology Unit (GB)
- Corresponding author
- Brand, Martin D
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2004-09
- Volume
- 37
- Issue
- 6
- Pages
- 755-767
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W1991238715
- Cited by
- 1,032
- References
- 113
- Citations by year
- 2026: 11 · 2025: 24 · 2024: 39 · 2023: 30 · 2022: 35 · 2021: 35 · 2020: 46 · 2019: 40 · 2018: 50 · 2017: 41 · 2016: 48 · 2015: 52 · 2014: 59 · 2013: 49 · 2012: 69
- FWCI
- 4.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mitochondrial superoxide, uncoupling proteins, UCP1, UCP2, UCP3, proton motive force, lipid peroxidation, 4-hydroxynonenal, proton conductance, oxidative damage, aging, adaptive thermogenesis, insulin secretion, pancreatic beta cells, mitochondrial bioenergetics
- MeSH terms
- Uncoupling Protein 2, Uncoupling Protein 3, Uncoupling Protein 1, Insulin Secretion, Aging, Aldehydes, Animals, Carrier Proteins, Electron Transport, Fatty Acids, Free Radicals, Glucose, Humans, Insulin, Ion Channels, Islets of Langerhans, Membrane Proteins, Mitochondria, Models, Biological, Oxygen, Protons, Superoxides, Lipid Peroxidation, Signal Transduction, Mice, Knockout, Mitochondrial Proteins, Membrane Transport Proteins, Mice
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