Cited by 1,032Mitochondrial Function and PathologyRedox biology and oxidative stressAutophagy in Disease and Therapy

Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins

Brand, Martin D, Affourtit, Charles, Esteves, Telma C, Green, Katherine, Lambert, Adrian J, Miwa, Satomi, Pakay, Julian L, Parker, Nadeene·2004·Free Radical Biology and Medicine

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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Crossref · 10.1016/j.freeradbiomed.2004.05.034

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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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