Superoxide activates mitochondrial uncoupling proteins

Echtay, Karim S.; Roussel, Damien; St-Pierre, Julie; Jekabsons, Mika B.; Cadenas, Susana; Stuart, Jeff A.; Harper, James A.; Roebuck, Stephen J.; Morrison, Alastair; Pickering, Susan; Clapham, John C.; Brand, Martin D.

doi:10.1038/415096a

Cited by 1,382Mitochondrial Function and PathologyATP Synthase and ATPases ResearchAdipose Tissue and Metabolism

Superoxide activates mitochondrial uncoupling proteins

Echtay, Karim S., Roussel, Damien, St-Pierre, Julie, Jekabsons, Mika B., Cadenas, Susana, Stuart, Jeff A., Harper, James A., Roebuck, Stephen J. +4 more·2002·Nature

DOI 10.1038/415096a

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Abstract

Uncoupling protein 1 (UCP1) diverts energy from ATP synthesis to thermogenesis in the mitochondria of brown adipose tissue by catalysing a regulated leak of protons across the inner membrane. The functions of its homologues, UCP2 and UCP3, in other tissues are debated. UCP2 and UCP3 are present at much lower abundance than UCP1, and the uncoupling with which they are associated is not significantly thermogenic. Mild uncoupling would, however, decrease the mitochondrial production of reactive oxygen species, which are important mediators of oxidative damage. Here we show that superoxide increases mitochondrial proton conductance through effects on UCP1, UCP2 and UCP3. Superoxide-induced uncoupling requires fatty acids and is inhibited by purine nucleotides. It correlates with the tissue expression of UCPs, appears in mitochondria from yeast expressing UCP1, and is absent in skeletal muscle mitochondria from UCP3 knockout mice. Our findings indicate that the interaction of superoxide with UCPs may be a mechanism for decreasing the concentrations of reactive oxygen species inside mitochondria.

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Superoxide in mitochondria can cause loss of membrane potential by stimulating uncoupling proteins.
“Moreover, superoxide in the mitochondria can cause a loss of membrane potential by stimulating uncoupling proteins (13).”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [13]
High levels of ROS may damage mitochondria, leading to opening of mitochondrial pores and loss of membrane polarization.
“High levels of ROS may damage mitochondria, leading to the opening of mitochondrial pores and allowing the influx of protons and ions, which leads to a loss of membrane polarization (13, 52).”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [13]
Proton conductance of UCP2 and UCP3 can be activated by matrix superoxide or 4-hydroxy-2-nonenal (4-HNE), a byproduct of lipid peroxidation.
“However, proton conductance of UCP2 and UCP3 can be activated by matrix superoxide or 4-hydroxy-2-nonenal (4-HNE), a byproduct of lipid peroxidation (45, 91, 93).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [93]

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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).”
Background
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Authors: Echtay, K. S., Roussel, D., St-Pierre, J., Jekabsons, M. B., Cadenas, S., Stuart, J. A., Harper, J. A., Roebuck, S. J., Morrison, A., Pickering, S., Clapham, J. C., & Brand, M. D.
Affiliations: MRC Mitochondrial Biology Unit (GB)
Institute for Comparative Genomics (CA)
GlaxoSmithKline (United Kingdom) (GB)
Corresponding author: Brand, Martin D.
ORCID: Echtay, Karim S.
Roussel, Damien
Jekabsons, Mika B.
Cadenas, Susana
Morrison, Alastair
Clapham, John C.
Brand, Martin D.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2002-01
Volume: 415
Issue: 6867
Pages: 96-99
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/415096a
OpenAlex: W2036573181
Cited by: 1,382
References: 34
Citations by year: 2026: 14 · 2025: 30 · 2024: 23 · 2023: 33 · 2022: 31 · 2021: 50 · 2020: 51 · 2019: 56 · 2018: 47 · 2017: 46 · 2016: 46 · 2015: 52 · 2014: 56 · 2013: 52 · 2012: 67
FWCI: 30.83
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Ellison Medical Foundation
National Institutes of Health
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords: uncoupling proteins, UCP1, UCP2, UCP3, superoxide, mitochondrial uncoupling, reactive oxygen species, thermogenesis, brown adipose tissue, fatty acids, purine nucleotides, skeletal muscle mitochondria, oxidative damage
MeSH terms: Uncoupling Protein 2, Uncoupling Protein 3, Uncoupling Protein 1, Animals, Adipose Tissue, Brown, Carrier Proteins, Food Deprivation, Glyburide, Hot Temperature, Intracellular Membranes, Ion Channels, Islets of Langerhans, Kidney, Liver, Membrane Potentials, Membrane Proteins, Mitochondria, Myocardium, Proteins, Protons, Saccharomyces cerevisiae, Spleen, Superoxides, Uncoupling Agents, Gene Deletion, Reactive Oxygen Species, Mice, Knockout, Muscle, Skeletal, Mitochondrial Proteins, Membrane Transport Proteins, Mice, Rats

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Superoxide activates mitochondrial uncoupling proteins

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