Superoxide activates mitochondrial uncoupling proteins

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 membrane1,2. The functions of its homologues, UCP2 and UCP3, in other tissues are debated3,4. UCP2 and UCP3 are present at much lower abundance than UCP1, and the uncoupling with which they are associated is not significantly thermogenic5,6. Mild uncoupling would, however, decrease the mitochondrial production of reactive oxygen species, which are important mediators of oxidative damage7,8. 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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Figure 1: Effect of superoxide on the proton conductance of skeletal muscle mitochondria: superoxide activation of UCP3.
Figure 2: Effect of superoxide on the proton conductance of mitochondria from different tissues: superoxide activation of UCP2.
Figure 3: Effect of superoxide on the proton conductance of mitochondria from brown adipose tissue and transgenic yeast: superoxide activation of UCP1.
Figure 4: Nucleotide specificity and affinity of UCP2 (kidney) and UCP3 (skeletal muscle).

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Acknowledgements

We thank A. Abuin for help in constructing the UCP3 knockout mice.

Author information

Correspondence to Martin D. Brand.

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