Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 37, Issue 6, Pages 755-767Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2004.05.034
Keywords
mitochondria; complex I; proton motive force; superoxide; lipid peroxidation; hydroxynonenal; uncoupling protein; aging; thermogenesis; insulin secretion; free radicals
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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). (C) 2004 Elsevier Inc. All rights reserved.
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