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

Free Radic Biol Med. 2004 Sep 15;37(6):755-67. doi: 10.1016/j.freeradbiomed.2004.05.034.


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).

Publication types

  • Review

MeSH terms

  • Aging
  • Aldehydes / chemistry
  • Animals
  • Carrier Proteins / physiology*
  • Electron Transport
  • Fatty Acids / metabolism
  • Free Radicals
  • Glucose / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Ion Channels
  • Islets of Langerhans / cytology
  • Lipid Peroxidation
  • Membrane Proteins / physiology*
  • Membrane Transport Proteins / physiology*
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / physiology*
  • Models, Biological
  • Oxygen / metabolism
  • Protons
  • Signal Transduction
  • Superoxides / metabolism*
  • Uncoupling Protein 1
  • Uncoupling Protein 2
  • Uncoupling Protein 3


  • Aldehydes
  • Carrier Proteins
  • Fatty Acids
  • Free Radicals
  • Insulin
  • Ion Channels
  • Membrane Proteins
  • Membrane Transport Proteins
  • Mitochondrial Proteins
  • Protons
  • UCP1 protein, human
  • UCP2 protein, human
  • UCP3 protein, human
  • Ucp1 protein, mouse
  • Ucp2 protein, mouse
  • Ucp3 protein, mouse
  • Uncoupling Protein 1
  • Uncoupling Protein 2
  • Uncoupling Protein 3
  • Superoxides
  • Glucose
  • 4-hydroxy-2-nonenal
  • Oxygen