Stimulation of mitochondrial proton conductance by hydroxynonenal requires a high membrane potential.

TitleStimulation of mitochondrial proton conductance by hydroxynonenal requires a high membrane potential.
Publication TypeJournal Article
Year of Publication2008
AuthorsParker, N, Vidal-Puig, A, Brand, MD
JournalBiosci Rep
Volume28
Issue2
Pagination83-8
Date Published2008 Apr
ISSN0144-8463
KeywordsAldehydes, Animals, Antioxidants, Ion Channels, Lipid Peroxidation, Membrane Potentials, Mice, Mitochondria, Mitochondrial ADP, ATP Translocases, Mitochondrial Proteins, Models, Biological, Muscle, Skeletal, Rats, Reactive Oxygen Species, Uncoupling Protein 1, Uncoupling Protein 3, Urocortins
Abstract

Mild uncoupling of oxidative phosphorylation, caused by a leak of protons back into the matrix, limits mitochondrial production of ROS (reactive oxygen species). This proton leak can be induced by the lipid peroxidation products of ROS, such as HNE (4-hydroxynonenal). HNE activates uncoupling proteins (UCP1, UCP2 and UCP3) and ANT (adenine nucleotide translocase), thereby providing a negative feedback loop. The mechanism of activation and the conditions necessary to induce uncoupling by HNE are unclear. We have found that activation of proton leak by HNE in rat and mouse skeletal muscle mitochondria is dependent on incubation with respiratory substrate. In the presence of HNE, mitochondria energized with succinate became progressively more leaky to protons over time compared with mitochondria in the absence of either HNE or succinate. Energized mitochondria must attain a high membrane potential to allow HNE to activate uncoupling: a drop of 10-20 mV from the resting value is sufficient to blunt induction of proton leak by HNE. Uncoupling occurs through UCP3 (11%), ANT (64%) and other pathways (25%). Our findings have shown that exogenous HNE only activates uncoupling at high membrane potential. These results suggest that both endogenous HNE production and high membrane potential are required before mild uncoupling will be triggered to attenuate mitochondrial ROS production.

DOI10.1042/BSR20080002
Alternate JournalBiosci. Rep.
Citation Key10.1042/BSR20080002
PubMed ID18384278
PubMed Central IDPMC2518262
Grant ListG0600717 / / Medical Research Council / United Kingdom
MC_U105663137 / / Medical Research Council / United Kingdom
065326/Z/01/Z / / Medical Research Council / United Kingdom
066750/B/01/Z / / Wellcome Trust / United Kingdom