A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling.

TitleA signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling.
Publication TypeJournal Article
Year of Publication2003
AuthorsEchtay, KS, Esteves, TC, Pakay, JL, Jekabsons, MB, Lambert, AJ, Portero-Otín, M, Pamplona, R, Vidal-Puig, AJ, Wang, S, Roebuck, SJ, Brand, MD
JournalEMBO J
Date Published2003 Aug 15
KeywordsAnimals, Atractyloside, Bongkrekic Acid, Drosophila melanogaster, Enzyme Inhibitors, Female, Guanosine Diphosphate, Humans, Kidney, Mice, Mice, Knockout, Mitochondria, Mitochondrial ADP, ATP Translocases, Models, Biological, Oxidative Phosphorylation, Protons, Rats, Reactive Oxygen Species, Saccharomyces cerevisiae, Signal Transduction, Structure-Activity Relationship, Tretinoin, Uncoupling Agents

Oxidative stress and mitochondrial dysfunction are associated with disease and aging. Oxidative stress results from overproduction of reactive oxygen species (ROS), often leading to peroxidation of membrane phospholipids and production of reactive aldehydes, particularly 4-hydroxy-2-nonenal. Mild uncoupling of oxidative phosphorylation protects by decreasing mitochondrial ROS production. We find that hydroxynonenal and structurally related compounds (such as trans-retinoic acid, trans-retinal and other 2-alkenals) specifically induce uncoupling of mitochondria through the uncoupling proteins UCP1, UCP2 and UCP3 and the adenine nucleotide translocase (ANT). Hydroxynonenal-induced uncoupling was inhibited by potent inhibitors of ANT (carboxyatractylate and bongkrekate) and UCP (GDP). The GDP-sensitive proton conductance induced by hydroxynonenal correlated with tissue expression of UCPs, appeared in yeast mitochondria expressing UCP1 and was absent in skeletal muscle mitochondria from UCP3 knockout mice. The carboxyatractylate-sensitive hydroxynonenal stimulation correlated with ANT content in mitochondria from Drosophila melanogaster expressing different amounts of ANT. Our findings indicate that hydroxynonenal is not merely toxic, but may be a biological signal to induce uncoupling through UCPs and ANT and thus decrease mitochondrial ROS production.

Alternate JournalEMBO J.
Citation Key10.1093/emboj/cdg412
PubMed ID12912909
PubMed Central IDPMC175801