A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling.
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.
Echtay
Karim S
KS
MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, UK.
Esteves
Telma C
TC
Pakay
Julian L
JL
Jekabsons
Mika B
MB
Lambert
Adrian J
AJ
Portero-Otín
Manuel
M
Pamplona
Reinald
R
Vidal-Puig
Antonio J
AJ
Wang
Steven
S
Roebuck
Stephen J
SJ
Brand
Martin D
MD
D000818:Animals; D001278:Atractyloside / Q000031:analogs & derivatives* / Q000494:pharmacology; D001865:Bongkrekic Acid / Q000494:pharmacology; D004331:Drosophila melanogaster / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006153:Guanosine Diphosphate / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000494:pharmacology; D008954:Models, Biological; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011522:Protons; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000494:pharmacology; D014475:Uncoupling Agents / Q000378:metabolism* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D011522:Protons; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D001865:Bongkrekic Acid; D006153:Guanosine Diphosphate; D001278:Atractyloside; D014212:Tretinoin; D000226:Mitochondrial ADP, ATP Translocases; C003853:carboxyatractyloside