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Title: A signalling role for 4 - hydroxy - 2 - nonenal in regulation of mitochondrial uncoupling
Authors: Echtay, Karim 
Esteves, Telma C.
Pakay, Julian L.
Jekabsons, Mika B.
Lambert, Adrian J.
Portero‐Otín, Manuel
Pamplona, Reinald
Vidal‐Puig, Antonio J.
Wang, Steven
Roebuck, Stephen J.
Brand, Martin D
Affiliations: Faculty of Medicine 
Keywords: ANT
Oxidative stress
Subjects: Obesity
Issue Date: 2003
Part of: EMBO journal
Volume: 22
Start page: 4103
End page: 4110
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.
Open URL: Link to full text
Type: Journal Article
Appears in Collections:Faculty of Medicine

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