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

By K. Echtay, Telma C Esteves, Julian L. Pakay, M. Jekabsons, A. J. Lambert, M. Portero-Otín, R. Pamplona, Antonio Vidal-Puig, Steven J. Wang, Stephen J Roebuck and 1 more. EMBO Journal, 2003

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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.

Subfields: Cell Biology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/d47f66d6c835f46b13a531f12e990c85cc2d3bd1

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Citations in the corpus

Role of ROS and RNS Sources in Physiological and Pathological Conditions (2016, background): “2 ∙− [281] and ONOO [282] increase mitochondrial proton leak by enhancing the extent of peroxidative processes [282, 283].”
Mitochondrial Dysfunction Accounts for the Stochastic Heterogeneity in Telomere-Dependent Senescence (2007, background): “Activity of uncoupling proteins, including UCP-2, is induced in response to lipid peroxidation products [63] or to superoxide anion in vitro [32] and in vivo [64].”
Diabetic cardiomyopathy, causes and effects (2010, background): “Mitochondrial ROS generation or lipid peroxides such as hydroxynonenal have been shown to activate uncoupling proteins in heart muscle mitochondria [95] and were found to be increased in the hearts of db/db mice [32].”
Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010, unknown): “Importantly, GDP-sensitive proton conductance triggered by superoxide or 4-HNE is not present in mitochondria from the muscle of UCP3 knockout mice (91) or from the kidney of UCP2-deficient mice (176).”
The mitochondrial uncoupling-protein homologues (2005, background): “— which have been shown to stimulate UCP-dependent proton leak directly in isolated mitochondri”
From bivalves to birds : oxidative stress and longevity (2010, background): “Role of uncoupling proteins (UCPs) in marine invertebrates Although UCPs are highly conserved in structure and are ubiquitously expressed in tissues ofmarine ectotherms including molluscs and fish (Mark, Lucassen & Pörtner 2006), they seem to be little involved in stress-induced mild uncoupling fol”
Life and death: metabolic rate, membrane composition, and life span of animals. (2007, background): “For example, the superoxide-initiated activation of proton conductance by UCP3, mentioned previously, has been shown to be mediated by the lipid peroxidation product 4-hydroxy-trans-2-nonenal (HNE) and its homologs (88).”