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Mechanismus der UCP-Aktivierung durch reaktive Aldehyde

Abstract
Free radicals (ROS) have been implicated in aetiology of many pathological states such as metabolic,
cardiovascular and inflammatory failures. Understanding ROS action mechanisms is crucial for the
development of potent therapeutic strategies in the treatment of these diseases. Uncoupling proteins (UCP)
are thought to be involved in ROS regulation by transporting protons through the inner mitochondrial
membrane, thereby diminishing transmembrane potential. On the other side, they are proposed to be
regulated by ROS. In our previous project (Po-524/3, German Research Foundation) we have shown, that
reactive aldehyde, 4-hydroxy-2-nonenal (HNE), leads to the increase of UCP1 activity only if fatty acids
(FA) are present. The main goal of the present project is the evaluation of mechanisms leading to FAmediated
uncoupling protein activation in the presence of HNE. We will test two main hypotheses
concerning the main mechanism of the proton transport mediated by HNE: (i) reactive aldehyde
influences lipid membrane parameters, leading to the facilitation of fatty acid transport (e.g. membrane
fluidity, dipole or surface membrane potential) or/and (ii) HNE binding to the protein leads to the transient
proton channel formation due to conformational change of protein. We use two different experimental
systems, bilayer lipid membranes reconstituted with uncoupling proteins and primary neuronal cell
cultures, which are supposed to complement each other. We will investigate the influence of other
biologically important reactive aldehydes such as malondialdehyde, 4-oxo-2-nonenal and 4-oxo-2-hexenal
on the protein transport function and evaluate possible mechanisms. From the results obtained we expect
to gain mechanistic insight into the controversially discussed regulation of UCP1 and UCP2 by HNE and
other reactive aldehydes, which is important for drug design.
Wissenschaftszweige, Statistik Austria Klassifikation
106006         Biophysik
301110         Physiologie
301114         Zellbiologie
301303         Medizinische Biochemie
Kurzbezeichnung
Mechanismus der UCP-Aktivierung
Projektleitung
Pohl Elena
Laufzeit
01.11.12-30.04.17
Art der Forschung
Grundlagenforschung
Beteiligte Vetmed-Organisationseinheiten
Institut für Physiologie, Pathophysiologie und Biophysik, Abteilung für Physiologie und Biophysik
Gefördert durch
FWF - Fonds zur Förderung der wissenschaftlichen Forschung, Sensengasse 1, 1090 Wien, Österreich

Link zur Projektdatenbank 'Project Finder'
6 Publikationen

Jovanović, O; Škulj, S; Pohl, EE; Vazdar, M (2019): Covalent modification of phosphatidylethanolamine by 4-hydroxy-2-nonenal increases sodium permeability across phospholipid bilayer membranes. Free Radic Biol Med. 2019; 143:433-440

Zimmermann, L; Moldzio, R; Vazdar, K; Krewenka, C; Pohl, EE (2017): Nutrient deprivation in neuroblastoma cells alters 4-hydroxynonenal-induced stress response. Oncotarget. 2017; 8(5):8173-8188
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Annibal, A; Riemer, T; Jovanovic, O; Westphal, D; Griesser, E; Pohl, EE; Schiller, J; Hoffmann, R; Fedorova, M (2016): Structural, biological and biophysical properties of glycated and glycoxidized phosphatidylethanolamines. Free Radic Biol Med. 2016; 95:293-307
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Jovanovic, O; Pashkovskaya, AA; Annibal, A; Vazdar, M; Burchardt, N; Sansone, A; Gille, L; Fedorova, M; Ferreri, C; Pohl, EE (2015): The molecular mechanism behind reactive aldehyde action on transmembrane translocations of proton and potassium ions. Free Radic Biol Med. 2015; 89:1067-1076
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Rupprecht, A; Sittner, D; Smorodchenko, A; Hilse, KE; Goyn, J; Moldzio, R; Seiler, AE; Bräuer, AU; Pohl, EE (2014): Uncoupling protein 2 and 4 expression pattern during stem cell differentiation provides new insight into their putative function. PLoS One. 2014; 9(2):e88474
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Malingriaux, EA; Rupprecht, A; Gille, L; Jovanovic, O; Jezek, P; Jaburek, M; Pohl, EE (2013): Fatty acids are key in 4-hydroxy-2-nonenal-mediated activation of uncoupling proteins 1 and 2. PLoS One. 2013; 8(10):e77786
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