title: The molecular mechanism behind reactive aldehyde action on transmembrane translocations of proton and potassium ions.
abstract: Membrane transporters are involved in enormous number of physiological and pathological processes. Under oxidative stress they become targets for reactive oxygen species and its derivatives which cause protein damage and/or influence protein function(s). The molecular mechanisms of this interaction are poorly understood. Here we describe a novel lipid-mediated mechanism by which biologically important reactive aldehydes (RAs; 4-hydroxy-2-nonenal, 4-hydroxy-2-hexenal and 4-oxo-2-nonenal) modify the activity of several membrane transporters. We revealed that investigated RAs covalently modify the membrane lipid phosphatidylethanolamine (PE), that lead to the formation of different membrane active adducts. Molecular dynamic simulations suggested that anchoring of PE-RA adducts in the lipid headgroup region is primarily responsible for changes in the lipid membrane properties, such as membrane order parameter, boundary potential and membrane curvature. These caused the alteration of transport activity of mitochondrial uncoupling protein 1, potassium carrier valinomycin and ionophore CCCP. In contrast, neither direct protein modification by RAs as previously shown for cytosolic proteins, nor its insertion into membrane bilayers influenced the studied transporters. Our results explain the diversity of aldehyde action on cell proteins and open a new field in the investigation of lipid-mediated effects of biologically important RAs on membrane receptors, channels and transporters.
authors.affiliation: Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Olga
authors.initials: O
authors.lastname: Jovanovic
authors.affiliation: Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Alina A
authors.initials: AA
authors.lastname: Pashkovskaya
authors.affiliation: Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Center for Biotechnology and Biomedicine, University of Leipzig, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Annibal
authors.affiliation: Division of Organic Chemistry and Biochemistry, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Mario
authors.initials: M
authors.lastname: Vazdar
authors.affiliation: Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Nadine
authors.initials: N
authors.lastname: Burchardt
authors.affiliation: ISOF, Consiglio Nazionale delle Ricerche, Bologna, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Sansone
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Lars
authors.initials: L
authors.lastname: Gille
authors.affiliation: Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Center for Biotechnology and Biomedicine, University of Leipzig, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Fedorova
authors.affiliation: ISOF, Consiglio Nazionale delle Ricerche, Bologna, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ferreri
authors.affiliation: Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria. Electronic address: elena.pohl@vetmeduni.ac.at.
authors.forename: Elena E
authors.initials: EE
authors.lastname: Pohl
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D005227:Fatty Acids / Q000032:analysis / Q000737:chemistry; D006801:Humans; D007473:Ion Channels / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry; D024101:Mitochondrial Proteins / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011188:Potassium / Q000737:chemistry*; D011487:Protein Conformation; D011522:Protons; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D000071256:Uncoupling Protein 1
chemical_list: C403894:4-oxo-2-nonenal; D000447:Aldehydes; D005227:Fatty Acids; D007473:Ion Channels; D008051:Lipid Bilayers; D024101:Mitochondrial Proteins; D011522:Protons; C000604371:UCP1 protein, human; D000071256:Uncoupling Protein 1; C045934:4-hydroxy-2-hexenal; C027576:4-hydroxy-2-nonenal; D011188:Potassium
keywords: Boundary potential; CCCP; HNE-adducts; Membrane conductance; Membrane lipids; Membrane order parameter; Michael adducts; Mitochondrial proteins; PE-adducts; Phloretin; Phosphatidylethanolamine; Planar bilayer membranes; Schiff bases; Surface potential; Transporters; Valinomycin