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The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins Under Oxidative Stress

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The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins Under Oxidative Stress molecules Review The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress Elena E. Pohl * and Olga Jovanovic * Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna A-1210, Austria * Correspondence: [email protected] (E.E.P.); [email protected] (O.J.) Received: 9 November 2019; Accepted: 10 December 2019; Published: 12 December 2019 Abstract: Reactive oxygen species (ROS) and their derivatives, reactive aldehydes (RAs), have been implicated in the pathogenesis of many diseases, including metabolic, cardiovascular, and inflammatory disease. Understanding how RAs can modify the function of membrane proteins is critical for the design of therapeutic approaches in the above-mentioned pathologies. Over the last few decades, direct interactions of RA with proteins have been extensively studied. Yet, few studies have been performed on the modifications of membrane lipids arising from the interaction of RAs with the lipid amino group that leads to the formation of adducts. It is even less well understood how various multiple adducts affect the properties of the lipid membrane and those of embedded membrane proteins. In this short review, we discuss a crucial role of phosphatidylethanolamine (PE) and PE-derived adducts as mediators of RA effects on membrane proteins. We propose potential PE-mediated mechanisms that explain the modulation of membrane properties and the functions of membrane transporters, channels, receptors, and enzymes. We aim to highlight this new area of research and to encourage a more nuanced investigation of the complex nature of the new lipid-mediated mechanism in the modification of membrane protein function under oxidative stress. Keywords: reactive aldehydes; hydroxynonenal; oxononenal; free fatty acids; mitochondrial uncoupling protein; lipid bilayer membranes 1. Reactive Oxygen Species and Their Derivatives, Reactive Aldehydes With regard to reactive oxygen species (ROS), these include unstable short-lived molecules that . contain oxygen (O2 ,H2O2, and OH−) and are highly reactive in cells. The term “ROS” is often . - substituted by the phrase “free radicals”; however, strictly speaking, only O2 and OH are considered free radicals. Besides oxygen, reactive species (RS) may contain nitrogen, carbon, sulfur, and halogens. Over 90% of ROS in eukaryotic cells are produced by mitochondria [1]. Mitochondria produce a substantial amount of superoxide anion at Complex I and via autoxidation of a ubisemiquinone . anion radical at Complex III, where O2 is released on both sides of the membrane (for recent reviews see [2–5]). Superoxide anion may give rise to a variety of reactive carbonyl species (RCS, reactive aldehydes (RAs)), which are three to nine carbons in length (Figure1). Of these, α,β-unsaturated aldehydes (4-hydroxy-trans-2-nonenal (HNE) and acrolein), di-aldehydes (malondialdehyde (MDA) and glyoxal), and keto-aldehydes (4-oxo-trans-2-nonenal (ONE) and isoketals (IsoK)) are the most toxic RAs (Figure2). Molecules 2019, 24, 4545; doi:10.3390/molecules24244545 www.mdpi.com/journal/molecules MoleculesMolecules2019 2019,,24 24,, 4545 x FOR PEER REVIEW 23of of 1515 ROS PLA2 O PUFA AA, 20:4, ω6 OH O EPA, 20:5, ω3 OH DHA, 22:6, ω3 OH O ω3 PUFA ω6 peroxidation α,β-unsaturated aldehydes OH OH HHE O HNE O O O OHE ONE O O OH HDDE MDA O O O O O OH COOH H Acrolein O Isoketals Modification Proteins Lipids DNA RA-amino acid RA-lipid RA-DNA adducts adducts adducts Change of lipid membrane properties Figure 1. Elevated levels of ROS induce PUFA peroxidation in the cell membrane and the formation Figure 1. Elevated levels of ROS induce PUFA peroxidation in the cell membrane and the of different α, β-unsaturated RAs which can react with proteins, lipids, and DNA. Abbreviations: AA, formation of different α, β-unsaturated RAs which can react with proteins, lipids, and DNA. arachidonic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HDDE, 4-hydroxydodeca- Abbreviations: AA, arachidonic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; (2E,6Z)-dienal; PLA2, phospholipase A2; PUFA, polyunsaturated fatty acid. HDDE, 4-hydroxydodeca-(2E,6Z)-dienal; PLA2, phospholipase A2; PUFA, polyunsaturated fatty acid. Molecules 2019, 24, 4545 3 of 15 Molecules 2019, 24, x FOR PEER REVIEW 4 of 15 -unsaturated aldehydes Short Hydroxyalkenals Ketoaldehydes HDDE Isoketals MDA HNE ONE Acrolein HHE OHE Lipophilicity Reactivity Toxicity / Inflammation FigureFigure 2.2. MainMain types types of αof, βα,β-unsaturated-unsaturated aldehydes aldehydes and relationsand relations between between their lipophilicity, their lipophilicity, reactivity, reactivityand toxicity., and Abbreviations toxicity. Abbreviations as used in as Figure used1 .in Figure 1. SeveralRAs can members be more destructiveof a mitochondrial than ROS membrane because (1) protein they have superfamily, a much longer known half-life as the (i.e., solute minutes carrier to familyhours instead(SLC25), of microsecondssuch as adenine to nanoseconds nucleotide transporter for most free (ANT) radicals), [20,21] and, (2) dicarboxylate the non-charged carrier structure [22], phosphate,of aldehydes aspartate allows themglutamate to migrate carrier long [23] distances, and members from the of production the uncoupling site through protein hydrophobic subfamily (UCP1membranes–4) were [6– 8proposed]. Reactivity to be between involved aldehydes in proton di fftransport.ers both qualitatively and quantitatively. The most extensivelyIt is well studied accepted aldehyde, that the HNE best is generatedinvestigated by member the oxidation of the of UCP lipids family containing—UCP1 polyunsaturated—uncouples subsomega-6trate acyloxidation groups, suchfromas mitochondrial arachidonic or linoleicATP synthesis groups, and by of thetransporting corresponding protons fatty acidsfrom (FAs).the intermembraneThis aldehyde elicitsspace deleteriousto the matrix eff [24ects–29] primarily. The protonophoric by oxidizing ability intracellular of other components, uncoupling including proteins isDNA, a longst lipids,and anding proteinsissue in controv [9]. Anotherersial aldehyde, debates [30] 4-oxo-2-hexenal. The proton- (OHE),transporting is generated capacity by of the UCP2 oxidation and UCP3of !-3 polyunsaturatedwas shown to be FAs, comparable which are commonly with the foundcapacity in dietary of UCP1 fish oilin andlipid soybean bilayer oil membranes [10]. OHE is reconstitutedthought to possess with recombinant DNA-damaging proteins potential (2–14/s, similar for a to review that of see HNE. [31] In). Several contrast, studies ONE wasin multiscale shown to andbe a biomimetic more reactive systems protein indicate modifier that and the cross-linking function of UCP2/UCP3 agent than HNE is associated [11]. It has with been the proposed transport that of differentthe greater metabolic neurotoxicity substrates of ONE [32 may–34] indicate, possibly di ffalongsideerent reactivity proton characteristics transport [26,35 than–37 those]. A of recent HNE. comparisonIn comparison, of wild MDA type possesses and UCP2 a stronger-/- or UCP3 mutagenic-/- knockout and mice carcinogenic [21] implied potential that both in mammalian proteins are cellsnot involvedthan HNE in [ 12H+]. transport. Unfortunately, the tissue(s) chosen in this study were previously shown to have Theno presence estimation or very of exact low RA abundance concentrations of UCP2/UCP3 in cells is under difficult physiological since concentrations conditions of [38,39 several]. µ M, the maximumNègre-Salvayre reported et al. for was the the cell first cytoplasm, to suggest are UCP2 averaged involvement values. However, in ROS regulation, it is plausible combining that RA theconcentration largely accepted levels mayview be that much a higherhigh mitochondrial locally for a short membrane period ofpotential time [13 leads]. Whereas to increased cellular productionconcentrations of ROS of (particularly HNE under superoxide physiological anion) conditions with the idea can that reach UCP2 0.3 diminishes mM, HNE the accumulates membrane potentialat concentrations by transporting up to proteins 5 mM in from cellular intermembrane membranes space under to conditionsthe mitochondrial of oxidative matrix stress[40]. This [14]. suggestionAlso, Esterbauer was extended et al. suggested by Brand that and HNE colleagues and other who aldehydesproposed that are unlikelyUCP activity to reach was physiologicalregulated by superoxideconcentrations [41] of or approximately RAs (HNE) [42] 100.µ AM[ coherent7]. However, theory much for a higher feedback levels mechanism may be transiently was formulated achieved wherebyin the vicinity increased of peroxidizing ROS production membranes would activate because uncoupling of the high to lipophilicity decrease ROS of formation; RA. As an oxidative example, damagewithin the would lipid thereby bilayer ofbe isolatedreduced peroxidizing (for review see microsomes, [43]). In contrast, the concentration Cannon’sHNE group, is approximatelyusing brown- fat4.5 mitochondria mM [13,15]. The from concentration UCP1-/- and ofsu anperoxide RA in thedismutase membrane (SOD is- strongly/-) knock- dependentout mice, showed on its lipophilicity that HNE couldand, for neither example, (re)activate is higher purine for ONE nucleotide and HNE-inhibited than for UCP1, 4-hydroxy-2-hexenal nor induce the (HHE)additional [16]. activation of innately active UCP1 [44]. No support
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