Interaction of aldehydes derived from lipid peroxidation and membrane proteins

Abstract

A great variety of compounds are formed during lipid peroxidation of polyunsaturated fatty acids of membrane phospholipids. Among them, bioactive aldehydes, such as 4-hydroxyalkenals, malondialdehyde (MDA) and acrolein, have received particular attention since they have been considered as toxic messengers that can propagate and amplify oxidative injury. In the 4-hydroxyalkenal class, 4-hydroxy-2-nonenal (HNE) is the most intensively studied aldehyde, in relation not only to its toxic function, but also to its physiological role. Indeed, HNE can be found at low concentrations in human tissues and plasma and participates in the control of biological processes, such as signal transduction, cell proliferation, and differentiation. Moreover, at low doses, HNE exerts an anti-cancer effect, by inhibiting cell proliferation, angiogenesis, cell adhesion and by inducing differentiation and/or apoptosis in various tumor cell lines. It is very likely that a substantial fraction of the effects observed in cellular responses, induced by HNE and related aldehydes, be mediated by their interaction with proteins, resulting in the formation of covalent adducts or in the modulation of their expression and/or activity. In this review we focus on membrane proteins affected by lipid peroxidation-derived aldehydes, under physiological and pathological conditions.

Keywords: aldehydes; human diseases; lipid peroxidation; membrane proteins; signal transduction.

Figure 1

Structures of 4-hydroxy-2-nonenal (HNE), malondialdehyde (MDA) and acrolein.

Figure 2

Structures and reactions of phosphatidylcholine γ-hydroxyalkenals (PC-HAs). In addition to 2-pentylpyrrole-modification of proteins by the electrophilic addition of HNE to ε-amino lysyl groups, carboxyalkylpyrrole-modified proteins are also formed by adduct formation with other γ-hydroxyalkenals (mirror images of esterified HNE) also formed, at the time of HNE formation, from the oxidation of PUFA-containing phospholipids. Legend: HHE, 4-hydroxy-2-hexenal; HNE, 4-hydroxy-2-nonenal; PL-PC, 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine; PA-PC, 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine; PD-PC, 1-palmitoyl-2-docosahexanoyl-sn-glycero-3-phosphocholine; HODA-PC, 9-hydroxy-12-oxo-10-dodecenoyl-phosphatidylcholine (this compound may also derive from 1-linoleoyl-2-arachidonoyl-sn-glycero-3-phosphocholine, LA-PC); HOOA-PC, 5-hydroxy-8-oxo-6-octenoyl-phosphatidylcholine; HOHA-PC, 4-hydroxy-7-oxo-5-heptenoyl-phosphatidylcholine; PP-protein, 2-pentylpyrrole-modified protein; EP-protein, 2-ethylpyrrole-modified protein; CPP-protein, carboxypropylpyrrole-modified protein; CEP-protein, carboxyethylpyrrole-modified protein [Reprinted with permission from Salomon et al. (2011)].

Figure 3

A redox model of Alzheimer's disease pathogenesis. Amyloid β-peptide (Aβ) is generated by proteolytic cleavage of Amyloid Precursor Protein (APP) by secretases. Aβ undergoes aggregation, with the formation of oligomers, which undergo a conformational transition to β-structured diffusible oligomers and eventually deposit as amyloid plaques in the ECM. Aβ oligomers insert in the plasma membrane, where they initiate lipid peroxidation, leading to the formation of reactive aldehydes, such as acrolein, MDA and HNE. Adduct formation compromises the function of critical proteins in a number of functional subsets of neurotransmission, energetic metabolism, mitochondrial function, antioxidant defenses, represented here by collapsin response mediated protein 2 (CRMP2), α-enolase, ATP synthase α subunit and heme oxygenase 1. Such process is self-feeding and ultimately leads to Alzheimer's disease [Redrawn with permission from Sultana et al. (2012)].