Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal

Abstract

Lipid peroxidation can be described generally as a process under which oxidants such as free radicals attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs). Over the last four decades, an extensive body of literature regarding lipid peroxidation has shown its important role in cell biology and human health. Since the early 1970s, the total published research articles on the topic of lipid peroxidation was 98 (1970-1974) and has been increasing at almost 135-fold, by up to 13165 in last 4 years (2010-2013). New discoveries about the involvement in cellular physiology and pathology, as well as the control of lipid peroxidation, continue to emerge every day. Given the enormity of this field, this review focuses on biochemical concepts of lipid peroxidation, production, metabolism, and signaling mechanisms of two main omega-6 fatty acids lipid peroxidation products: malondialdehyde (MDA) and, in particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only its physiological and protective function as signaling molecule stimulating gene expression and cell survival, but also its cytotoxic role inhibiting gene expression and promoting cell death. Finally, overviews of in vivo mammalian model systems used to study the lipid peroxidation process, and common pathological processes linked to MDA and 4-HNE are shown.

Figure 1

Fenton and Haber-Weiss reaction. Reduced form of transition-metals (Mⁿ) reacts trough the Fenton reaction with hydrogen peroxide (H₂O₂), leading to the generation of ^•OH. Superoxide radical (O₂ ^•−) can also react with oxidized form of transition metals (M⁽ⁿ⁺¹⁾) in the Haber-Weiss reaction leading to the production of Mⁿ, which then again affects redox cycling.

Figure 2

Lipid peroxidation process. In Initiation, prooxidants abstract the allylic hydrogen forming the carbon-centered lipid radical; the carbon radical tends to be stabilized by a molecular rearrangement to form a conjugated diene (step 1). In the propagation phase, lipid radical rapidly reacts with oxygen to form a lipid peroxy radical (step 2) which abstracts a hydrogen from another lipid molecule generating a new lipid radical and lipid hydroperoxide (step 3). In the termination reaction, antioxidants donate a hydrogen atom to the lipid peroxy radical species resulting in the formation of nonradical products (step 4).

Figure 3

MDA formation and metabolism. MDA can be generated in vivo by decomposition of arachidonic acid (AA) and larger PUFAs as a side product by enzymatic processes during the biosynthesis of thromboxane A₂ (TXA₂) and 12-l-hydroxy-5,8,10-heptadecatrienoic acid (HHT) (blue pathway), or through nonenzymatic processes by bicyclic endoperoxides produced during lipid peroxidation (red pathway). One formed MDA can be enzymatically metabolized (green pathway). Key enzymes involved in the formation and metabolism of MDA: cyclooxygenases (1), prostacyclin hydroperoxidase (2), thromboxane synthase (3), aldehyde dehydrogenase (4), decarboxylase (5), acetyl CoA synthase (6), and tricarboxylic acid cycle (7).

Figure 4

Enzymatic production of 4-HNE and metabolism. In plant enzymatic route to 4-HNE includes lipoxygenase (LOX), -hydroperoxide lyase (HPL), alkenal oxygenase (AKO), and peroxygenases. 4-HNE metabolism may lead to the formation of corresponding alcohol 1,4-dihydroxy-2-nonene (DHN), corresponding acid 4-hydroxy-2-nonenoic acid (HNA), and HNE–glutathione conjugate products. 4-HNE conjugation with glutathione s-transferase (GSH) produce glutathionyl-HNE (GS-HNE) followed by NADH-dependent alcohol dehydrogenase (ADH-)catalysed reduction to glutathionyl-DNH (GS-DNH) and/or aldehyde dehydrogenase (ALDH-)catalysed oxidation to glutathionyl-HNA (GS-HNA). 4-HNE is metabolized by ALDH yielding HNA, which is metabolized by cytochrome P450 (CYP) to form 9-hydroxy-HNA (9-OH-HNA). 4-HNE may be also metabolized by ADH to produce DNH.

Figure 5

Nonenzymatic 4-HNE production. Initial abstraction of bisallylic hydrogen of lipoic acid (LA) produces fatty radicals. 4-HNE formation starting with 9- and 13-hydroperoxyoctadecadienoate (HPODE) (red and blue pathways, resp.). 4-HNE is generated by beta-scission of a hydroxyalkoxy radical that is produced after cyclization of alkoxy radical in the presence of transition metal ions and two molecules of oxygen; this reaction involves hydrogen abstraction (1). Peroxy radical cyclizes to form a dioxetane which is oxygenated to peroxy-dioxetane that is fragmented and after two hydrogen abstractions produce 4-HNE (2). Hydroperoxyl radical is oxygenated to dioxetane that is further fragmented to produce 4-hydroperoxy-2E-nonenal (4-HPNE), an immediate precursor of 4-HNE (3). Bicyclic endoperoxides react with reduced form of transition metal, such as iron (Fe²⁺) to produce alkoxyl radicals which after reaction with oxygen (O₂), hydrogen abstraction (H⁺), and fragmentation produce 4-HNE (4). Alkoxyl radical after cyclization, oxygenation, hydrogen abstraction, oxidation of transition metal, hydrolysis, and rearrangement yields 4-HNE (5). With arachidonic acid, 11- and 15- hydroperoxyeicosatetraenoic acids (HPETE) are the precursors to form 4-HNE via the analogous mechanisms.

Figure 6

4-HNE promotes cell survival or induces cell death. Depending on cell type, damage/repair capacities and cellular metabolic circumstances 4-HNE can promote cell survival or induce cell death. 4-HNE at physiological levels is enzymatically metabolized and at low levels plays an important role as signaling molecule stimulating gene expression, enhance cellular antioxidant capacity and exert adaptive response; at medium levels organelle and protein damage lead to induction of autophagy, senescence, or cell cycle arrest and at high or very high levels promote adducts formation and apoptosis or necrosis cell death, respectively.

Figure 7

Mechanisms showing how cumene hydroperoxide produces lipophilic cumoxyl and cumoperoxyl radicals. Cumene hydroperoxide in presence of transition metal ions produces cumoxyl radical (step 1), which abstracts a hydrogen (H) from a lipid (PUFA) molecule (LH) generating cumyl alcohol and lipid radical (L^•) that reacts readily with oxygen promoting the initiation or propagation of lipid peroxidation. (Step 2). Cumoxyl radical can also react with other cumene hydroperoxide molecules to yield cumyl alcohol and cumoperoxyl radical (step 3). Finally, cumoperoxil radical may abstract hydrogen (H) from the closest available lipid to produce a new cumene hydroperoxide and lipid radical (L^•) which then again affects lipid peroxidation cycling (step 4). Cumoperoxyl radical may also react with oxygen to yield a new cumoxyl radical thus initiating a chain reaction (step 5).