Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance

Abstract

During the last three decades, 4-hydroxy-2-nonenal (HNE), a major α,β-unsaturated aldehyde product of n-6 fatty acid oxidation, has been shown to be involved in a great number of pathologies such as metabolic diseases, neurodegenerative diseases and cancers. These multiple pathologies can be explained by the fact that HNE is a potent modulator of numerous cell processes such as oxidative stress signaling, cell proliferation, transformation or cell death. The main objective of this review is to focus on the different aspects of HNE-induced cell death, with a particular emphasis on apoptosis. HNE is a special apoptotic inducer because of its abilities to form protein adducts and to propagate oxidative stress. It can stimulate intrinsic and extrinsic apoptotic pathways and interact with typical actors such as tumor protein 53, JNK, Fas or mitochondrial regulators. At the same time, due to its oxidant status, it can also induce some cellular defense mechanisms against oxidative stress, thus being involved in its own detoxification. These processes in turn limit the apoptotic potential of HNE. These dualities can imbalance cell fate, either toward cell death or toward survival, depending on the cell type, the metabolic state and the ability to detoxify.

Figure 1

Reactivity of HNE. Here are represented the potential reactions of HNE on the hydroxyl, carbonyl and double bond groups. HNE is biotransformed, but it can also react with proteins according to the Michael addition and the Schiff base formation and DNA by epoxidation

Figure 2

Main extrinsic apoptotic pathway induced by HNE and Daxx-dependent-negative feedback. Extrinsic cell death can be mediated by Fas receptor, via the induction of Fas expression at the membrane or the direct binding of HNE on Fas, leading to its aggregation, independent on FasL and DISC formation. This latter process involves the ASK1/JNK pathway triggering AP-1-dependent transcription. In purple is represented the negative feedback with Daxx, modulating Fas-apoptotic signal. AP-1: activator protein 1; ASK1: apoptosis signal-regulating kinase 1; Daxx: death domain-associated protein; FADD: Fas-associated protein with death domain; FasL: Fas ligand; HNE: hydroxynonenal; and JNK: c-Jun N-terminal kinase

Figure 3

Intrinsic apoptotic pathway is induced by oxidative stress, p53 and mitochondrial membrane disturbances. cyt.c: cytochrome c; HNE: hydroxynonenal; and MOMP: mitochondrial outer membrane permeabilization

Figure 4

Putative pathways involved in HNE detoxification. The conjugation of HNE with glutathione by GST is the main step of detoxification. The renewal of cellular GSH pool is dependent on cysteine content, regulation by xCT. The oxidation pathway via ALDHs family is supposed to be activated when stress is moderate. The reduction pathway with AKRs family is thought to be activated in case of acute stress. DHN: 1,4-dihydroxy-2-nonene; HNA: 4-hydroxynonenoic acid; AOR: aldehyde oxydoreductase; AKR: aldo-keto reductase; GST: glutathione S-transferase; ALDH: aldehyde dehydrogenase; xCT: cystine transporter; MRP: multidrug-resistant protein; RLIP76: RalA-binding protein 16 encoded 76-kDa splice variant; and Trx1: thioredoxine reductase 1

Figure 5

Summary of cell fate upon HNE exposure. When a cell is exposed to a low dose of HNE, HNE can be removed by detoxification processes and the viability is not compromised. Upon a high dose of HNE, the response will depend on the capacity of the cell to eliminate HNE by detoxification. This capacity is controlled by three parameters: the cell type, the antioxidant defense (notably Nrf2) and the energetic adaptability. If the damages are important, the cells can only ‘subsist' by autophagy; senescence or cell cycle arrest. Otherwise, cell death is induced according to different pathways like apoptosis, necrosis or atypical cell death, sum up as ‘cell sabotage'. Chemopreventive strategies can directly target the detoxification process to eliminate HNE or directly prevent its formation. Nrf2: nuclear factor (erythroid-derived 2)-like 2