4-Hydroxy-2-nonenal: a critical target in oxidative stress?

Abstract

In this perspective, we summarize and discuss critical advancements in the study of 4-hydroxy-2-nonenal (4-HNE) as it relates to diseases and clinical complications either caused or exacerbated by oxidative stress. Since its identification in 1980, 4-HNE has been extensively studied with an emphasis on its formation, its role in pathology, and its targets. As a reactive aldehyde, and a product of lipid peroxidation, studies corroborate its ability to disrupt signal transduction and protein activity, as well as induce inflammation and trigger cellular apoptosis in conditions of oxidative stress. Notably, we discuss the role of natural enzymes involved in the regulation of 4-HNE, and how they can be applied to its detoxification in various physiological conditions.

Keywords: 4-HNE; ALDH2; ROS; mitochondria; oxidative stress.

Fig. 1.

4-Hydroxy-2-nonenal (4-HNE) physiological and cytotoxic effects. A: 4-HNE has been shown to cause cytoplasmic Ca²⁺ accumulation via inhibition of (Ca²⁺/Mg²⁺)-ATPase and Ca²⁺-ATPase. B: 4-HNE was found to induce the expression of proinflammatory cytokines by regulation of nuclear factor-κB (NF-κB), direct activation, and stimulation of monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor-α (TNF-α), and/or transforming growth factor-β1 (TGF-β1). C: 4-HNE is reported to upregulate the expression of NF-κB, which leads to cell proliferation and differentiation. D: typically, 4-HNE facilitates the formation of 1,4-Michael addition adducts with cysteine, lysine, and histidine residues of various targets. These adducts often result in protein inactivation or dysfunction. 4-HNE adduction with uncoupling proteins (UCPs) and adenine nucleotide translocase (ANT) has been shown to serve as a mechanism of physiological regulation of proton leak. This results in a feedback loop that naturally regulates mitochondrial membrane potential but can lead to mitochondrial dysfunction. E: 4-HNE has been shown to affect mitochondria by impairing ATPase activity, disrupting oxygen consumption, and altering membrane fluidity. F: elevated levels of 4-HNE have been shown to trigger premature apoptosis via adduct formation with c-Jun NH₂-terminal kinase (JNK), inhibition of NF-κB formation, and upregulation of apoptosis promoting proteins such as activating protein-1 (AP-1).

Fig. 2.

Mechanisms of 4-HNE detoxification and inhibition. A: subjection to sources of oxidative stress leads to production of ROS. These reactive species induce lipid peroxidation at the cell membrane, which gives rise to a toxic byproduct: 4-HNE. This cytotoxic aldehyde is then free to form protein adducts with various targets via Michael addition, which often results in protein dysfunction and even cell death. B and C: two molecules were recently identified as possible therapeutic targets for 4-HNE-mediated cellular damage in hyperoxic acute lung injury (HALI). B: in HALI, deletion of ASK1 is associated with a decrease in ROS-mediated damage, which may suggest a role in inhibition of lipid peroxidation by-products. C: knockdown of the P2X7 membrane receptor is shown to inhibit 4-HNE production via mediation of ROS levels. D: quercetin is an experimental chemical compound that has been found to act as an antioxidant, before, during, and after macular degeneration. E–H: AKRs, ALDHs, and GSTs exist as therapeutic targets in many pathologies; their modification of 4-HNE is widely known and beginning to be a target of recent research. E: ARKs detoxify 4-HNE by reducing an active group on the molecule. F: ALDH2 (specifically) is a known cytoprotective molecule that detoxifies 4-HNE in the mitochondria by oxidizing its carbonyl group to form a carboxylic acid. G: Alda-1 is a chemically synthesized small molecule that, when administered, serves as a molecular activator of ALDH2, effectively upregulating ALDH2-mediated detoxification of 4-HNE. H: GST is an enzyme that has been shown to induce retro-Michael addition, or conjugation with 4-HNE, forming 4-HNE derivatives and inactive isoforms.