Lipid peroxidation in cell death

Abstract

Disruption of redox homeostasis is a key phenotype of many pathological conditions. Though multiple oxidizing compounds such as hydrogen peroxide are widely recognized as mediators and inducers of oxidative stress, increasingly, attention is focused on the role of lipid hydroperoxides as critical mediators of death and disease. As the main component of cellular membranes, lipids have an indispensible role in maintaining the structural integrity of cells. Excessive oxidation of lipids alters the physical properties of cellular membranes and can cause covalent modification of proteins and nucleic acids. This review discusses the synthesis, toxicity, degradation, and detection of lipid peroxides in biological systems. Additionally, the role of lipid peroxidation is highlighted in cell death and disease, and strategies to control the accumulation of lipid peroxides are discussed.

Keywords: Antioxidant; Ferroptosis; Lipid oxidation; Neurodegeneration; Oxidation; Peroxidation.

Figure 1

General mechanism for peroxidation of PUFAs. A hydrogen atom at a bisallylic position is remove using either a radical or a redox active metal to generate a resonance stabilized carbon centered radical. The double bonds of the acid isomerize to form the more thermodynamically stable conjugated diene prior to reacting with molecular oxygen.

Figure 2

The three steps of non-enzymatic lipid peroxidation. In the initiation step the first radicals are generated by redox active labile iron. In the propagation step radicals are able to react with new substrates, creating new radicals. The propagation step repeats until the termination step, where radicals are ‘quenched’ by antioxidants or reacting with another radical.

Figure 3

Lipid peroxide degradation. (A) Structures of common lipid peroxide degradation products. (B) Two mechanistic hypotheses to explain the formation of 4-HNE via a peroxide intermediate 4-HPNE (C) Malondialdehyde can form Schiff bases with primary amines. In the first condensation, the resulting imine tautomerizes to the enamine before condensing with a second primary amine. (D) 4-hydroxynonenal is a Michael receptor that reacts with nucleophilic side chains such as cysteine.

Figure 4

Catalytic reduction of lipid peroxides by GPX4. GPX4 (green) uses a highly nucleophilic selenocysteine to attack a lipid peroxide, generating a selenenic acid intermediate and a lipid hydroxide. The selenenic acid is further reduced by two successive equivalents of glutathione (GSH).