Cell Death via Lipid Peroxidation and Protein Aggregation Diseases

Abstract

Lipid peroxidation of cellular membranes is a complicated cellular event, and it is both the cause and result of various diseases, such as ischemia-reperfusion injury, neurodegenerative diseases, and atherosclerosis. Lipid peroxidation causes non-apoptotic cell death, which is associated with cell fate determination: survival or cell death. During the radical chain reaction of lipid peroxidation, various oxidized lipid products accumulate in cells, followed by organelle dysfunction and the induction of non-apoptotic cell death. Highly reactive oxidized products from unsaturated fatty acids are detected under pathological conditions. Pathological protein aggregation is the general cause of these diseases. The cellular response to misfolded proteins is well-known as the unfolded protein response (UPR) and it is partially concomitant with the response to lipid peroxidation. Moreover, the association between protein aggregation and non-apoptotic cell death by lipid peroxidation is attracting attention. The link between lipid peroxidation and protein aggregation is a matter of concern in biomedical fields. Here, we focus on lethal protein aggregation in non-apoptotic cell death via lipid peroxidation. We reviewed the roles of protein aggregation in the initiation and execution of non-apoptotic cell death. We also considered the relationship between protein aggregation and oxidized lipid production. We provide an overview of non-apoptotic cell death with a focus on lipid peroxidation for therapeutic targeting during protein aggregation diseases.

Keywords: cell signaling; lipid peroxidation; non-apoptotic cell death; protein aggregation.

Figure 3

A schematic showing the protein aggregation, endoplasmic reticulum (ER) stress response, and cell fate. Protein aggregation is a main feature of the neurodegenerative diseases [88]. Some of the proteins induced by ER stress have ferroptosis-inhibiting activities.

Figure 4

The molecular link between lipid peroxidation and protein aggregation in neurodegenerative diseases. Both lipid peroxidation and protein aggregation simultaneously occur in neuron and neuronal cells, leading to organelle dysfunction and cell death. ALS is a neurological disease characterized by progressive degeneration of nerve cells in the brain and spinal cord. Mutant superoxide dismutase 1 (SOD1) is expressed in a subgroup of familial ALS. Similarly, HD is caused by the huntingtin protein (HTT). The mutant proteins aggregate in the striatum of HD patients. In AD patients, tau fibrils and amyloid β aggregates are detected in the brain. Cerebral atrophy, which is the loss of cerebral brain cells, also occurs in AD patients. In PD, although α-synuclein is increased, the number and sizes of dopaminergic neurons are reduced in the substantia nigra. The bottom panel indicates major neurodegenerative diseases and their associated regions [120,121].

Figure 1

Oxidation of polyunsaturated fatty acids (PUFAs) and production of lipid mediators. Anti-inflammatory lipid mediators, such as resolvin, protectin, and lipoxin, are produced from PUFAs. Pro-inflammatory lipid mediators, such as prostaglandin, thromboxane, and leukotriene, are also metabolized from PUFAs. The highly reactive chemicals, including hydroperoxide and aldehyde, have the binding activities of biomolecules in the cells, which lead to cell death. The illustration was adapted from Iuchi (2021).

Figure 2

The simplified mechanisms of lipid peroxidation-induced cell death. PUFAs are oxidized by enzymatic and non-enzymatic reactions, and the products induce organelle dysfunction, iron-metabolism disturbance, Ca²⁺-signaling alternation, and cell death, which are regulated by the glutathione (GSH) synthesis signal, antioxidants, and oxidative stress response. The illustration was adapted from Iuchi (2021).