Abstract
Simple SummaryIt is essential for cellular homeostasis that biomolecules, such as DNA, proteins, and lipids, function properly. Disturbance of redox homeostasis produces aberrant biomolecules, including oxidized lipids and misfolded proteins, which increase in cells. Aberrant biomolecules are removed by excellent cellular clearance systems. However, when excess aberrant biomolecules remain in the cell, they disrupt organelle and cellular functions, leading to cell death. These aberrant molecules aggregate and cause apoptotic and non-apoptotic cell death, leading to various protein aggregation diseases. Thus, we investigated the cell-death cross-linking between lipid peroxidation and protein aggregation.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.
Highlights
Lipids are essential for various biological functions
This review summarizes the current views on the relationship between lipid peroxidation and protein aggregation in neurodegenerative diseases, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD)
LLPS-regulators such as metals overlap those of lipid-peroxidation-induced cell death, indicating that LLPS may be a new organelle that regulates and cleans the misfolded proteins induced by lipid peroxidation
Summary
Lipids are essential for various biological functions. They play three important roles in cells: they maintain the cellular membrane structure, regulate cellular signaling, and store energy. These radicals attack other unsaturated fatty acids, leading to sequential oxidation, known as radical chain reactions [2] Biomolecules such as DNA, proteins, and lipids in cells are directly oxidized by RONS under oxidative stress conditions, and they form oxidized DNA bases, misfolded proteins, and oxidized lipids, respectively. Protein aggregation diseases are associated with the dysfunction of tissues and organs following oxidative stress in the body [4]. The mechanisms underlying these diseases are involved in the dysfunction of organelles. Lipid-peroxidation-induced cell death is associated with protein aggregation, and leads to the disturbance of organelle and cellular functions. This review summarizes the current views on the relationship between lipid peroxidation and protein aggregation in neurodegenerative diseases, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD)
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