Lipid Oxidation at the Crossroads: Oxidative Stress and Neurodegeneration Explored in Caenorhabditis elegans

Abstract

Lipid metabolism plays a critical role in maintaining cellular integrity, especially within the nervous system, where lipids support neuronal structure, function, and synaptic plasticity. However, this essential metabolic pathway is highly susceptible to oxidative stress, which can lead to lipid peroxidation, a damaging process induced by reactive oxygen species. Lipid peroxidation generates by-products that disrupt many cellular functions, with a strong impact on proteostasis. In this review, we explore the role of lipid oxidation in protein folding and its associated pathological implications, with a particular focus on findings in neurodegeneration from Caenorhabditis elegans studies, an animal model that remains underutilized. Additionally, we highlight the effectiveness of different methodologies applied in this nematode to deepen our understanding of this intricate process. In the nervous system of any animal, including mammals and invertebrates, lipid oxidation can disturb the delicate balance of cellular homeostasis, leading to oxidative stress, the build-up of toxic by-products, and protein misfolding, key factors in neurodegenerative diseases. This disruption contributes to the pathogenesis of neurodegenerative disorders such as Alzheimer's, Parkinson's, or Huntington's disease. The findings from Caenorhabditis elegans studies offer valuable insights into these complex processes and highlight potential avenues for developing targeted therapies to mitigate neurodegenerative disease progression.

Keywords: C. elegans; lipid metabolism; lipid oxidation; neurodegenerative disorders; protein misfolding.

Figure 1

Processes that contribute to lipid oxidation within cells drive neuronal death. (A) Lipid peroxidation and β-oxidation are distinct processes involving lipid oxidation, each with different outcomes. In peroxidation, ROS drives oxidation, resulting in the formation of various oxidized species that impair cellular functions. In contrast, β-oxidation involves the breakdown of lipids into smaller molecules through the β-oxidation spiral and the tricarboxylic acid cycle (TCA) cycle, generating energy for the cell. (B) Iron enters cells via transferrin–receptor endocytosis, releasing Fe³⁺, which is reduced to Fe²⁺. In the cytoplasm, Fe²⁺ undergoes the Fenton reaction with hydrogen peroxide (H₂O₂), generating highly reactive hydroxyl radicals (•OH). These radicals initiate lipid peroxidation, damaging PUFAs in cellular membranes and producing toxic by-products. This oxidative stress disrupts membranes, impairs autophagic flow and mitochondrial function, and damages proteins and DNA, triggering neuronal death through apoptosis and inflammation, a process implicated in a range of neurodegenerative diseases.

Figure 2

C. elegans is a very useful animal model used to research neurodegeneration. (A) The nematode C. elegans has one of the shortest lifespans among commonly used animal models in basic and applied research. With a lifespan of approximately three weeks, it offers a significant advantage over models such as Drosophila (three months) and various vertebrates, whose lifespans range from one to several years. (B) Several neurodegenerative disease models have been established in C. elegans, including polyQ- and α-synuclein-induced toxicity models, where aggregation-prone proteins are fused to fluorescent tags to visualize in vivo aggregation dynamics. Other models express panneuronally distributed polyQ repeats or β-amyloid, which induce motor behavior impairments and allow for monitoring of protein aggregation. Additionally, models expressing mHtt in mechanosensory neurons are used to assess neuronal functionality, while the expression of mutant proteins in ASH neurons, which are bimodal (responding to both mechanical and chemical stimuli), leads to cell death.