Ferroptosis is a form of regulated cell death that is intricately linked to cellular metabolism. In the forefront of research on ferroptosis, the peroxidation of polyunsaturated fatty acids has emerged as a key driver of oxidative damage to cellular membranes leading to cell death. Here, we review the involvement of polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs), lipid remodeling enzymes and lipid peroxidation in ferroptosis, highlighting studies revealing how using the multicellular model organism Caenorhabditis elegans contributes to the understanding of the roles of specific lipids and lipid mediators in ferroptosis.

The nematode Caenorhabditis elegans has emerged as an important model for studies of the regulation of fat storage. C. elegans feed on bacteria, and various strains of E. coli are commonly used in research settings. However, it is not known whether particular bacterial diets affect fat storage and metabolism. Fat staining of fixed nematodes, as well as biochemical analysis of lipid classes, revealed considerable differences in fat stores in C. elegans growing on four different E. coli strains. Fatty acid composition and carbohydrate levels differ in the E. coli strains examined in these studies, however these nutrient differences did not appear to have a causative effect on fat storage levels in worms. Analysis of C. elegans strains carrying mutations disrupting neuroendocrine and other fat-regulatory pathways demonstrated that the intensity of Nile Red staining of live worms does not correlate well with biochemical methods of fat quantification. Several neuroendocrine pathway mutants and eating defective mutants show higher or lower fat storage levels than wild type, however, these mutants still show differences in fat stores when grown on different bacterial strains. Of all the mutants tested, only pept-1 mutants, which lack a functional intestinal peptide transporter, fail to show differential fat stores. Furthermore, fatty acid analysis of triacylglycerol stores reveals an inverse correlation between total fat stores and the levels of 15-methylpalmitic acid, derived from leucine catabolism. These studies demonstrate that nutritional cues perceived in the intestine regulate fat storage levels independently of neuroendocrine cues. The involvement of peptide transport and the accumulation of a fatty acid product derived from an amino acid suggest that specific peptides or amino acids may provide nutritional signals regulating fat metabolism and fat storage levels.

Monounsaturated fatty acids are essential components of membrane and storage lipids. Their synthesis depends on the conversion of saturated fatty acids to unsaturated fatty acids by Δ9 desaturases. Caenorhabditis elegans has three Δ9 desaturases encoded by the genes fat-5, fat-6, and fat-7. We generated nematodes that display a range of altered fatty acid compositions by constructing double-mutant strains that combine mutations in fat-5, fat-6, and fat-7. All three double-mutant combinations have reduced survival at low temperatures. The fat-5;fat-6 double mutants display relatively subtle fatty acid composition alterations under standard conditions, but extreme fatty acid composition changes and reduced survival in the absence of food. The strain with the most severe defect in the production of unsaturated fatty acids, fat-6;fat-7, exhibits slow growth and reduced fertility. Strikingly, the fat-6;fat-7 double-mutant animals have decreased fat stores and increased expression of genes involved in fatty acid oxidation. We conclude that the Δ9 desaturases, in addition to synthesizing unsaturated fatty acids for properly functioning membranes, play key roles in lipid partitioning and in the regulation of fat storage.

Lipid and carbohydrate metabolism are highly conserved processes that affect nearly all aspects of organismal biology. Caenorhabditis elegans eat bact