Worms, Fat, and Death: Caenorhabditis elegans Lipid Metabolites Regulate Cell Death

Abstract

Caenorhabditis elegans is well-known as the model organism used to elucidate the genetic pathways underlying the first described form of regulated cell death, apoptosis. Since then, C. elegans investigations have contributed to the further understanding of lipids in apoptosis, especially the roles of phosphatidylserines and phosphatidylinositols. More recently, studies in C. elegans have shown that dietary polyunsaturated fatty acids can induce the non-apoptotic, iron-dependent form of cell death, ferroptosis. In this review, we examine the roles of various lipids in specific aspects of regulated cell death, emphasizing recent work in C. elegans.

Keywords: apoptosis; ferroptosis; polyunsaturated fatty acids.

Figure 1

The pathway for polyunsaturated fatty acid biosynthesis and the incorporation of fatty acids into glycerophospholipids in C. elegans. Enzyme names are abbreviated in black over the arrows. POD-2, acetyl-CoA carboxylase; FASN-1, fatty acid synthase; ELO, elongase, FAT-5 ∆9 desaturase; FAT-6/-7, ∆9 desaturases; FAT-2, ∆12 desaturase; FAT-1, omega-3 desaturase; FAT-3, ∆6 desaturase; FAT-4, ∆5 desaturase; ACS; acyl CoA synthetases; GPATs; glycerol-3 phosphate acyl transferases; LPAATs, lysophosphatidic acid acyl transferases; LPIN-1, lipin; CDGS-1, CDP-diacylglycerol synthase; DGATs; diacylglycerol acyl transferases. The metabolites in the pathways are enclosed in bubbles. SA, stearic acid; PA, palmitoleic acid; VA, vaccenic acid; OA, oleic acid; LA, linoleic acid; ALA, alpha linolenic acid; GLA, gamma linolenic acid; DGLA, dihomo gamma linolenic acid; AA, arachidonic acid; STA, stearidonic acid; ETA, eicosatetraenoic acid; EPA, eicosapentaenoic acid; FA-CoA, fatty acids conjugated to CoA; G3P, glucose-3 phosphate; LPA; lysophosphatidic acid; PA, phosphatidic acid; DAG, diacylglycerol; CDP-DAG, cytidine diphosphate diacylglycerol; TAG, triacylglycerols; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; PI, phosphatidylinositol; CL, cardiolipin. Adapted from [52].

Figure 2

Phospholipids in C. elegans apoptosis. (A) Phosphatidylserine (PS) plays a role in the specification of the apoptotic cell. TAT-1 is involved in regulating asymmetry of PS in the plasma membrane and this activity is reduced upon cell death activation. CED-3 proteolytically activates WAH-1, which acts to translocate to SCRM-1 and increase the number of PS molecules in the outer leaflet. CED-3 also proteolytically activates CED-8 in the plasma membrane to translocate PS from the inner leaflet to the outer leaflet. Adapted from [93]. (B) During the execution phase, the dying cell is engulfed by the neighboring cell in C. elegans. The PS serves as a “eat me” signal to the neighboring cell which will engulf the apoptotic cell through two arms of the engulfment pathway: the CEDl-1/CED-6/CED-7/DYN-1 pathway and the CED-2/CED-5/CED-12/CED-10 pathway leading to elongation of pseudopodal arms around the corpse. Adapted from [34]. (C) PIP3 accumulation is required to consume the dead cell in phagosomal sealing. Phosphotidylinositol-4,5-bisphosphate (PIP2) accumulates in unsealed phagosomes while phosphotidylinolsitol-3-phosphate (PIP3) accumulates in sealed phagsosomes. Adapted from [94].

Figure 3

Dietary DGLA induces ferroptosis in C. elegans and human cancer cells. Worms are stained with DAPI showing (A) healthy germ cells in untreated worms and contrasts (B) sterile worms depleted of germ cells after DGLA-induced ferroptosis. HT-1080 cancer cells co-treated with Hoechst and the lipid peroxidation probe, C11-BODIPY, and further treated (C) without DGLA (red; non-oxidized) and (D) with DGLA (yellow; oxidized) that undergo ferroptosis. Adapted from [43].

Figure 4

Exogenous DGLA induces ferroptosis by accumulation of lipid peroxides and epoxides of DGLA and further exacerbated by ferrous iron and lipid oxidizing enzymes. This activates lipid repair pathways, including GPXs and can be inhibited by iron chelators and radical trapping antioxidants. Finally, ether lipids play a protective function in DGLA-induced ferroptotic cell death by inhibiting lipid peroxidation. Adapted from [43].