Lipid homeostasis and regulated cell death

Abstract

Modern lipidomics analysis paints a dynamic picture of membrane organizations, as changing and adapting lipid assemblies that play an active role in cellular function. This article highlights how the lipid composition of membranes determines specific organelle functions, how homeostatic mechanisms maintain these functions by regulating physical properties of membranes, and how cells disrupt lipid homeostasis to bring about regulated cell death (RCD). These are broad phenomena, and representative examples are reviewed here. In particular, the mechanisms of ferroptosis - a form of RCD brought about by lipid peroxidation - are highlighted, demonstrating how lipid metabolism drives cells' lipid composition toward states of increased sensitivity to lipid oxidation. An understanding of these interactions has begun to give rise to lipid-based therapies. This article reviews current successes of such therapies, and suggests directions for future developments.

Figure 1

Summary of lipid homeostasis and regulated cell death. A) Several lipid membranes in a cell are shown. These include the plasma membrane, inner mitochondrial membrane, outer mitochondrial membrane, lysosomal membrane, nuclear membrane, rough endoplasmic reticulum, smooth endoplasmic reticulum, and golgi membranes. Each organelle facilitates different lipid metabolism pathways, and thus alters local lipid composition. Lipid trafficking is depicted by membrane contact sites and vesicular traffic. B) Lipid homeostasis maintains stable lipid composition, and its disruption leads to cell death. Peroxidized polyunsaturated fatty acids (ox-PUFAs) – shown with red dots – are reduced to lipid alcohols by glutathione peroxidase (GPx4) with glutathione (GSH) as a substrate, and this facilitates a stable ongoing lipid turnover (top branching arrow). The inhibition of GPx4 allows for the accumulation of ox-PUFAs, leading to cell death by ferroptosis (bottom branching arrow). C) The lipid compositions of several organelles.

Figure 2

The role of lipids in three forms of regulated cell death. A) Apoptosis involves lipids at many stages. Sphingolipid (SP) traffic from the ER promotes the activation of BCL2-associated X (BAX) and BCL2-antagonist/killer (BAK). When cardiolipin (CL) is oxidized, protein cytochrome c (cyt c) is released from the inner mitochondrial membrane through BAK/BAX in the outer mitochondrial membrane. B) Necroptosis requires RIPK3 to phosphorylate MLKL, which oligomerizes to form MLKL complexes. These complexes translocate to lipid rafts in the plasma membrane, bind to phosphatidylinositol phosphate (PIP) lipids, and open a pore that causes membrane leakage. C) Ferroptosis is driven by the accumulation of oxidized PUFAs, which result from the depletion of GSH or inhibition of GPX4 – a lipid repair enzyme. Ferrostatin-1 (Fer-1) or vitamin E can inhibit the destruction of the oxidized membrane, but in their absence the membrane is destroyed and toxic reactive oxygen fragments are released into the cell. (panels B and C adapted from [39])