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Review
. 2016 Jul;23(7):1099-109.
doi: 10.1038/cdd.2016.25. Epub 2016 Mar 11.

Emerging roles for lipids in non-apoptotic cell death

L Magtanong  1 , P J Ko  1 , S J Dixon  1
Affiliations
Review

Emerging roles for lipids in non-apoptotic cell death

L Magtanong et al. Cell Death Differ. 2016 Jul.

Abstract

Non-apoptotic regulated cell death (RCD) is essential to maintain organismal homeostasis and may be aberrantly activated during certain pathological states. Lipids are emerging as key components of several non-apoptotic RCD pathways. For example, a direct interaction between membrane phospholipids and the pore-forming protein mixed lineage kinase domain-like (MLKL) is needed for the execution of necroptosis, while the oxidative destruction of membrane polyunsaturated fatty acids (PUFAs), following the inactivation of glutathione peroxidase 4 (GPX4), is a requisite gateway to ferroptosis. Here, we review the roles of lipids in the initiation and execution of these and other forms of non-apoptotic cell death. We also consider new technologies that are allowing for the roles of lipids and lipid metabolism in RCD to be probed in increasingly sophisticated ways. In certain cases, this new knowledge may enable the development of therapies that target lipids and lipid metabolic processes to enhance or suppress specific non-apoptotic RCD pathways.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of lipids and lipid diversity. (a) Six categories of lipids important for mammalian cell function (see also lipidmaps.org for more information). (b) An example of structural diversity in the glycerophospholipid class. Glycerophospholipids can be esterified at two positions (R1 and R2, respectively) with distinct FAs. SFAs and MUFAs can be synthesized de novo or taken up from the environment. PUFAs are taken up from the environment or synthesized from essential PUFA precursors like linoleic acid (LA, 18:2n-6). The head group conjugated to the phosphate can be one of the several molecules (ethan.: ethanolamine). Inositol can be further modified by phosphorylation, generating additional diversity. The example molecule shows a PC conjugated to an SFA, stearic acid (R1=18:0), and a PUFA, arachidonic acid (R2=20:4n-6)
Figure 2
Figure 2
Lipids as triggers of non-apoptotic cell death. (a) During the process of post-lactational regression, mammary epithelial cells take up MFGs, a type of storage lipid. MFGs containing OA (18:1n-9) can damage lysosomal membranes, leading to the release of cathepsins and induction of non-apoptotic cell death. It is unclear whether lysosomal damage is triggered by OA conjugated to the glycerol backbone or OA liberated from the glycerol backbone by a lysosomal lipase. Stat3 promotes this process in several ways, including enhancing the size (and potentially the sensitivity to damage) of the lysosomal membrane, upregulating the expression of cathepsins, and inhibiting the expression of the cathepsin inhibitor Spi2a. (b) In macrophages, LPS together with palmitate triggers lysosomal damage and non-apoptotic cell death. (c) A synthetic small molecule, CIL56, can trigger caspase-independent cell death that is suppressed by deleting ACACA, which encodes ACC1, or inhibiting ACC activity using TOFA. The lethal mechanism is unclear, but may involve the accumulation of malonyl-CoA and inhibition of mitochondrial β-oxidation, leading to the simultaneous accumulation of multiple FAs to toxic levels and/or depletion of the products of β-oxidation (NADH, FADH2, ATP)
Figure 3
Figure 3
Role for lipids as executioners of non-apoptotic cell death. (a) Necroptosis involves the activation of RIPK1, which phosphorylates RIPK3 (denoted by the circled P), which then in turn phosphorylates MLKL. MLKL interacts with specific PIPs on lipid bilayers within the cell, including PI(5)P and PI(4,5)P2. The formation of PIPs from PIs requires various PI kinases such as PIKfyve. Phosphorylated MLKL undergoes a confirmational change that allows it to bind PIPs on the plasma membrane and, presumably, form a lethal membrane pore. The stoichiomety of the pore-forming MLKL oligomer is debated. (b) Ferroptosis requires membrane-resident PUFAs, depicted as pink chains, such as arachidonic acid (AA, 20:4n-6). For death to proceed, PUFAs must be acylated by acyl-CoA synthetase long-chain family member 4 (ACSL4) and inserted into lysophospholipids by lysophosphatidylcholine acyltransferase 3 (LPCAT3). Ferroptosis involves oxidation (orange dots) of membrane PUFAs. It is thought that this leads to fragmentation of these oxidized species, generating toxic aldehydes like 4-hydroxynonenal (4-HNE). Cell death is due to physical destruction of the membrane. Death can be prevented by synthetic or natural lipophilic antioxidants such as ferrostatin-1 (Fer-1) or vitamin E (Vit. E), respectively.
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