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)