Emerging roles for lipids in non-apoptotic cell death

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.

MYC is a positive regulator of choline metabolism and impedes mitophagy-dependent necroptosis in diffuse large B-cell lymphoma

“…33 Alterations in lipid metabolism may damage cellular and subcellular membrane, cause imbalance between mitochondrial fusion and fission, initiate mitophagy and lead to necroptosis. Therefore, PCYT1A may not only act as a downstream effector of MYC on regulation of choline metabolism, but also a biomarker of MYC-mediated lymphoma cell necroptosis and lymphoma progression in DLBCL.…”

Metabolic networks in ferroptosis (Review)

“…As a novel form of RCD, ferroptosis has begun to attract increased attention (1)(2)(3)(4). Ferroptosis is an iron-dependent and peroxidation-driven form of cell death that is distinct from apoptosis, necrosis and other types of cell death in terms of morphology, genetics, metabolism and molecular biology (2,(5)(6)(7)(8)(9)(10).…”

“…Ferroptosis is driven by inhibition of extracellular cysteine uptake and inactivation of the function of GPX4 (5,15). These processes lead to the depletion of polyunsaturated fatty acids (PUFAs) in lipid bilayers and the accumulation of lipid-based reactive oxygen species (L-ROS) (2,3,7,9,15).…”

Lipid homeostasis and regulated cell death

“…There are several forms of regulated cell death (RCD) that use lipids as key parts of cell death pathways, either as initiators of cell death, mediators of cell death, or as key targets for modification and destruction [39]. These include apoptosis, necroptosis, and ferroptosis, which navigate cells to death in a controlled manner through separate biological pathways.…”

“…Lipids are involved in all stages of apoptosis [39]. The FA palmitate acts as a signal that initiates apoptosis by triggering an ER stress response, while ceramide transduces this signal.…”