Cell death and cancer: Metabolic interconnections

Abstract

Recent findings in the cell death field have transformed our understanding of the interplay between metabolism and cell death in the context of cancer. In this review, we discuss the relationships between metabolism and the cell death pathways of apoptosis, necroptosis, pyroptosis, and ferroptosis, with a particular focus on recent advancements. We will also explore the regulation of metabolism by the BCL-2 family and the participation of oncometabolites in the regulation of cell death. Finally, we examine the emerging links between cell death signaling and cellular persistence. As we highlight in this review, the intersection of metabolic and cell death pathways has implications for cancer cell survival, treatment resistance, and the tumor microenvironment.

Keywords: BCL-2; CP: Cancer; CP: Metabolism; apoptosis; cancer; cell death; ferroptosis; metabolism; necroptosis.

Figure 1

Metabolic pathways Several metabolic pathways interact with regulated cell death pathways, including glycolysis, the pentose phosphate pathway (PPP), fatty acid β-oxidation, the TCA cycle and the ETC. Isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH) and fumarate hydratase (FH) are essential enzymes of the TCA cycle, while gain of function mutant IDH (mIDH) converts α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (D2HG). NADH and FADH2 are utilised by the complexes of the ETC within the inner mitochondrial membrane (IMM) to produce the proton gradient that is harnessed for oxidative phosphorylation (OXPHOS). The flow of electrons (orange) from electron carriers through ETC Complexes I - IV, Coenzyme Q10 (CoQ) and cytochrome c (Cyt c) is shown in orange.

Figure 2

Regulated cell death pathways MOMP and the mitochondrial pathway of apoptosis are tightly controlled by the balance of pro-survival and pro-apoptotic proteins of the BCL-2 family. Apoptotic triggers permit the activation of BAK and BAX which oligomerise, releasing cytochrome c. Cytochrome c promotes caspase-9 activation, which in turn activates caspases -3 and -7. The death receptor apoptotic pathway occurs downstream of death receptor ligation (TNFR1, TRAIL-R1/R2), and requires caspase-8. Necroptosis occurs downstream of death receptor ligation following inactivation or loss of caspase-8, during which phosphorylation and oligomerisation of MLKL leads to plasma membrane permeabilisation and death. In the canonical pyroptotic pathway, infammasomes are activated by PAMPs and DAMPs, promoting caspase-1 cleavage and GSDMD cleavage to release the GSDMD N-terminal fragment which mediates membrane rupture. Ferroptosis is characterised by accumulation of iron-dependent lipid peroxides at the plasma membrane. The selenoprotein glutathione peroxidase 4 (GPX4) detoxifies membrane-bound phospholipid peroxides using glutathione (GSH) as a cofactor. System x_c^- serves to import cystine (Cys) which is reduced intracellularly to cysteine and incorporated into GSH, fuelling GPX4 function. Ferroptosis suppressor protein 1 (FSP1) acts in parallel to GPX4 through the regeneration of extramitochondrial ubiquinone, a key radical trapping antioxidant, using NADPH as an electron donor.

Figure 3

Interaction of oncometabolites with regulated cell death pathways Oncometabolite accumulation following mutation or inactivation of the TCA enzymes IDH, SDH and FH is linked to the regulation of cell death. Of note, D2HG promotes apoptotic resistance which in turn sensitises to BH3 mimetics. Oncometabolites also exert immunomodulatory effects on CD8⁺ T cells.

Figure 4

Apoptotic and ferroptotic signaling in persister cell generation and survival Chemotherapy or BH3 mimetics induce miMOMP in a subset of cancer cells, a crucial step in the development of drug-tolerant persisters. These persister cells exhibit enriched epithelial-mesenchymal transition (EMT) and stress response signatures, leading to changes in lipid metabolism that increase their sensitivity to ferroptosis and dependence on GPX4. Additionally, persisters display heightened mitochondrial metabolism, resulting in elevated mitochondrial ROS.