Mitochondria-associated cell death pathways. (IMAGE)
Caption
Mitochondria are involved in apoptosis, necrosis, pyroptosis, and iron death. At present, the research on cell apoptosis is relatively thorough, and the mechanism of mitochondria in it has also been elucidated. Mitochondria are indispensable in the process of cell apoptosis. The research on the other three cell death modes is not as clear as cell apoptosis, and the role of mitochondria in them is not indispensable.
(A) Apoptosis. The BCL2 protein family drives MOMP to promote mitochondrial CytC release from the intermembrane space, then combines with APAF1, and finally activates caspase to cause apoptosis.. IPAs can inhibit cell apoptosis by inhibiting the activation of caspase-3 and caspase-7.
(B) Necrosis. RIPK1 and RIPK3 form a tumor to activate MLKL, and make the cell membrane permeable, leading to endocytosis. Mitochondria can promote phosphorylation of RIPK1 through ROS, thereby promoting necrosis. RIPK3 can, in turn, promote the increase of ROS
(C) Pyroptosis. Inflammatory caspases cut GSDMD and activate it, making the cell membrane permeable, releasing inflammatory factors, and leading to cell death. The generation of ROS by mitochondria in response to stress can activate NLRP3 inflammasomes, thereby inducing pyroptosis. At the same time, activated caspase-1 can also initiate mitochondrial apoptosis.
(D) Ferroptosis, when ferritin in mitochondria chelates with free iron ions in cells. When mitochondrial function is abnormal, iron ion accumulation participates in the Fenton reaction, causing lipid peroxidation, resulting in lipid accumulation and imbalance of intracellular redox balance, leading to cell death
(E) Cuproptosis. FDX1 reduces Cu2+ to Cu+ and facilitates the lipoylation of DLAT. Accumulated Cu+ binds to lipoylated DLAT, instigating its aggregation and triggering proteotoxic stress.
BAX, BCL2-associated X protein; BAK, BCL2 antagonist/killer; MOMP, mitochondrial outer membrane permeabilization; CytC, cytochrome C; APAF1, apoptotic protease activating factor 1; TNF, tumor necrosis factor; RIPK, receptor-interacting protein kinase; TCA, tricarboxylic acid; ROS, reactive oxygen species; MLKL, mixed lineage kinase domain-like pseudo kinase; NLRP3, nucleotide-binding oligomerization domain-like receptor protein 3; G-SDMD, gasdermin-D; IL-18, interleukin 18; GSH, glutathione; GPX4, glutathione peroxidase 4; FDX1, ferredoxin 1; LA, lipoic acid; DLAT, dihydrolipoamide S-acetyltransferase; LIAS, lipoic acid synthetase.
Credit
Chen Huang, Zichuan Xie, Jiajin Li, Chenliang Zhang
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