PMC

The pores of death.

Summary of some mechanisms of neuronal death.

Neuronal death induced by axotomy.

Forms of ischemia-induced neuronal death in penumbra.

Parthanatos: poly ADP-ribose polymerase 1 (PARP-1)-mediated cell death.

Alzheimer’s disease pathology and links to neuronal death.

Excitotoxicity. Glutamate induces neuronal death by multiple mechanisms. Autophagic cell death may also contribute. Outcome is dependent on neuronal type, stimulus strength and duration, preconditioning, age, gender, etc.

Brain ischemia. Brain ischemia induces a necrotic core, delayed neuronal death in the penumbra (where hypoxia is not so deep), and secondary neuronal loss in connected areas of the brain.

Necroptosis. Activation of death receptors or Toll-like receptors activates NF-κB-mediated inflammation via ubiquinated RIPK1, but deubiquinated RIPK1 can form a complex with RIPK3 that can induce necrosis if and only if caspase-8 is inhibited, preventing cleavage of RIPK1. RIPK1 phosphorylates RIPK3, which phosphorylates MLKL1, which permeabilizes membranes.

Pyroptosis. Inflammation causes expression and activation of the inflammasome, causing activation of caspase-1, which cleaves 1) pro-IL-1β to IL-1β, a key inflammatory cytokine, and 2) gasdermin D (and/or DFNA5) to an NH₂-terminal fragment that oligomerizes into pores.

Ferroptosis. Ferroptosis results from excessive peroxidation of membrane lipids, promoted by reduced iron (Fe²⁺) and inhibited by glutathione peroxidase 4, which depends on glutathione, which in turn depends on cystine supplied by the cystine/glutamate exchanger (X_c⁻). Red text indicates inducers of ferroptosis, and green text indicates inhibitors of ferroptosis.

Lysosomal cell death. Multiple stimuli can cause lysosomal membrane permeabilization (LMP), releasing cathepsin proteases that induce cell death by multiple routes. LMP may also cause the release of calcium, which activates calpain, as well as DNase II and other hydrolases (e.g., lipases).

Oncosis. Ischemia, mitochondrial dysfunction, and/or excessive ATP consumption cause cellular ATP depletion, resulting in 1) failure of sodium pump resulting in cell swelling to rupture, and 2) failure of calcium pumps resulting in calcium activation of proteases and phospholipases that degrade the cell.

Bax signaling at the mitochondria. BH3-only proteins activate Bax to oligomerize and form pores in the outer mitochondrial membrane, causing cytochrome c release and inhibition of complex II, inhibition of respiration and ROS production, activating the protease OMA-1 to remodel the inner mitochondrial membrane, which enables greater cytochrome c release, which triggers caspase activation and apoptosis.

Autophagy and autophagic cell death. Autophagy normally promotes survival during starvation or growth factor withdrawal, but, if excessive, can cause autophagic cell death, characterized by the accumulation of autophagic vacuoles. Note the cross talk between autophagy and apoptosis as Beclin-1 is held via its BH3 motif in an inactive state by binding to anti-apoptotic Bcl2 family members or to Bim when it is tethered on microtubules.

Phagoptosis is cell death resulting from phagocytosis of the cell. Neuronal stress can result in exposure of ‟eat me” signals such as phosphatidylserine, which bind opsonins such as MFG-E8 or GAS6 that engage phagocytic receptors VNR (vitronectin receptor) and MERTK, respectively. Complement factors C1 and C3 binding to neurons can induce uptake via CR3. Phagoptosis is increased in inflammatory conditions that stress neurons and increase phagocytosis.

Neuronal death induced by protein aggregates. Protein aggregates can trigger the unfolded protein response (UPR) or form membrane pores that elevate calcium and ROS levels, which can trigger cell death by multiple mechanisms. Protein aggregates can also clog protein import into organelles, induce stress granule formation, interfere with RNA and heat shock proteins, and impair the proteasome/autophagy, but how these connect to specific cell death pathways is not clear.

Cell death by mitochondrial permeability transition. Calcium and ROS trigger formation of the permeability transition pore (mPTP) in the inner mitochondrial membrane, consisting probably of the adenine nucleotide carrier (ANT) and cyclophilin D (CypD), or possibly the phosphate carrier (PiC) or ATP synthase, and regulated by VDAC and hexokinase on the outer membrane. mPTP causes ATP depletion and thus necrosis, but also may cause cytochrome c release to trigger apoptosis if sufficient ATP is still present.

Overview of apoptosis. The internal (mitochondrial) pathway of apoptosis is triggered within the cell, causing expression or activation of BH3-only proteins that activate Bax (and/or Bak in some cells) to form pores in the outer mitochondrial membrane, releasing cytochrome c to bind APAF-1, activating caspase-9 to cleave and activate downstream caspases, which degrades cellular proteins. The external (death receptor) pathway starts outside the cell with death ligands activating death receptors to activate caspase-8, which either cleaves downstream caspases or cleaves and activates the BH3-only protein Bid. Anti-apoptotic proteins, such as Bcl-2, hold inactive Bax or BH3-ony proteins.