Apoptotic cell death in disease-Current understanding of the NCCD 2023

Abstract

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.

Fig. 1. Principal causes of the therapeutic failure of intrinsic or extrinsic apoptosis inhibitors.

The clinical development and success of agents inhibiting apoptosis is limited by multiple contributory causes, including potential non-apoptotic, accessory or even protective roles of the targeted proteins (exemplified by the involvement of certain BCL2 family members, caspases and death receptors in processes as diverse as inflammation, cell differentiation, cell proliferation and cell survival), the high interconnectivity between RCD pathway (potentially leading to the activation of compensatory RCD variants in response to the inhibition of a specific RCD type), the low specificity and selectivity of the inhibitors developed so far (exemplified by the broad-spectrum caspase inhibitors) and the difficulty to precisely determine and quantify cell death in vivo. RCD regulated cell death.

Fig. 2. Molecular machinery of the intrinsic apoptosis.

Intrinsic apoptosis can be activated by a range of extracellular or intracellular stimuli, including, but not limited to, DNA damage, endoplasmic reticulum (ER) or oxidative stress, growth factor withdrawal or microtubular alterations. The critical step of the intrinsic apoptosis is the activation of the pro-apoptotic effectors of the BCL2 family, BAX, BAK and possibly BOK, which drives the outer membrane permeabilization (MOMP) and commits cells to death. MOMP results in the release from the mitochondrial intermembrane space into the cytosol of proapoptotic proteins, including CYCS and SMAC. CYCS assembles with APAF1, dATP and pro-CASP9 into the apoptosome, leading to the activation of CASP9, which in turn promotes the activation of the executioner caspases CASP3 and CASP7. The activation of the executioner caspases is facilitated by SMAC, which sequesters and/or degrades members of IAP family that inhibit apoptosis.

Fig. 3. Impact of intrinsic apoptosis players on neurological disorders.

Intrinsic apoptosis is directly or indirectly involved in the pathogenesis of multiple neurological disorders, including neurodegenerative diseases, brain damage caused by traumatic injury or neurotoxicity as well as neuromuscular and retinal disorders.

Fig. 4. Molecular machinery of the extrinsic apoptosis pathway.

Extrinsic apoptosis is initiated by the binding of FASL to FAS or TRAIL to TRAIL-R1 or TRAIL-R2, which promotes the assembly, on the cytoplasmic tail of these death receptors, of a platform known as the DISC. Extrinsic apoptosis is also triggered by the binding of TNF to TNF-R1, which promotes the assembly of the Complex II. The DISC comprises FADD, c-FLIPs and pro-CASP8. Complex II is a platform consisting of FADD and pro-CASP8 in association with either TRADD (complex IIa) or RIPK1 (complex IIb). The assembly of these complexes promotes the activation of CASP8, which mediates CASP3 and CASP7 activation either directly, by catalyzing the proteolytic activation of CASP3 and CASP7 (in type I cells) or indirectly, via the proteolytic activation of the BH3-only protein BID and outer membrane permeabilization (MOMP) (in type II cells). At least in some cells, extrinsic apoptosis can also be induced by dependence receptors like DCC, NTRK3, PTCH1, or UNC5A-D, which are activated by decreased concentration of the related ligand, as illustrated in the figure. However, the role of this pathway in normal physiology and disease is not yet established.

Fig. 5. Impact of extrinsic apoptosis players on neurological disorders.

Death receptor-induced apoptosis is directly or indirectly involved in the pathogenesis of multiple neurological disorders, including neurodegenerative diseases, in brain damage due to traumatic injury or neurotoxicity as well as in neuromuscular and retinal disorders.