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Controlling cell death is crucial for the maintenance of organismal homeostasis, as both increased and insufficient cell death, and/or the elimination of dead cells, can have adverse effects on health. There are different modes of cell death, regulated and non-regulated. The Reviews in this series discuss our current understanding of the different cell death mechanisms; their crosstalk and interaction with other cellular pathways; their roles in physiology and human disease; and the potential of modulating cell death for therapeutic purposes.
The proteins apoptosis regulator BAX (BAX), BCL-2 homologous antagonist/killer (BAK) and BCL-2-related ovarian killer protein (BOK), gasdermins and mixed lineage kinase domain-like protein (MLKL) are key executioners of regulated cell death by forming pores across the plasma or mitochondrial membrane. This Review discusses structural rearrangements during activation and oligomerization of these proteins and highlights commonalities and differences of pore formation mechanisms.
Ferroptosis is a form of regulated cell death driven by iron-dependent phospholipid peroxidation. Since its formal identification in 2012, multiple studies have addressed molecular mechanisms, regulation and functions of ferroptosis, associating this cell death modality with various pathologies, but also proposing its roles in normal physiology and potential for therapeutic targeting.
Dispensable, infected or neoplastic cells are removed by programmed cell death, including pathways for apoptosis, necroptosis and pyroptosis. Owing to differences in their mechanisms and physiological outcomes, these cell death pathways have traditionally been viewed as separate entities, but it has become clear that they are mechanistically and functionally connected.
Development and homeostasis are dependent on rapid cell turnover, achieved by the programmed death and subsequent engulfment and breakdown of cells, a process known as efferocytosis. Defects in efferocytosis have been linked to a wide range of diseases; ongoing research therefore aims to better understand efferocytosis processes so as to uncover new therapeutic targets.
Mitochondria are key executioners of apoptosis. However, it has recently become clear that beyond driving apoptosis, mitochondria also contribute to pro-inflammatory signalling and other types of regulated cell death. These functions are relevant to disease and could be targeted in the treatment of, for example, degenerative disorders, infection and cancer.
BCL-2 family proteins are the mediators of apoptotic cell death. The balance between pro-apoptotic and pro-survival BCL-2 family members is differently regulated in various physiological contexts to modulate cellular apoptotic susceptibility. Perturbation of this balance causes excessive or insufficient cell death, leading to diseases such as neurodegeneration and cancer.