What are the mechanisms of programmed cell death, including apoptosis, autophagy, and ferroptosis?

From the Guidelines

Cells can die through several regulated pathways including apoptosis, autophagy, and ferroptosis, with each mechanism having distinct characteristics and roles in development, tissue homeostasis, and disease processes. Apoptosis is a programmed cell death mechanism characterized by cell shrinkage, nuclear fragmentation, and formation of membrane-bound vesicles called apoptotic bodies, which are then engulfed by phagocytes without triggering inflammation, as controlled by caspase enzymes and initiated through either intrinsic (mitochondrial) or extrinsic (death receptor) pathways 1.

Autophagy is both a survival and death mechanism where cells digest their own components by forming autophagosomes that fuse with lysosomes, breaking down cellular materials for recycling or elimination of damaged organelles. While primarily protective, excessive autophagy can lead to cell death, and its relationship with ferroptosis is complex, with evidence suggesting that autophagy can have both promoting and protective effects on ferroptotic cell death, but the underlying mechanisms and checkpoints regulating these opposing effects are still poorly understood 1.

Key characteristics of these pathways include:

• Apoptosis: caspase activation, apoptotic body formation, and no inflammation
• Autophagy: formation of autophagosomes, digestion of cellular components, and potential for cell death
• Ferroptosis: iron-dependent, accumulation of lipid peroxides and reactive oxygen species, mitochondrial shrinkage, and increased membrane density, without caspase activation or apoptotic body formation. Understanding these distinct death pathways is crucial for elucidating their roles in development, tissue homeostasis, and disease processes, including cancer, neurodegeneration, and inflammatory conditions, and for the development of precision therapies that harness the therapeutic potential of these interconnected processes 1.

From the Research

Mechanisms of Programmed Cell Death

The mechanisms of programmed cell death, including apoptosis, autophagy, and ferroptosis, are complex and interconnected.

• Apoptosis is a form of programmed cell death that is regulated by various signal transduction pathways, but the provided studies do not directly discuss its mechanisms.
• Autophagy is a conserved intracellular degradation system that plays a dual role in cell death, depending on context and phase 2.
• Ferroptosis is a newly defined form of regulated cell death characterized by iron overload, lipid reactive oxygen species (ROS) accumulation, and lipid peroxidation, which is different from necrosis, apoptosis, autophagy, and other forms of regulated cell death in morphology, biochemistry, function, and gene expression 3.

Relationship Between Autophagy and Ferroptosis

There is a connection between autophagy and ferroptosis, with autophagy playing a crucial role in the regulation of ferroptosis.

• Activation of ferroptosis is indeed dependent on the induction of autophagy 4.
• Many ferroptosis regulators, such as SLC7A11, GPX4, NRF2, p53, HSPB1, CISD1, FANCD2, and ACSL4, have been identified as potential regulators of autophagy 4.
• Autophagy is involved in the initial step of ferroptosis under the action of histone elements such as NCOA4, RAB7A, and BECN1 5.

Interplay Between Autophagy and Cell Death Pathways

The interplay between autophagy and cell death pathways is complex and bidirectional.

• Autophagy can modulate other vital processes such as programmed cell death (e.g., apoptosis), inflammation, and adaptive immune mechanisms and thereby influence disease pathogenesis 2.
• Autophagy may modulate the outcome of other regulated forms of cell death such as necroptosis 2.
• Autophagy can dampen inflammatory responses, including inflammasome-dependent caspase-1 activation and maturation of proinflammatory cytokines 2.
• Autophagy may also act as a regulator of caspase-1-dependent cell death (pyroptosis) 2.
• The complex interplay between autophagy and cell death pathways can contribute to promote different modes of cell death, either through highly regulated signaling events or in a more uncontrolled inflammatory manner 6.