What are the mechanisms of cell death, including apoptosis and autophagy (autophagic cell death)?

From the Guidelines

Cells can die through two main regulated processes: apoptosis and autophagy, with apoptosis being a programmed cell death mechanism and autophagy being primarily a survival mechanism that can lead to cell death when excessive. The mechanisms of cell death, including apoptosis and autophagy, are complex and highly dependent on the specific context, as suggested by recent studies 1. Apoptosis is characterized by cell shrinkage, DNA fragmentation, and the formation of membrane-bound vesicles called apoptotic bodies, which are then engulfed by neighboring cells or immune cells. This process is triggered by either intrinsic signals, such as DNA damage or cellular stress, or extrinsic signals, such as death ligands binding to cell surface receptors. Key proteins involved in apoptosis include caspases, which are enzymes that execute the death program, and members of the Bcl-2 family that regulate the process.

Autophagy, on the other hand, is a process where cells digest their own components, allowing them to recycle nutrients during starvation or remove damaged organelles. During autophagy, portions of the cytoplasm are enclosed in double-membrane vesicles called autophagosomes, which then fuse with lysosomes for degradation. While autophagy is primarily a survival mechanism, it can lead to cell death when prolonged or excessive. The relationship between autophagy and cell death remains controversial, with some studies suggesting that autophagy can have both promoting and protective effects on cell death, depending on the context 1.

Some of the key features of cell death, including apoptosis and autophagy, are:

• Apoptosis: programmed cell death mechanism, characterized by cell shrinkage, DNA fragmentation, and formation of apoptotic bodies
• Autophagy: primarily a survival mechanism, characterized by the formation of autophagosomes and degradation of cellular components
• Key proteins involved: caspases, Bcl-2 family members, and autophagy-related proteins
• Triggers: intrinsic signals (DNA damage, cellular stress), extrinsic signals (death ligands), and environmental factors (starvation, hypoxia)

The correct classification of cell death into specific subroutines is crucial for its therapeutic implications, as different cell death modes may have different responses to treatment, as suggested by earlier studies 1. Therefore, understanding the mechanisms of cell death, including apoptosis and autophagy, is essential for the development of novel therapeutic approaches for diseases associated with dysregulated cell death.

From the Research

Mechanisms of Cell Death

The mechanisms of cell death, including apoptosis and autophagy, are complex and interconnected processes that regulate cell survival and death under stress conditions 2, 3, 4, 5, 6.

• Apoptosis is a process that aims to remove damaged or unwanted cells from the body with minimal damage to surrounding tissues 2, 4.
• Autophagy, on the other hand, promotes the removal of damaged organelles, protein aggregates, and cellular pathogens, stimulating cell survival 2, 3, 4, 5, 6.
• The signaling pathways involved in the regulation of apoptosis and autophagy largely overlap, leading to both competition and unidirectional interaction 2, 3, 6.

Signaling Pathways and Molecular Interactions

The signaling pathways involved in apoptosis and autophagy are regulated by various molecular interactions, including:

• Mitochondrial dysfunction, oxidative stress, calcium ion concentration, reactive oxygen species, and endoplasmic reticulum stress 3.
• Key signaling molecules such as p53 and VEGF, which mediate angiogenic pathways and trigger apoptotic and autophagic pathways 3.
• The involvement of signaling molecules such as mTOR, Bcl-2, BH3 family members, caspases, AMPK, PI3K/Akt/GSK3β, and p38/JNK/MAPK in the pathogenesis and progression of neurodegenerative diseases 3.

Autophagy and Apoptosis Cascade

The autophagy and apoptosis cascade is a complex process that determines the fate of cellular organelles and proteins involved in human health and disease 3, 6.

• Autophagy can lead to cell death, and the same stresses can stimulate both autophagy and apoptosis 4, 5.
• The molecular connections between autophagy and cell death are complicated, and autophagy may promote or inhibit cell death in different contexts 5.
• The discovery of Beclin-1's interacting partners has resulted in the identification of Bcl-2 as a central regulator of autophagy and apoptosis 6.