Apoptosis: A Comprehensive Overview of Signaling Pathways, Morphological Changes, and Physiological Significance and Therapeutic Implications

Abstract

Cell survival and death are intricately governed by apoptosis, a meticulously controlled programmed cell death. Apoptosis is vital in facilitating embryonic development and maintaining tissue homeostasis and immunological functioning. It is a complex interplay of intrinsic and extrinsic signaling pathways that ultimately converges on executing the apoptotic program. The extrinsic pathway is initiated by the binding of death ligands such as TNF-α and Fas to their respective receptors on the cell surface. In contrast, the intrinsic pathway leads to increased permeability of the outer mitochondrial membrane and the release of apoptogenic factors like cytochrome c, which is regulated by the Bcl-2 family of proteins. Once activated, these pathways lead to a cascade of biochemical events, including caspase activation, DNA fragmentation, and the dismantling of cellular components. Dysregulation of apoptosis is implicated in various disorders, such as cancer, autoimmune diseases, neurodegenerative disorders, and cardiovascular diseases. This article focuses on elucidating the molecular mechanisms underlying apoptosis regulation, to develop targeted therapeutic strategies. Modulating apoptotic pathways holds immense potential in cancer treatment, where promoting apoptosis in malignant cells could lead to tumor regression. This article demonstrates the therapeutic potential of targeting apoptosis, providing options for treating cancer and neurological illnesses. The safety and effectiveness of apoptosis-targeting drugs are being assessed in ongoing preclinical and clinical trials (phase I-III), opening the door for more effective therapeutic approaches and better patient outcomes.

Keywords: apoptosis; morphological changes; physiological significance; signaling pathways; therapeutic strategies.

Figure 1

The common types of cell death: programmed cell death and necrosis. Programmed cell death includes mainly apoptosis and non-apoptotic forms of cell death, such as autophagy, necroptosis, and apoptosis-like programmed cell death. Abbreviations: RIPK1/3: receptor interacting serine threonine kinase 1/3; MLKL: mixed lineage kinase domain-like.

Figure 2

The intrinsic and extrinsic pathways of apoptosis. Intrinsic pathway is activated by various intracellular signals, like hypoxia, DNA damage, oxidative stress, etc., leading to mitochondrial dysfunction and release of pro-apoptotic factors like cytochrome c leading to activation of initiator caspase 9. The extrinsic pathway is activated by TNFα/Fas ligands which bind to their respective receptors on the cell membrane, leading to activation of initiator caspase 8. Initiator caspases (caspase 8, 9, 10) are pivotal in both pathways and catalyze the proteolytic maturation of effector caspases (such as caspase 3, 6, 7), leading to the initiation of a caspase cascade, ultimately resulting in cell demolition. The p53 tumor suppressor protein induces transcription of various pro-apoptotic genes like BAX, BAK, DR-5, NOXA, and PUMA and inhibits transcription of the anti-apoptotic gene BCL-2. This intricate network of interactions eventually triggers the apoptotic process. Abbreviations: BAX: Bcl-2-associated protein x; BAK: Bcl-2 homologs antagonist/killer; DR-5: death receptor 5; NOXA: pro-apoptotic member of BH3 only protein; PUMA: p53 upregulated modulator of apoptosis; p53: tumor protein P53.

Figure 3

Role of mitochondrial outer membrane pores (MOMPs) in apoptosis. (a) Various internal stresses lead to MOMP formation, which leads to the release of cytochrome c into the cytoplasm, resulting in the activation of caspases and finally culminating in apoptosis or cell death through a caspase-independent manner (CICD); (b) cellular stress activates BH3 proteins (Bim, Bid) and p53 which either directly activate BAX or BAK to form pores in the OMM and finally result in apoptosis or inhibit anti-apoptotic proteins (BCL-2, BCL-xL and MCL-1) by de-repressor BH3-only proteins (like Bik, Noxa, Puma, etc.). Abbreviations: BCL-2: B-cell leukemia/lymphoma 2 protein; BCL-Xl: B-cell lymphoma extra-large; BAX: Bcl-2-associated protein x; BAK: Bcl-2 homologs antagonist/killer; Bid: BH3-interacting domain death agonist; Bim: Bcl-2-interacting mediator of cell death; Bik: BCL-2-interacting killer; MCL-1: myeloid cell leukemia sequence 1; NOXA: pro-apoptotic member of BH3 only protein; OMM: outer mitochondrial membrane; IMM: inner mitochondrial membrane; IMS: intermembrane space; PUMA: p53 upregulated modulator of apoptosis; p53: tumor protein P53.

Figure 4

Apoptotic stimuli activate mitochondria to release Cyt c into the cytoplasm. Cyt c, once in the cytoplasm, binds with Apaf-1 and procaspase-9 to form a complex called the apoptosome. The apoptosome leads to the activation of procaspase-9 to caspase-9 which leads to activation of executioner caspase-3 which favors apoptotic cell death. HSP at different levels controls the apoptotic cascade right from Cyt c to caspase-3. Smac/Diablo and HtrA2 negatively regulate XIAP. AIF and Endo-G, once released, cause chromatin condensation and DNA fragmentation (hallmarks of apoptosis) in a caspase-independent fashion. Abbreviations: AIF: apoptosis-inducing factor; Apaf: apoptotic protein-activating factor; casp-9, caspase-9; Cyt.c, cytochrome c; Endo-G: endonuclease-G; HSP: heat shock protein; HtrA2/Omi: high-temperature requirement protein A2; Smac/DIABLO: Second mitochondria-derived activator of caspases/Direct Inhibitor of Apoptosis-Binding protein with a low isoelectric point; XIAP: X-linked inhibitor of apoptosis protein.