Journal of Clinical & Experimental Pathology
Open Access

In multicellular organisms, the process of apoptosis sometimes referred to as programmed cell death, which is strictly regulated and necessary for preserving tissue integrity, development, and cellular homeostasis. Apoptosis, which was first identified in the 1970s, is essential for many physiological functions, such as immune system control, embryogenesis, and the removal of damaged or possibly dangerous cells. Many proteins and regulatory molecules interact in intricate ways through signaling pathways to orchestrate apoptosis.

Members of the B-cell lymphoma 2 (Bcl-2) protein families are important apoptosis regulators and they control Mitochondrial Outer Membrane Permeabilization (MOMP), which can have either an anti or pro-apoptotic effect. A family of cysteine proteases essential to the execution stage of apoptosis, caspases, are activated by cytochrome c, which in turn activates the apoptosome complex.

Caspases cleave a myriad of cellular substrates, resulting in characteristic morphological and biochemical changes, including chromatin condensation, DNA fragmentation, membrane blebbing, and formation of apoptotic bodies. These alterations facilitate the orderly dismantling of the cell, without causing inflammation or damage to neighboring cells, distinguishing apoptosis from necrosis. Apoptosis is tightly regulated by a balance between pro and anti-apoptotic signals. Various extracellular and intracellular stimuli can induce apoptosis through both intrinsic and extrinsic pathways. In the intrinsic pathway, intracellular stress signals such as DNA damage, oxidative stress, or growth factor withdrawal converge to activate pro-apoptotic Bcl-2 family members, leading to mitochondrial outer membrane permeabilization and caspase activation. In contrast, the extrinsic pathway is initiated by the binding of death ligands such as Tumor Necrosis Factor (TNF) or Fas ligand to their respective death receptors on the cell surface, culminating in the activation of caspases though the formation of Death-Inducing Signaling Complexes (DISCs).

Many regulatory mechanisms modulate the sensitivity of cells to apoptotic signals, including post-translational modifications of apoptotic proteins, transcriptional regulation of pro and anti-apoptotic genes, and the action of microRNAs and long non-coding RNAs. Dysregulation of apoptosis can have profound consequences, contributing to various pathological conditions, including cancer, neurodegenerative diseases, autoimmune disorders, and developmental abnormalities. Apoptosis plays a crucial role in diverse physiological processes, ranging from embryonic development to tissue homeostasis and immune regulation. During embryogenesis, apoptosis facilitates morphogenetic processes by sculpting tissues and organs, eliminating redundant structures, and regulating cell numbers.

For instance, the formation of digits in vertebrate limbs involves apoptosis-mediated inter-digital tissue regression, which separates individual digits and changes the final limb morphology.

In adult organisms, apoptosis maintains tissue homeostasis by eliminating aged, damaged, or superfluous cells, thereby preventing the accumulation of aberrant cells that could potentially develop into tumors. For example, in the hematopoietic system, apoptosis regulates the turnover of blood cells, ensuring a balance between cell production and elimination. Similarly, in the immune system, apoptosis eliminates activated lymphocytes following an immune response, preventing prolonged inflammation and autoimmunity. Additionally, apoptosis is essential for preserving the integrity and architecture of tissue. Apoptosis controls cell turnover in epithelial tissues and removes cells that separate from the basement membrane, thereby halting the spread of potentially cancerous cells. Apoptosis also helps with tissue remodeling and repair processes like wound healing and tissue regeneration by removing damaged or senescent cells and making it easier for phagocytic cells to be recruited to remove debris from the cell.

Dysregulation of apoptosis is implicated in a wide range of human diseases, including cancer, neurodegenerative disorders, autoimmune diseases, and developmental abnormalities. Tumor cells in cancer exhibit evasion of apoptosis as a defining characteristic, which enables them to endure and multiply in the face of harmful circumstances such hypoxia, food deprivation, and chemotherapy. Cancer cells often acquire mutations or epigenetic modifications that dysregulate apoptotic signaling pathways. This makes the cells resistant to stimuli that cause cell death, promotes tumor development, and increases resistance to treatment.

On the other hand, in neurodegenerative illnesses including ALS, Parkinson's disease, and Alzheimer's disease, excessive apoptosis can lead to tissue degradation and malfunction. In autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA), dysregulated apoptosis contributes to the breakdown of immune tolerance and the development of autoantibodies against selfantigens. Defective clearance of apoptotic cells by phagocytes leads to the release of intracellular antigens and inflammatory cytokines, triggering immune responses against self-tissues and promoting tissue damage and inflammation. Furthermore, aberrant apoptosis contributes to developmental abnormalities and congenital disorders. Defects in apoptotic pathways can disrupt normal embryonic development, leading to structural malformations, growth retardation, and embryonic lethality. Insights into basic biological processes and potential directions for therapeutic intervention will continue to come from more study into the molecular mechanisms of apoptosis and its roles in health and illness.