19.1 Mechanisms of apoptosis
3 min read•july 22, 2024
Cells have a built-in self-destruct button called . It's like a controlled demolition, neatly dismantling the cell without harming its neighbors. This process is crucial for keeping our bodies in balance, removing old or damaged cells, and shaping our organs during development.
Apoptosis can be triggered from inside or outside the cell. Inside, stress or DNA damage sets off a chain reaction in mitochondria. Outside, death signals activate receptors on the cell surface. Both paths lead to protein-cutting enzymes called caspases that chop up the cell's components.
Apoptosis Pathways and Mechanisms
Intrinsic vs extrinsic apoptosis pathways
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- Intrinsic (mitochondrial) pathway triggered by internal cellular stress (DNA damage, oxidative stress)
- Involves family proteins that regulate mitochondrial membrane permeability
- (Bax, Bak) promote release
- (Bcl-2, Bcl-xL) inhibit cytochrome c release
- Cytochrome c binds Apaf-1 and procaspase-9 to form the complex
- Apoptosome activates caspase-9, which then activates (caspase-3, -6, -7)
- Involves family proteins that regulate mitochondrial membrane permeability
- Extrinsic (death receptor) pathway initiated by external signals (TNF, FasL, TRAIL) binding to death receptors
- Death receptors (TNF receptor, Fas, TRAIL receptors) recruit FADD adaptor protein
- FADD binds procaspase-8 and -10 to form the (DISC)
- DISC activates caspase-8 and -10, which directly activate effector caspases
- Caspase-8 can also cleave Bid, linking extrinsic pathway to intrinsic pathway via mitochondria
Role of caspases in apoptosis
- Caspases are cysteine-aspartic proteases that execute apoptosis by cleaving cellular substrates
- (caspase-8, -9, -10) activated by intrinsic or extrinsic pathways
- Initiator caspases cleave and activate effector caspases (caspase-3, -6, -7)
- Effector caspases cleave various substrates leading to
- Cleavage of releases , fragmenting DNA into nucleosomal units
- Cleavage of cytoskeletal proteins (actin, fodrin) causes cell shrinkage and
- Cleavage of nuclear lamins facilitates nuclear envelope breakdown and chromatin condensation
Morphological changes during apoptosis
- Cell shrinkage due to cytoskeletal protein cleavage and ion channel dysregulation
- Increased cytoplasmic density and organelle compaction
- Distinguishes apoptosis from necrotic cell swelling and lysis
- Membrane blebbing forms apoptotic bodies containing cellular contents
- Enables efficient phagocytic clearance by neighboring cells or macrophages
- Prevents inflammatory response and tissue damage
- by caspase-activated DNase (CAD) between nucleosomes
- Produces characteristic "DNA ladder" pattern on gel electrophoresis
- Reflects organized nuclear dismantling, unlike random DNA degradation in necrosis
- Chromatin condensation and nuclear fragmentation
- on outer plasma membrane leaflet signals phagocytosis
Apoptosis in tissue homeostasis
- Balances cell proliferation and death to maintain constant cell numbers in tissues
- Removes damaged, infected, or senescent cells (skin, gut epithelium)
- Sculpts tissues during development (interdigital web regression, palate fusion)
- Eliminates cells with DNA damage or mutations to prevent cancer initiation
- Removes virus-infected cells to limit viral spread and tissue damage
- Regulates immune cell populations to maintain self-tolerance and prevent autoimmunity
- Deletes self-reactive T and B lymphocytes in thymus and bone marrow
- Terminates immune responses by eliminating activated lymphocytes
- Apoptosis dysregulation leads to pathologies
- Insufficient apoptosis: cancer, autoimmunity, viral persistence
- Excessive apoptosis: neurodegeneration, ischemic injury, AIDS
Key Terms to Review (28)
Annexin v staining: Annexin V staining is a laboratory technique used to identify and quantify apoptotic cells by detecting phosphatidylserine exposure on the cell membrane. During the early stages of apoptosis, phosphatidylserine, which is normally located on the inner leaflet of the plasma membrane, translocates to the outer leaflet, making it accessible for binding with annexin V. This binding allows researchers to distinguish between viable, apoptotic, and necrotic cells, providing valuable insights into the mechanisms of programmed cell death.
Anti-apoptotic proteins: Anti-apoptotic proteins are a class of proteins that prevent programmed cell death, or apoptosis, allowing cells to survive under conditions that would typically trigger this process. These proteins play a critical role in regulating cell fate by inhibiting pro-apoptotic signals and promoting cell survival, which is essential for maintaining tissue homeostasis and function. Understanding their mechanisms helps clarify how disruptions in apoptosis can lead to various diseases, including cancer.
Apoptosis: Apoptosis is a programmed cell death process that plays a crucial role in maintaining cellular homeostasis and regulating development. This highly controlled mechanism allows the body to eliminate damaged, unwanted, or potentially harmful cells without triggering inflammation, connecting tightly with various cellular processes and signaling pathways.
Apoptosome: An apoptosome is a large protein complex that plays a crucial role in the process of apoptosis, or programmed cell death. It is formed in response to cellular stress or damage and serves as a platform for activating initiator caspases, which then trigger the execution phase of apoptosis. By facilitating the activation of these caspases, the apoptosome ensures that cells can effectively undergo a controlled and organized death, preventing the release of harmful substances into the surrounding tissue.
Apoptotic morphological changes: Apoptotic morphological changes refer to the distinct structural alterations that occur in cells undergoing programmed cell death, or apoptosis. These changes are crucial for the elimination of damaged or unwanted cells without causing inflammation in surrounding tissues, and include features like cell shrinkage, nuclear condensation, and the formation of membrane-bound apoptotic bodies. Understanding these changes helps elucidate the mechanisms of apoptosis and its role in development and disease.
Bcl-2: Bcl-2 is a protein that plays a crucial role in regulating apoptosis, or programmed cell death, by inhibiting the process. It is part of a larger family of proteins that either promote or prevent apoptosis, and its primary function is to block the release of cytochrome c from mitochondria, which prevents the activation of caspases and promotes cell survival. Understanding bcl-2 is essential for comprehending the delicate balance between cell death and survival, which is particularly significant in cancer biology.
Cad endonuclease: Cad endonuclease is a specific enzyme that plays a crucial role in the process of apoptosis, or programmed cell death, by cleaving DNA at particular sites. This enzyme is particularly significant as it facilitates the fragmentation of genomic DNA, which is one of the hallmark features of apoptotic cells. By orchestrating the breakdown of DNA, cad endonuclease helps ensure that cells undergoing apoptosis are effectively eliminated without causing inflammation or damage to surrounding tissues.
Caspase activation: Caspase activation refers to the process through which caspases, a family of cysteine proteases, are activated to execute apoptosis, or programmed cell death. This activation is a critical step in the intrinsic and extrinsic pathways of apoptosis, leading to cellular disassembly and ultimately cell death. The controlled activation of caspases ensures that cells can remove damaged or unwanted cells effectively, playing a vital role in tissue homeostasis and development.
Cellular homeostasis: Cellular homeostasis is the process through which cells maintain a stable internal environment despite external changes. This involves regulating various factors such as ion concentrations, pH levels, and metabolic pathways to ensure optimal functioning. The balance achieved through these mechanisms is crucial for cell survival and is tightly linked to processes like apoptosis, where the cell decides whether to live or die based on its internal state and external signals.
Cytochrome c: Cytochrome c is a small heme protein found in the mitochondria of eukaryotic cells, playing a crucial role in the electron transport chain and cellular respiration. It functions as an electron carrier, shuttling electrons between complex III and complex IV, and is essential for ATP production during oxidative phosphorylation. Additionally, cytochrome c has important implications in programmed cell death, linking energy metabolism to apoptosis.
Death receptor pathway: The death receptor pathway is a specific signaling mechanism that triggers apoptosis through the activation of cell surface receptors known as death receptors. When ligands bind to these receptors, they initiate a cascade of intracellular events that lead to programmed cell death, playing a critical role in maintaining cellular homeostasis and regulating immune responses.
Death-inducing signaling complex: The death-inducing signaling complex (DISC) is a multiprotein complex that forms in response to the binding of death ligands to their respective death receptors on the cell surface, triggering apoptosis. This complex plays a crucial role in mediating extrinsic pathways of cell death, orchestrating a series of molecular events that lead to programmed cell death.
Dna fragmentation: DNA fragmentation refers to the process where DNA strands are broken into smaller pieces, which is a key feature of apoptosis. This fragmentation is an indicator that a cell is undergoing programmed cell death, leading to the eventual dismantling of cellular components. It is a crucial mechanism for maintaining homeostasis and preventing the proliferation of damaged or unwanted cells.
Effector caspases: Effector caspases are a group of cysteine proteases that play a central role in the execution phase of apoptosis, which is the process of programmed cell death. They are responsible for cleaving specific cellular substrates, leading to the morphological and biochemical changes associated with apoptosis. Their activation is crucial for dismantling the cell in an orderly manner, ensuring that cellular components are safely recycled or disposed of without causing inflammation.
Extrinsic Apoptosis: Extrinsic apoptosis is a programmed cell death pathway that is initiated by external signals, typically through the activation of death receptors on the cell surface. This mechanism plays a crucial role in regulating immune responses and eliminating damaged or infected cells, linking extracellular signals to the internal apoptotic machinery. The process is vital for maintaining tissue homeostasis and is distinct from intrinsic apoptosis, which is triggered by internal cellular stress or damage.
Icad: Icad, or inhibitor of cadherin, is a protein that plays a crucial role in the regulation of apoptosis by modulating cell adhesion through its interactions with cadherins. By influencing the stability of adherens junctions, icad helps determine whether a cell will undergo programmed cell death, making it a significant player in maintaining tissue homeostasis and regulating responses to stress or damage.
Immune response: The immune response is the body's defense mechanism against pathogens and foreign substances, involving a complex interplay of cells and molecules that work together to identify and eliminate threats. It consists of both innate and adaptive responses, enabling the body to react quickly to infections and to remember previous encounters for faster responses in the future.
Initiator caspases: Initiator caspases are a specific group of protease enzymes that play a crucial role in the initiation phase of apoptosis, or programmed cell death. They act as key regulators that activate downstream effector caspases, which then execute the death program by cleaving various cellular substrates. By triggering the apoptotic cascade, initiator caspases help maintain cellular homeostasis and eliminate damaged or unwanted cells in an organism.
Intrinsic apoptosis: Intrinsic apoptosis is a form of programmed cell death that is initiated from within the cell, typically in response to internal stress signals such as DNA damage, oxidative stress, or loss of growth factors. This process is characterized by the release of cytochrome c from the mitochondria, leading to the activation of caspases that ultimately execute cell death. Intrinsic apoptosis plays a crucial role in maintaining cellular homeostasis and eliminating damaged or unwanted cells.
Membrane blebbing: Membrane blebbing is a cellular process characterized by the bulging or protrusion of the cell membrane, often seen during apoptosis. This phenomenon is a hallmark of programmed cell death, where the cell undergoes morphological changes, including the formation of membrane extensions called blebs. These blebs are formed due to cytoskeletal reorganization and are crucial for the eventual breakdown of cellular integrity during apoptosis.
Mitochondrial pathway: The mitochondrial pathway is a key mechanism of apoptosis, or programmed cell death, which involves the release of pro-apoptotic factors from mitochondria into the cytosol. This pathway is critical for the initiation of the apoptotic process and is regulated by a balance between pro-apoptotic and anti-apoptotic proteins, ultimately influencing cell survival. Understanding this pathway helps reveal how cells decide to undergo apoptosis in response to various cellular stresses or signals.
Phagocytes: Phagocytes are specialized immune cells that play a crucial role in the body's defense mechanism by engulfing and digesting cellular debris, pathogens, and other foreign substances. These cells are essential for maintaining tissue homeostasis and initiating the immune response, especially during instances of apoptosis, where they help clear dying cells and prevent inflammation.
Phosphatidylserine exposure: Phosphatidylserine exposure refers to the process where phosphatidylserine, a phospholipid normally located on the inner leaflet of the plasma membrane, becomes externalized to the outer surface of the cell membrane. This event is a key indicator of apoptosis, as it serves as an 'eat me' signal for phagocytic cells, prompting their recognition and engulfment of dying cells. The movement of phosphatidylserine to the cell surface is mediated by various mechanisms, including the activation of scramblases and the inactivation of flippases during programmed cell death.
Pro-apoptotic proteins: Pro-apoptotic proteins are essential molecules that promote programmed cell death, or apoptosis, by triggering various signaling pathways within a cell. These proteins play a crucial role in regulating the balance between life and death in cells, and they are particularly important in maintaining tissue homeostasis, eliminating damaged or unwanted cells, and responding to cellular stress. By activating apoptotic pathways, pro-apoptotic proteins help prevent the proliferation of potentially harmful cells, such as those that could become cancerous.
Programmed cell death: Programmed cell death, or apoptosis, is a regulated process by which cells intentionally undergo death to maintain homeostasis and normal functioning within an organism. This mechanism is crucial for removing damaged, diseased, or unnecessary cells without causing harm to the surrounding tissues, playing a significant role in development, immune response, and overall cellular health.
Survival signals: Survival signals are essential biochemical cues that promote cell survival by inhibiting apoptosis, the programmed cell death process. These signals ensure that cells continue to function and proliferate by preventing the activation of pro-apoptotic pathways, allowing the organism to maintain homeostasis and respond appropriately to various stimuli.
Tissue remodeling: Tissue remodeling is the dynamic process through which tissues undergo structural changes in response to various physiological stimuli, injury, or developmental signals. This process involves the degradation of existing extracellular matrix components and the synthesis of new ones, allowing tissues to adapt, repair, and maintain their functional integrity. It plays a crucial role in processes like wound healing, organ development, and the response to mechanical stress.
Tunel Assay: The TUNEL assay (Terminal deoxynucleotidyl transferase dUTP nick end labeling) is a laboratory technique used to detect DNA fragmentation that results from apoptotic signaling pathways. This method is crucial for understanding the mechanisms of apoptosis, as it allows researchers to visualize and quantify the extent of cell death through the identification of fragmented DNA in dying cells. By labeling the ends of fragmented DNA, the TUNEL assay provides insights into how apoptosis is regulated and how it affects cell survival.