Apoptosis refers to the orderly death of cells under certain conditions in order to maintain internal environment stability. Apoptosis is different from cell necrosis. Apoptosis is not a passive process, but an active process. It involves the activation, expression and regulation of a series of genes; it is not a type of autologous injury under pathological conditions. Phenomenon, but a process of death actively striving for better adaptation to the living environment. From the perspective of cell function, apoptosis is of great significance to multicellular organisms. On the one hand, during the process of biological development, apoptosis can eliminate non-functional, unwanted, abnormal and harmful cells, optimize the structure of tissues and cells, and ensure the normal individual development. On the other hand, throughout the life of the organism, many abnormal cells are produced every day, such as cancerous cells, senescent cells, and cells invaded by microorganisms. Apoptosis clears these cells and is replaced by newly born, functioning cells. Therefore, the birth and death of cells in the body are in a dynamic equilibrium, thereby maintaining the stability and normal function of the number of cells in the body's tissues and organs.
Figure 1. Apoptosis, programmed death, an active death process adopted by the body to better adapt to the living environment
Apoptotic signal transduction pathway
The process of apoptosis can be roughly divided into the following stages: Accepting the apoptotic signal → the interaction between apoptosis regulating molecules → the activity of the proteolytic enzyme (Caspase) → entering a continuous reaction process. Due to the different initiation stages of apoptosis, it can be divided into three main pathways, namely the mitochondrial pathway, the endoplasmic reticulum pathway, and the death receptor pathway.
Mitochondrial pathway, which activates Caspase by releasing apoptotic enzyme activating factor from mitochondria. Mitochondria is the control center of cell life activity. It is not only the center of cellular respiratory chain and oxidative phosphorylation, but also the center of apoptosis regulation. This pathway consists of members of the Bcl-2 family. Containing BH3 domains and other members of the Bcl-2 family (Bax subfamily members) that bind to the outer mitochondrial membrane or are present in the cytoplasm Bax, Bak, etc. Interact with each other, resulting in oligomerization of the latter and insertion into the mitochondrial membrane, which results in changes in mitochondrial membrane permeability, loss of transmembrane potential, and release of cytochrome C (Cytc) and other proteins. Cytc release is a key step in the mitochondrial apoptotic pathway. Cytochrome C released into the cytoplasm can bind to apoptosis-associated factor 1 (Apaf-1) in the presence of dATP to form a multimer, and then through the caspase recruitment domain at the amino terminus of Apaf-1 ,CARD) recruits Caspase-9 precursors in the cytoplasm and promotes caspase-9 to form apoptotic bodies. Activated caspase-9 can activate other caspases such as caspase-3 and caspase-7, thereby inducing cells Apoptosis. In addition, mitochondria also release apoptosis-inducing factors which are involved in activating caspase. Pro-apoptotic factors can induce the release of cytochrome C and the formation of apoptotic bodies.
Figure 2. Cyt C-mediated apoptotic pathway.
The endoplasmic reticulum pathway, which is caused by endoplasmic reticulum abnormalities, is not triggered by apoptosis signals that target cell membranes or mitochondria. The endoplasmic reticulum is the main site for protein synthesis in cells, and it is also the main reservoir of Ca2+. Disruption of the endoplasmic reticulum Ca2+ balance or excessive accumulation of endoplasmic reticulum proteins is a key step. They induce the expression of Caspase-12 located in the endoplasmic reticulum membrane and induce the transfer of cytoplasmic Caspase-7 to the surface of the endoplasmic reticulum. Caspase-7 can activate Caspase-12, and activated Caspase-12 can further cut Caspase-3 and trigger apoptosis.
Figure 3. PERK pathway.
Death receptor pathway: Various external factors act as initiators of apoptosis, and then pass on apoptotic signals through different signaling systems, causing apoptosis. Death receptors are a class of transmembrane proteins that belong to the tumor necrosis factor receptor (TNFR) gene superfamily. The extracellular part contains a cysteine-rich region, and the cytoplasmic region has a structure composed of homologous amino acid residues and has a proteolytic function, which is called a "death domain". There are five known death receptors, TFR-1, Fas, DR3, DR4 and DR5.The corresponding ligands of the first three receptors are TNF, FasL, Apo-3L, and the latter two are Apo-2L (TRAIL). For example, the ligand FasL can first induce the trimerization of Fas.
Figure 4. Apoptotic death receptor pathway.
The death domains of Fas molecules cluster together, attracting another protein FADD with the same death domain in the cytoplasm, forming an apoptosis-inducing complex on the cell membrane, thereby activating caspase8, and then causing a subsequent cascade reaction, Cells undergo apoptosis.