37.8:
Necrosis
Necrosis is a type of cell death where the cell membrane ruptures, and the released cellular components cause local inflammation.
Necrosis occurs in both a non-programmed and a programmed manner.
Non-programmed necrosis is a passive process that does not involve a specific intracellular signaling pathway. It is triggered when a cell is damaged by severe stress, such as physical injury.
The accompanying mitochondrial damage causes a decrease in ATP production. There is also an increase in intracellular calcium concentration, which leads to cell swelling and bursting.
Programmed necrosis or necroptosis is a backup pathway for apoptosis that occurs when procaspases are not correctly activated. Necroptosis is regulated by the kinases RIP1 and RIP3 that form complexes with apoptotic signaling pathway components.
RIP3 phosphorylates the pore-forming protein MLKL, causing it to oligomerize and form a pore in the membrane. This opening allows a calcium and sodium ion influx, resulting in membrane rupture and cell death.
37.8:
Necrosis
Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become anucleated and die, but their architecture remains intact, due to damage to the proteolytic enzymes responsible for cell digestion. Fibrinoid necrosis occurs in blood vessels when the endothelium is damaged, and fibrin is deposited on the vessel wall. Fat necrosis occurs when damage to adipose tissue releases the lipids stored in these cells. For example, during acute pancreatitis, the pancreatic enzymes digest the surrounding fat cells. These fatty acids that are released combine with calcium and produce chalky white soap deposits. Liquefactive necrosis is typically seen in the nervous system, where the necrotic tissue is digested into a viscous liquid. It can be present not only during an infection but also under hypoxic conditions, such as a nerve infraction.
Alternate Pathways of Cell Death
In addition to apoptosis and necrosis, cells also exhibit death by necroptosis. Necroptosis has characteristics of both necrosis and apoptosis. It follows a specific signaling pathway like apoptosis, but similar to necrosis, it results in membrane rupture and cell death. Necroptosis occurs during neurodegeneration, ischemia, and infection. Other forms of cell death include mitochondrial permeability transition (MPT) driven necrosis, parthanatos, and ferroptosis. During MPT-driven necrosis, an overload of Ca2+ and oxidative stress increases cyclophilin D production. This, in turn, increases mitochondrial permeability, resulting in mitochondrial rupture. The parthanatos pathway is initiated by the poly(ADP-ribose) polymerase 1 or PARP1 in response to excessive DNA damage due to factors such as oxidative stress. The long poly(ADP-ribose) polymers then bind apoptosis-inducing factors (AIF) that bring about cell death by increasing mitochondrial membrane permeability and chromatin fragmentation. In addition to DNA damage, oxidative stress can also lead to an accumulation of lipid peroxides resulting in cell death. This process is dependent on the availability of iron and is thus termed ferroptosis.