Necrosis

Non-programmed necrosis is a passive process triggered by severe stress like physical injury, causing mitochondrial damage and ATP depletion. Programmed necrosis, or necroptosis, is a regulated backup pathway activated when apoptotic signaling fails. Both result in membrane rupture and cell death, but necroptosis involves specific kinase signaling through RIP1 and RIP3 proteins.

Necroptosis shares characteristics of both necrosis and apoptosis. Like apoptosis, it follows a specific signaling pathway regulated by kinases RIP1 and RIP3. However, similar to necrosis, necroptosis results in membrane rupture and cell lysis rather than controlled cell death. Necroptosis occurs during neurodegeneration, ischemia, and infection when the extrinsic apoptotic pathway is blocked.

Coagulative necrosis preserves cell architecture despite cell death due to intact proteolytic enzymes. Liquefactive necrosis, common in the nervous system, digests tissue into viscous liquid. Fibrinoid necrosis occurs in blood vessels when fibrin deposits on damaged endothelium. Fat necrosis releases lipids that combine with calcium, forming chalky deposits, often seen in acute pancreatitis.

Severe stress such as physical injury damages mitochondria, decreasing ATP production. This energy depletion causes intracellular calcium concentration to increase, leading to cell swelling. The accumulation of calcium and loss of cellular control ultimately causes the cell membrane to rupture, releasing cellular components that trigger local inflammation.

The kinase RIP3 phosphorylates MLKL, a pore-forming protein, causing it to oligomerize and form pores in the cell membrane. These membrane openings allow calcium and sodium ions to flood into the cell, disrupting osmotic balance and causing membrane rupture. This ion influx ultimately results in cell death and the release of inflammatory cellular contents.

Ferroptosis is a form of cell death triggered by oxidative stress that causes lipid peroxide accumulation. This process depends on iron availability, distinguishing it from other cell death pathways. Ferroptosis represents an alternative mechanism of cell death beyond necrosis and apoptosis, occurring when cells experience excessive oxidative damage.

Mitochondrial permeability transition (MPT) driven necrosis occurs when calcium overload and oxidative stress increase cyclophilin D production. This elevation increases mitochondrial membrane permeability, causing mitochondrial rupture. MPT-driven necrosis represents an alternative pathway of cell death that can be triggered by severe cellular stress conditions.