Necroptosis

Necroptosis is a form of programmed cell death that is morphologically similar to necrosis but is regulated by specific signaling pathways. Unlike apoptosis, which is a form of programmed cell death that occurs in a controlled and non-inflammatory manner, necroptosis results in cell lysis and the release of cellular contents, leading to inflammation.

Mechanism

Necroptosis is primarily mediated by the receptor-interacting protein kinases RIPK1 and RIPK3. Upon activation by various stimuli, such as tumor necrosis factor (TNF), these kinases form a complex known as the necrosome. The necrosome then phosphorylates and activates the pseudokinase MLKL (mixed lineage kinase domain-like protein), which translocates to the plasma membrane and disrupts its integrity, leading to cell death.

Key Proteins Involved

• RIPK1: Receptor-interacting serine/threonine-protein kinase 1
• RIPK3: Receptor-interacting serine/threonine-protein kinase 3
• MLKL: Mixed lineage kinase domain-like protein

Biological Significance

Necroptosis plays a crucial role in various physiological and pathological processes. It serves as a defense mechanism against certain pathogens that inhibit apoptosis. Additionally, necroptosis is involved in inflammatory diseases, neurodegenerative diseases, and ischemia-reperfusion injury.

Pathological Implications

Dysregulation of necroptosis has been implicated in several diseases:

• Inflammatory diseases: Excessive necroptosis can contribute to chronic inflammation and tissue damage.
• Neurodegenerative diseases: Abnormal activation of necroptosis pathways has been observed in conditions such as Alzheimer's disease and Parkinson's disease.
• Ischemia-reperfusion injury: Necroptosis contributes to cell death and tissue damage following the restoration of blood supply after a period of ischemia.

Research and Therapeutic Potential

Understanding the molecular mechanisms of necroptosis has opened new avenues for therapeutic interventions. Inhibitors targeting key components of the necroptosis pathway, such as RIPK1 and RIPK3, are being explored for their potential to treat inflammatory and neurodegenerative diseases.

See Also

• Apoptosis
• Necrosis
• Programmed cell death
• Inflammation
• Neurodegeneration

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