A cell undergoes regulated necrosis triggered by TNF-alpha binding when caspases are inhibited. This pathway activates RIPK3 which phosphorylates MLKL. What is the mechanism by which phospho-MLKL causes cell death?
- A Phospho-MLKL translocates to mitochondria and inhibits Complex I, inducing ATP depletion and oncotic necrosis
- B Phospho-MLKL activates caspase-3 via the cytochrome c/Apaf-1 apoptosome pathway
- C Phospho-MLKL activates gasdermin D cleavage via NLRP3 inflammasome
- D Phospho-MLKL oligomerises and inserts into the plasma membrane forming pores, disrupting osmotic homeostasis and causing membrane rupture (necroptosis) ✓
Explanation
Necroptosis is a programmed form of regulated necrosis dependent on RIPK1-RIPK3-MLKL signalling. When caspase-8 is inhibited (e.g., by viral proteins or pharmacological blockade), RIPK1 recruits and activates RIPK3 via the RHIM domain. RIPK3 phosphorylates MLKL (mixed lineage kinase domain-like pseudokinase) at Thr357/Ser358, inducing its conformational change, oligomerisation, and translocation to the inner plasma membrane leaflet where it forms tetrameric pores. These MLKL pores disrupt ionic gradients, causing cellular swelling and membrane rupture — the hallmark of necroptotic cell death. Gasdermin D cleavage characterises pyroptosis (inflammasome pathway), not necroptosis.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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