regulation of mitochondrial membrane permeability involved in programmed necrotic cell death

Definition

Target type: biologicalprocess

Any regulation of mitochondrial membrane permeability that is involved in programmed necrotic cell death. [GOC:dph, GOC:mtg_apoptosis, GOC:TermGenie, PMID:22493254]

Programmed necrotic cell death, also known as necroptosis, is a regulated form of cell death that shares similarities with both apoptosis and necrosis. Unlike apoptosis, which relies on caspase activation, necroptosis is caspase-independent and involves the formation of a complex called the necrosome. This complex forms at the mitochondrial membrane and comprises receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL).

The initiation of necroptosis is triggered by various stimuli, including TNF-alpha, TLR3/4 agonists, and DNA damage. Upon stimulation, RIPK1 gets activated and recruits RIPK3 through homotypic interactions. The RIPK1-RIPK3 complex then recruits MLKL, which undergoes phosphorylation by RIPK3. Phosphorylated MLKL oligomerizes and translocates to the mitochondrial membrane.

MLKL's interaction with the mitochondrial membrane is crucial for the regulation of mitochondrial membrane permeability (MMP). MLKL can disrupt the integrity of the mitochondrial outer membrane (MOM), leading to the release of pro-apoptotic proteins like cytochrome c into the cytosol. This release activates the caspase cascade, triggering apoptosis.

However, the primary role of MLKL in necroptosis is not to induce apoptosis but rather to directly increase MMP through a distinct mechanism. MLKL, upon oligomerization, forms pores in the mitochondrial membrane. These pores allow the passage of ions and small molecules, leading to mitochondrial dysfunction and the collapse of the mitochondrial membrane potential (ΔΨm). The loss of ΔΨm disrupts ATP production, leading to energy depletion and cellular demise.

The regulation of MMP by MLKL is a crucial step in necroptosis. By disrupting the MOM and increasing MMP, MLKL triggers a cascade of events that ultimately lead to cell death. The formation of the necrosome and the subsequent activation of MLKL represent a tightly controlled process that ensures proper execution of necroptosis. This regulated form of cell death plays a vital role in various physiological and pathological processes, including development, tissue homeostasis, and the immune response.'
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Proteins (2)

Compounds (5)