Necroptotic Cell Death Signaling and Execution Pathway: Lessons from Knockout Mice

Figure 2

Schematic overview of the multiple signaling pathways to apoptosis, necroptosis and autophagy. TNF-α binding to TNFR causes the assembly of a membrane-proximal supramolecular complex including (but not limited to) TRADD, FADD, and RIPK1 (receptor interacting protein kinase 1). Recruitment and activation of caspase-8 play a crucial role in initiation of apoptotic or necrotic cell death. Active caspase-8 cleaves Bid, generating tBid, with together with Bax and Bak promote the mitochondria outer membrane permeabilization (MOMP) allowing the release of cytochrome . Cleavage of both RIP1 and RIP3 by caspase-8 leads to apoptosis, whereas phosphorylation of RIP1 and RIP3 protein kinases causes their activation and in turn the recruitment of MLKL (mixed lineage kinase domain-like). MLKL is phosphorylated by RIP3 and initiated structural changes that led to its insertion in the plasma membrane and formation channels. MLKL channels increase Na⁺ influx, osmotic pressure, and membrane rupture, ending with cell death by necroptosis. Membrane rupture promotes the release of cellular contents and, in particular, various endogenous DAMPs. Various chemotherapeutical drugs, chemical and biological stressors, cause mitochondrial dysfunctions and consequently increase the level of ROS (reactive oxygen species, ROS) generation and collapse of electrochemical gradient, which compromise the ADP/ATP exchange transporter. High Ca²⁺ upload in the matrix favors the transient or irreversible opening or closure of the outer/inner mitochondrial permeability transition pore complex (MPTPC) that is well known to participate in the mitochondrial permeability transition (MPT). This is accompanied by mitochondrial depolarization, loss of membrane potential (ΔΨm), and massive swelling due to influx of ions and water into the matrix. Depending on the extension of cell injury, the cells undergo apoptosis, necrosis, or autophagy programs. Autophagy of damaged organelles constitutes a survival response that prevents cell death. VDAC: the voltage-dependent anion channel, also known as porin; DAMPs: damaged associated-molecular patterns; TNFα: tumor necrosis factor α; TNFR: tumor necrosis factor receptor; FADD: Fas-associated death domain protein; Z-VAD.fmk: Z-Val-Ala-Asp(OMe)-fluoromethylketone; LMP: lysosomal membrane permeabilization; PTPC: permeability transition pore complex; Smac: second mitochondria-derived activator of caspase.