Fig. 1.

Interweaving apoptosis and necroptosis pathways after neonatal HI insult.

A) Neonatal HI induces mitochondrial accumulation of calcium, increased production of reactive oxygen species, and suppression of mitochondrial respiration that culminates in MOMP. Changes in Bcl-2 family proteins induce Bax-dependent MOMP leading to the release of cytochrome c (cyt c) and apoptosis-inducing factor (AIF). Cyt c induces apoptosome formation leading to caspase-3 activation, caspase-activated DNase (CAD) and DNA degradation. AIF forms a complex with cyclophilin A (CyA) which translocates to the nucleus and induces chromatinolysis and apoptotic cell death. B) Concomitantly, inflammatory microglia and astroglia will release tumor necrosis factor-α (TNF-α) or other ligands (FasL, TWEAK, TRAIL and lipopolysaccharide, LPS) leading to the activation of death receptors, which in turn can induce both apoptosis and necroptosis depending on the availability of caspases. Recruitment of TRADD (or other adaptor proteins) and RIP1 will lead to caspase-8 activation and cleavage of Bid leading to apoptotic cell death. Alternatively, under conditions when caspase-8 is inhibited, TRADD facilitates the interaction and activation of RIP1 and RIP3. RIP3 phosphorylates and recruits MLKL to the necrosome which can then be targeted to both plasma and mitochondria-associated endoplasmic reticulum membranes triggering increased reactive oxygen species, fission and necroptosis. Alternative non-mitochondrial mechanisms may also play a role in the induction of necroptosis.