Editors' ChoiceCell death

Condemned by metabolism

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Science Signaling  20 Feb 2018:
Vol. 11, Issue 518, eaat3384
DOI: 10.1126/scisignal.aat3384

The kinase RIP3 increases aerobic flux to produce reactive oxygen species, which enhances necrosome formation and necroptosis.

During necroptosis, a programmed form of cell death characterized by rupture of the plasma membrane, the proinflammatory cytokine tumor necrosis factor–α (TNF-α) triggers the formation of the necrosome. This protein complex enables the activation of the kinase RIP3, which phosphorylates the protein MLKL. Phosphorylated MLKL oligomerizes and disrupts the plasma membrane. Noting that reactive oxygen species (ROS) enhance necrosome assembly and that mitochondrial ROS are produced during aerobic respiration, Yang et al. investigated the connection between aerobic respiration and necroptosis. Exposure to TNF-α increased aerobic respiration [as assessed by the oxygen consumption rate (OCR)] and ROS production in various cell types. The pyruvate dehydrogenase complex (PDC), which consists of three enzymes, converts pyruvate (which is generated by glycolysis) to acetyl-CoA (which is metabolized by aerobic respiration). Deficiency in an enzyme in the PDC decreased TNF-α–induced necroptosis. TNF-α exposure induced the localization of RIP3 to mitochondria in an MLKL-dependent manner and promoted the interaction of RIP3 with components in the PDC complex. RIP3 phosphorylated the E3 component at Thr135, a phosphorylation event that was critical for the increase in OCR induced by TNF-α. These results describe a feed-forward pathway that supports the formation of the protein complexes required for necroptosis.

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