Aerobic pyruvate metabolism sensitizes cells to ferroptosis primed by GSH depletion, 2021, Vuckovic et al

Highlights
• Ferroptosis is activated by the synergy between low GSH and glucose aerobic metabolism.

• GSH depletion enhances superoxide production by the pyruvate dehydrogenase complex.

• Superoxide is produced by autoxidation of dihydrolipoamide.

• Protonated superoxide is proposed generating traces of lipid hydroperoxides.

Abstract
Ferroptosis is a form of non-accidental, regulated form of cell death operated by lipid peroxidation under strict control of GPx4 activity. This is consistent with the notion that lipid peroxidation is initiated by radicals produced from decomposition of traces of pre-existing lipid hydroperoxides. The question, therefore, emerges about the formation of these traces of lipid hydroperoxides interacting with Fe2+. In the most realistic option, they are produced by oxygen activated species generated during aerobic metabolism. Screening for metabolic sources of superoxide supporting ferroptosis induced by GSH depletion, we failed to detect, in our cell model, a role of respiratory chain. We observed instead that the pyruvate dehydrogenase complex -as other α keto acid dehydrogenases already known as a major source of superoxide in mitochondria-, supports ferroptosis. The opposite effect on ferroptosis by silencing either the E1 or the E3 subunit of the pyruvate dehydrogenase complex pointed out the autoxidation of dihydrolipoamide as the source of superoxide. We finally observed that GSH depletion activates superoxide production, seemingly through the inhibition of the specific kinase that inhibits pyruvate dehydrogenase. In summary, this set of data is compatible with a scenario where the more electrophilic status produced by GSH depletion not only activates ferroptosis by preventing GPx4 activity, but also favors the formation of lipid hydroperoxides. In an attractive perspective of tissue homeostasis, it is the activation of energetic metabolism associated to a decreased nucleophilic tone that, besides supporting energy demanding proliferation, also sensitizes cells to a regulated form of death.

Paywall, https://www.sciencedirect.com/science/article/abs/pii/S089158492100143X

 

Although I don´t understand all details, it seems very interesting.

For readability:

which is not really a surprise, it has been noted that superoxide is actively produced, and as a byproduct unimportant, quantity-wise. Though can´t provide the sources right now.