Heat stress induces ferroptosis in a photosynthetic prokaryote

Ferroptosis is an oxidative and iron-dependent form of regulated cell death (RCD) recently described in eukaryotic organisms like animals, plants and parasites. Here we report that a similar process takes place in the photosynthetic prokaryote Synechocystis sp. PCC 6803 in response to heat stress. After a heat shock, Synechocystis PCC 6803 cells undergo a cell death pathway that can be suppressed by the canonical ferroptosis inhibitors, CPX or Fer-1, or by external addition of calcium (Ca++), glutathione (GSH) or ascorbic acid (AsA). Moreover, as described for eukaryotic cells ferroptosis, this pathway is characterized by an early depletion of the antioxidants GSH and AsA, and by lipid peroxidation. In general, prokaryotes membranes contain poorly oxidizable saturated or monounsaturated lipid molecules, it was thought that free prokaryotes were not susceptible to ferroptosis but interestingly, that is not the case of cyanobacteria, which contain thylakoid membranes that are enriched in polyunsaturated-fatty-acid-containing phospholipids. These results indicate that all of the hallmarks described for eukaryotic ferroptosis are conserved in photosynthetic prokaryotes and suggest that ferroptosis might be an ancient cell death program.