Abstract/Summary

Abstract Iron is in an essential micronutrient in living systems. However, it is also potentially toxic and so the concentration of chelatable iron within cells is tightly regulated to prevent catalytic formation of harmful reactive oxygen species (ROS). Ferritins play a key role in iron homeostasis by storing excess iron as an insoluble ferric mineral within the protein. When bacterial cells become iron deficient, this store may be accessed by reduction/solubilisation of the iron. Bacterioferritins utilise heme, bound at an inter‐subunit site, to support electron transfer to the stored mineral. Electrons for heme reduction are shuttled from NADPH via Bfd, a [2Fe–2S] cluster‐containing ferredoxin. This raises the paradox that the synthesis of an iron‐dependent protein co‐factor is required under conditions of iron‐deficiency so that stored iron can be utilised. Here, we show that exposure of Bfd to ROS suppresses the capacity of the protein to stimulate iron release from bacterioferritin. We propose that reliance of iron release on Bfd evolved to ensure that chelatable iron levels do not increase under oxidative stress conditions. Thus, the Bfd iron–sulfur cluster functions as a “biological fuse” in providing a fail‐safe that immediately halts iron release once ROS accumulate to damaging concentrations.