Human mitochondrial ferritin exhibits highly unusual iron-O2 chemistry distinct from that of cytosolic ferritins
Ferritins are ubiquitous proteins that function in iron storage and detoxification. Mammalian tissues that are metabolically highly active contain, in addition to the ubiquitous cytosolic ferritin, a ferritin that is localised to mitochondria. Mitochondrial ferritin (FtMt) functions to protect against oxidative stress and is found at higher levels in disease states that are associated with abnormal iron accumulation, such as Alzheimers and Parkinsons. Here we demonstrate that, despite 80% sequence identity with cytosolic human H-chain ferritin, Fe2+ oxidation at the catalytic diiron ferroxidase centre of FtMt proceeds via a distinct mechanism involving radical formation on a strictly conserved Tyr residue (Tyr34), and a mixed-valent ferroxidase centre (MVFC) that is readily detected under the O2-limiting conditions typical of mitochondria. Tyr34 is key for the activation of O2 and stability of the MVFC. The highly unusual iron-O2 chemistry exhibited by FtMt demonstrates that high levels of sequence identity between enzymes does not guarantee similarity of catalytic mechanism; here we explore the possible origin of the mechanistic differences between FtMt and cytosolic human H-chain ferritin.