Chemically and Biologically Harmless versus Harmful Ferritin/Copper–Metallothionein Couples

The simultaneous measurement of the decrease of available Fe II ions and the increase of available Fe III ions allowed the analysis of the ferroxidase activity of two distinct apoferritins. Although recombinant human apo- ferritin (HuFtH) rapidly oxidizes Fe II to Fe III , this iron is not properly stored in the ferritin cavity, as otherwise occurs in horse-spleen H/L-apoferritin (HsFt; H = heavy subunit, L = light subunit). Iron storage in these apoferritins was also studied in the presence of two copper-loaded mammalian metallothioneins (MT2 and MT3), a scenario that occurs in different brain-cell types. For HuFtH, unstored Fe III ions trig- ger the oxidation of Cu-MT2 with concomitant Cu I release. In contrast, there is no reaction with Cu-MT2 in the case of HsFt. Similarly, Cu-MT3 does not react during either HuFtH or HsFt iron reconstitution. Significantly, the combination of ferritin and metallothionein isoforms reported in glia and neuronal cells are precisely those combinations that avoid a harmful release of Fe II and Cu I ions.