LAUSR

ABSTRACT This review discusses the chemical mechanisms of ascorbate‐dependent reduction and solubilization of ferritin's ferric iron core and subsequent release of ferrous iron. The process is accelerated by low concentrations of Fe(II) that increase ferritin's intrinsic ascorbate oxidase activity, hence increasing the rate of ascorbate radical formation. These increased rates of ascorbate oxidation provide reducing equivalents (electrons) to ferritin's core and speed the core reduction rates with subsequent solubilization and release of Fe(II). Ascorbate‐dependent solubilization of ferritin's iron core has consequences relating to the interpretation of 59Fe uptake sourced from 59Fe‐lebelled holotransferrin into ferritin. Ascorbate‐dependent reduction of the ferritin core iron solubility increases the size of ferritin's iron exchangeable pool and hence the rate and amount of exchange uptake of 59Fe into ferritin, whilst simultaneously increasing net iron release rate from ferritin. This may rationalize the inconsistency that ascorbate apparently stabilizes 59Fe ferritin and retards lysosomal ferritinolysis and whole cell 59Fe release, whilst paradoxically increasing the rate of net iron release from ferritin. This capacity of ascorbate and iron to synergise ferritin iron release has pathological significance, as it lowers the concentration at which ascorbate activates ferritin's iron release to within the physiological range (50–250 &mgr;M). These effects have relevance to inflammatory pathology and to the pro‐oxidant effects of ascorbate in cancer therapy and cell death by ferroptosis. Graphical abstract Figure. No Caption available. HighlightsLow ascorbate and labile iron concentrations synergise ferritin iron mobilization.Ascorbate and iron synergise ferritin’s intrinsic ascorbate oxidase activity.Ascorbate‐induced reduction of ferritin’s core raises its iron exchange capacity.Raised exchange capacity increases ferritin’s ascorbate‐dependent 59Fe uptake.Ferritin’s raised 59Fe exchange is often confused with increased net iron uptake.Synergetic ascorbate‐ iron‐ferritin iron release has pathological implications.