Vitamin C and Iron

Highlights

• Ascorbate is a vitamin cofactor and an enhancer of dietary iron absorption.
• Ascorbate regulates cellular iron uptake, ferritin expression, and cell iron efflux.
• Ascorbate is a novel reductant actively involved in (non)transferrin iron uptake.
• Ascorbate regulates the IRP–IRE and HIFα systems in iron metabolism.
• Ascorbate is a regulator of mammalian iron metabolism and homeostasis.

Ascorbate stimulates iron uptake by an intracellular reductive mechanism

We recently demonstrated that Asc regulates iron uptake from Tf in a variety of human cell types. This observation is intriguing, as Asc is a ubiquitous and normally abundant cellular reductant in vivo, yet it is absent under standard cell culture conditions. Significantly, typical physiological plasma Asc concentrations enhance iron uptake by Asc-derived cells by up to 100% from Tf, which is accompanied by a corresponding increase in cellular ferritin expression and ferritin-iron loading. (R1)

A few quotes from a referenced paper:

At typical plasma concentrations, ascorbate significantly increased 59Fe uptake from transferrin by 1.5–2-fold in a range of cells. Moreover, ascorbate enhanced ferritin expression and increased 59Fe accumulation in ferritin. (R2)

Importantly, neither N-acetylcysteine nor buthionine sulfoximine, which increase or decrease intracellular glutathione, respectively, affected transferrin-dependent ⁵⁹Fe uptake. Thus, ascorbate’s stimulatory effect is not due to a general increase in cellular reducing capacity.

Ascorbate also did not affect expression of transferrin receptor 1 or ¹²⁵I-transferrin cellular flux.

However, transferrin receptors, endocytosis, vacuolar-type ATPase activity and endosomal acidification were required for ascorbate’s stimulatory activity. Therefore, ascorbate is a novel modulator of the classical transferrin Fe uptake pathway, acting via an intracellular reductive mechanism. (R2)

Ascorbate decreases amount of NADPH

Importantly, we also showed that this was not due to a general increase in cellular reducing capacity in the presence of Asc or to a specific increase in NADPH. In fact, incubation of SK-Mel-28 cells with a physiological level of Asc (50 μM) resulted in depletion of cellular NADPH, but not total NADP.

This finding is consistent with the involvement of NADPH and thioredoxin reductase during intracellular Asc recycling reactions. (R2)

Ascorbate may be involved in iron release from ferritin

The major mechanism of iron release from ferritin under in vivo conditions is autolysosomal proteolysis, although proteasomal degradation of the protein can also occur. Lysosomal degradation of ferritin requires the action of the autophagic apparatus.

Interestingly, in vitro studies with isolated ferritins indicate that reductive mobilization reactions, which can be mediated by Asc, are involved in iron release from ferritin.

The in vivo relevance of this protein-degradation-independent release of iron from ferritin, which occurs through the eight hydrophilic channels in the ferritin protein, is unclear. (R2)