The active role of vitamin C in mammalian iron metabolism: much more than just enhanced iron absorption!

Free Radic Biol Med. 2014 Oct;75:69-83. doi: 10.1016/j.freeradbiomed.2014.07.007. Epub 2014 Jul 15.


Ascorbate is a cofactor in numerous metabolic reactions. Humans cannot synthesize ascorbate owing to inactivation of the gene encoding the enzyme l-gulono-γ-lactone oxidase, which is essential for ascorbate synthesis. Accumulating evidence strongly suggests that in addition to the known ability of dietary ascorbate to enhance nonheme iron absorption in the gut, ascorbate within mammalian systems can regulate cellular iron uptake and metabolism. Ascorbate modulates iron metabolism by stimulating ferritin synthesis, inhibiting lysosomal ferritin degradation, and decreasing cellular iron efflux. Furthermore, ascorbate cycling across the plasma membrane is responsible for ascorbate-stimulated iron uptake from low-molecular-weight iron-citrate complexes, which are prominent in the plasma of individuals with iron-overload disorders. Importantly, this iron-uptake pathway is of particular relevance to astrocyte brain iron metabolism and tissue iron loading in disorders such as hereditary hemochromatosis and β-thalassemia. Recent evidence also indicates that ascorbate is a novel modulator of the classical transferrin-iron uptake pathway, which provides almost all iron for cellular demands and erythropoiesis under physiological conditions. Ascorbate acts to stimulate transferrin-dependent iron uptake by an intracellular reductive mechanism, strongly suggesting that it may act to stimulate iron mobilization from the endosome. The ability of ascorbate to regulate transferrin iron uptake could help explain the metabolic defect that contributes to ascorbate-deficiency-induced anemia.

Keywords: Ascorbate; Dcytb; Ferritin; Free radicals; HIF; IRP; Iron; Transferrin; Vitamin C.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anemia / metabolism
  • Animals
  • Ascorbic Acid / metabolism*
  • Astrocytes / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Biological Transport
  • Erythropoiesis
  • Ferritins / biosynthesis
  • Ferritins / metabolism
  • Hemochromatosis / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Iron / metabolism*
  • Transferrin / metabolism
  • beta-Thalassemia / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Transferrin
  • endothelial PAS domain-containing protein 1
  • Ferritins
  • Iron
  • Ascorbic Acid