Ascorbic Acid Route to the Endoplasmic Reticulum: Function and Role in Disease

Significance: Humans cannot synthesize ascorbic acid (AscH2) (vitamin C), so deficiencies in dietary AscH2 cause the life-threatening disease of scurvy and many other diseases. After oral ingestion, plasma AscH2 concentrations are strictly controlled by transporters, which are required for entry into the cell and into intracellular organelles. Recent Advances: Besides its general antioxidant function, AscH2 is a cofactor for endoplasmic reticulum (ER)-localized collagen hydroxylases. Its important role in ER homeostasis is also highlighted by the fact that AscH2 deficiency in auxotrophic species triggers ER stress. Critical Issues: Characterizations of the molecular basis of diseases suggest that intracellular AscH2 deficiency is due not only to limited dietary access but also to its limited intracellular transport and net loss under conditions of intracellular hyperoxidation in the ER. This essay will offer an overview of the different transporters of vitamin C regulating its intracellular concentration, its function inside the ER, and the phenotypes of the diseases that can be triggered by increased depletion of this vitamin in the ER. Future Directions: When considering the benefits of increasing dietary AscH2, it is important to consider pharmacokinetic differences in the bioavailability between orally and intravenously administered AscH2: the latter bypasses intestinal absorption and is, therefore, the only route that can lead to the high plasma concentrations that may provide some health effects, and it is this route that needs to be chosen in clinical trials for those diseases associated with a deficiency of AscH2.