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

Humans cannot synthesize ascorbic acid (AscH) (vitamin C), so deficiencies in dietary AscH cause the life-threatening disease of scurvy and many other diseases. After oral ingestion, plasma AscH concentrations are strictly controlled by transporters, which are required for entry into the cell and into intracellular organelles. Besides its general antioxidant function, AscH is a cofactor for endoplasmic reticulum (ER)-localized collagen hydroxylases. Its important role in ER homeostasis is also highlighted by the fact that AscH deficiency in auxotrophic species triggers ER stress. Characterizations of the molecular basis of diseases suggest that intracellular AscH 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. When considering the benefits of increasing dietary AscH, it is important to consider pharmacokinetic differences in the bioavailability between orally and intravenously administered AscH: 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 AscH. 34, 845-855.