Community Hub0 Subscribers
Community hub
Dehydroascorbic acid
View on Wikipediafrom Wikipedia
 | |
| Names | |
|---|---|
| IUPAC name
L-threo-Hexo-2,3-diulosono-1,4-lactone
| |
| Systematic IUPAC name
(5R)-5-[(1S)-1,2-Dihydroxyethyl]oxolane-2,3,4-trione | |
| Identifiers | |
3D model (JSmol)
|
|
| ChEBI | |
| ChemSpider | |
| ECHA InfoCard | 100.007.019 |
PubChem CID
|
|
| UNII | |
CompTox Dashboard (EPA)
|
|
| |
| |
| Properties | |
| C6H6O6 | |
| Molar mass | 174.108 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
| |
Dehydroascorbic acid (DHA) is the major oxidized form of ascorbic acid (vitamin C). It is actively imported into the endoplasmic reticulum of cells via glucose transporters.[1] It is trapped therein by reduction back to ascorbic acid by glutathione and other thiols.[2] The (free) chemical radical semidehydroascorbic acid (SDA) also belongs to the group of oxidized ascorbic acids.
Structure and physiology
[edit]
|
|
|
Top: ascorbic acid
(reduced form of vitamin C)
Bottom: dehydroascorbic acid
(nominal oxidized form of vitamin C)
(reduced form of vitamin C)
Bottom: dehydroascorbic acid
(nominal oxidized form of vitamin C)
Although sodium-dependent transporters for vitamin C exists, it is present mainly in specialized cells whereas the glucose transporters, most notably GLUT1, transport DHA in most cells,[3] where recycling back to ascorbic acid generates the necessary enzyme cofactor and intracellular antioxidant, (see Transport to mitochondria).
The structure shown here for DHA is the commonly shown textbook structure. This 1,2,3-tricarbonyl is too electrophilic to survive more than a few milliseconds in aqueous solution, however. The actual structure shown by spectroscopic studies is the result of rapid hemiketal formation between the 6-OH and the 3-carbonyl groups. Hydration of the 2-carbonyl is also observed.[4] The lifetime of the stabilized species is commonly said to be about 6 minutes under biological conditions.[1] Destruction results from irreversible hydrolysis of the lactone bond, with additional degradation reactions following.[5] Crystallization of solutions of DHA gives a pentacyclic dimer structure of indefinite stability. Recycling of vitamin C via active transport of DHA into cells, followed by reduction and reuse, mitigates the inability of humans to synthesize it from glucose.[6]
Transport to mitochondria
[edit]Vitamin C accumulates in mitochondria, where most of the free radicals are produced, by entering as DHA through the glucose transporter GLUT10. Ascorbic acid protects the mitochondrial genome and membrane.[3]
Transport to the brain
[edit]Vitamin C does not pass from the bloodstream into the brain, although the brain is one of the organs that have the greatest concentration of vitamin C. Instead, DHA is transported through the blood–brain barrier via GLUT1 transporters, and then reduced back to ascorbic acid.[8]
Use
[edit]Dehydroascorbic acid has been used as a vitamin C dietary supplement.[9]
As a cosmetic ingredient, dehydroascorbic acid is used to enhance the appearance of the skin.[10] It may be used in a process for permanent waving of hair[11] and in a process for sunless tanning of skin.[12]
In a cell culture growth medium, dehydroascorbic acid has been used to assure the uptake of vitamin C into cell types that do not contain ascorbic acid transporters.[13]
As a pharmaceutical agent, some research has suggested that administration of dehydroascorbic acid may confer protection from neuronal injury following an ischemic stroke.[8] The literature contains many reports on the antiviral effects of vitamin C,[14] and one study suggests dehydroascorbic acid has stronger antiviral effects and a different mechanism of action than ascorbic acid.[15] Solutions in water containing ascorbic acid and copper ions and/or peroxide, resulting in rapid oxidation of ascorbic acid to dehydroascorbic acid, have been shown to possess powerful but short-lived antimicrobial, antifungal, and antiviral properties, and have been used to treat gingivitis, periodontal disease, and dental plaque.[16][17] A pharmaceutical product named Ascoxal is an example of such a solution used as a mouth rinse as an oral mucolytic and prophylactic agent against gingivitis.[17][18] Ascoxal solution has also been tested with positive results as a treatment for recurrent mucocutaneous herpes,[18] and as a mucolytic agent in acute and chronic pulmonary disease such as emphysema, bronchitis, and asthma by aerosol inhalation.[19]
References
[edit]- ^ a b May, J. M. (1998). "Ascorbate function and metabolism in the human erythrocyte". Frontiers in Bioscience. 3 (4): d1–10. doi:10.2741/a262. PMID 9405334.
- ^ Welch, R. W.; Wang, Y.; Crossman, A. Jr.; Park, J. B.; Kirk, K. L.; Levine, M. (1995). "Accumulation of Vitamin C (Ascorbate) and Its Oxidized Metabolite Dehydroascorbic Acid Occurs by Separate Mechanisms". Journal of Biological Chemistry. 270 (21): 12584–12592. doi:10.1074/jbc.270.21.12584. PMID 7759506.
- ^ a b Lee, Y. C.; Huang, H. Y.; Chang, C. J.; Cheng, C. H.; Chen, Y. T. (2010). "Mitochondrial GLUT10 facilitates dehydroascorbic acid import and protects cells against oxidative stress: Mechanistic insight into arterial tortuosity syndrome". Human Molecular Genetics. 19 (19): 3721–33. doi:10.1093/hmg/ddq286. PMID 20639396.
- ^ Kerber, R. C. (2008). ""As Simple as Possible, but Not Simpler"—The Case of Dehydroascorbic Acid". Journal of Chemical Education. 85 (9): 1237. Bibcode:2008JChEd..85.1237K. doi:10.1021/ed085p1237.
- ^ Kimoto, E.; Tanaka, H.; Ohmoto, T.; Choami, M. (1993). "Analysis of the transformation products of dehydro-L-ascorbic acid by ion-pairing high-performance liquid chromatography". Analytical Biochemistry. 214 (1): 38–44. doi:10.1006/abio.1993.1453. PMID 8250252.
- ^ Montel-Hagen, A.; Kinet, S.; Manel, N.; Mongellaz, C.; Prohaska, R.; Battini, J. L.; Delaunay, J.; Sitbon, M.; Taylor, N. (2008). "Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C". Cell. 132 (6): 1039–48. doi:10.1016/j.cell.2008.01.042. PMID 18358815.
- ^ Koliou, Eleftheria K.; Ioannou, Panayiotis V. (February 2005). "Preparation of dehydro-l-ascorbic acid dimer by air oxidation of l-ascorbic acid in the presence of catalytic amounts of copper(II) acetate and pyridine". Carbohydrate Research. 340 (2): 315–318. doi:10.1016/j.carres.2004.11.015. PMID 15639252.
- ^ a b Huang, J.; Agus, D. B.; Winfree, C. J.; Kiss, S.; Mack, W. J.; McTaggart, R. A.; Choudhri, T. F.; Kim, L. J.; Mocco, J.; Pinsky, D. J.; Fox, W. D.; Israel, R. J.; Boyd, T. A.; Golde, D. W.; Connolly, E. S. Jr (2001). "Dehydroascorbic acid, a blood–brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke". Proceedings of the National Academy of Sciences of the United States of America. 98 (20): 11720–11724. Bibcode:2001PNAS...9811720H. doi:10.1073/pnas.171325998. PMC 58796. PMID 11573006.
- ^ Higdon, Jane (May 2001). "The Bioavailability of Different Forms of Vitamin C". The Linus Pauling Institute. Retrieved 2010-11-10.
- ^ Kitt, D.Q. (2012), Topical Dehydroascorbic Acid (Oxidized Vitamin C) Permeates Stratum Corneum More Rapidly Than Ascorbic Acid, retrieved 2012-07-31
- ^ US Patent 6,506,373 Archived 2020-12-25 at the Wayback Machine (issued January 14, 2003)
- ^ U.S. Patent Application No. 10/685,073 Archived 2020-12-25 at the Wayback Machine Publication No. 20100221203 (published September 2, 2010)
- ^ Heaney ML, Gardner JR, Karasavvas N, Golde DW, Scheinberg DA, Smith EA, O'Conner OA (2008). "Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs". Cancer Research. 68 (19): 8031–8038. doi:10.1158/0008-5472.CAN-08-1490. PMC 3695824. PMID 18829561.
- ^ Jariwalla, R.J. & Harakeh S. (1997). Mechanisms underlying the action of vitamin C in viral and immunodeficiency disease. In L. Packer & J. Fuchs (Eds.), Vitamin C in health and disease (pp. 309-322). New York:Marcell Dekker, Inc.
- ^ "Ericsson, Sten et al. "Anti Infectant Topical Preparations." U.S. Patent 3,065,139, filed November 9, 1954 and issued November 20, 1962" (PDF). Archived from the original (PDF) on March 4, 2016. Retrieved July 28, 2012.
- ^ a b "Fine, Daniel. "Gel composition for reduction of gingival inflammation and retardation of dental plaque." U.S Patent 5,298,237, filed Jan.24, 1992 and issued March 29, 1994" (PDF). Archived from the original (PDF) on March 4, 2016. Retrieved July 28, 2012.
- ^ a b Hovi T, Hirvimies A, Stenvik M, Vuola E, Pippuri R (1995). "Topical treatment of recurrent mucocutaneous herpes with ascorbic acid-containing solution". Antiviral Res. 27 (3): 263–70. doi:10.1016/0166-3542(95)00010-j. PMID 8540748.
- ^ Fisher AJ, Ten Pas RH (1966). "Clinical evaluation of Ascoxal: a new mucolytic agent". Anesthesia and Analgesia. 45 (5): 531–534. doi:10.1213/00000539-196645050-00003. PMID 5330913.
Further reading
[edit]- Nualart F, Rivas C, Montecinos V, Godoy A, Guaiquil V, Golde D, Vera J (2003). "Recycling of vitamin C by a bystander effect". J Biol Chem. 278 (12): 10128–33. doi:10.1074/jbc.M210686200. hdl:10533/174378. PMID 12435736.
External links
[edit]
Media related to Dehydroascorbic acid at Wikimedia Commons
Dehydroascorbic acid
View on Grokipediafrom Grokipedia
Chemical properties
Molecular structure
Dehydroascorbic acid possesses the molecular formula C6H6O6. It serves as the primary oxidized form of L-ascorbic acid (vitamin C), generated through the reversible loss of two hydrogen atoms from the enediol group in ascorbic acid, which converts the enediol moiety into a pair of adjacent carbonyl groups.[5][6] In its predominant form, dehydroascorbic acid adopts a bicyclic lactone structure consisting of a five-membered furanone ring fused with a hemiketal ring, where one of the carbonyl groups (at position 3) is hydrated to form the hemiketal linkage with the hydroxyl group on the side chain; the remaining carbonyl at position 2 and the lactone carbonyl at position 5 define key functional groups.[6] This bicyclic hemiketal configuration predominates in aqueous solution and crystalline states, distinguishing it from the less stable open-chain diketo representation sometimes depicted in older literature. The stereochemistry mirrors that of L-ascorbic acid, retaining the L-threo configuration with chiral centers at C4 (now C5 in the ring, R) and C5 (now the side chain C1, S) of the original hexonic acid backbone, as reflected in its systematic IUPAC name: (5R)-5-[(1S)-1,2-dihydroxyethyl]oxolane-2,3,4-trione.[7] In comparison to ascorbic acid's planar enediol system within a similar lactone ring, dehydroascorbic acid's structure introduces ring strain and hydration effects that stabilize the bicyclic form, influencing its reactivity while preserving the overall carbon skeleton.[6]Physical characteristics
Dehydroascorbic acid is typically observed as a white to off-white or light yellow crystalline powder under standard conditions.[8] Its molecular formula is C₆H₆O₆, with a molecular weight of 174.11 g/mol. The compound exhibits moderate solubility in polar solvents. It is soluble in water to approximately 10 mM (1.74 mg/mL) with gentle warming, though solubility increases with heating to 60°C; it is also soluble in ethanol and methanol but insoluble in non-polar solvents such as ether, benzene, and chloroform.[8][5][9][10] This behavior stems from its polar oxygen-containing functional groups, which facilitate interactions with protic solvents. Dehydroascorbic acid lacks a defined melting point and instead decomposes at 225–230°C.[8][5] Optically, dehydroascorbic acid shows a UV absorbance maximum at 210 nm, attributable to its conjugated diketo system, with minimal absorption above 220 nm.[11] The compound has a pKa of approximately 3.9, reflecting the acidity of its carboxyl-like group.[5]Reactivity and stability
Dehydroascorbic acid (DHA) represents the fully oxidized form of ascorbic acid, the active component of vitamin C, and does not undergo further oxidation under physiological conditions due to its stable structure.[12] Its primary chemical reactivity involves facile reduction back to ascorbic acid via a two-electron transfer, a reversible process that maintains the vitamin C pool in biological and chemical systems.[13] Alternatively, DHA undergoes irreversible hydrolysis to 2,3-diketogulonic acid, a degradation product that lacks vitamin C activity, through ring-opening of its lactone moiety in aqueous environments.[14] The reduction of DHA to ascorbic acid proceeds according to the equation:
This reaction is commonly facilitated by chemical reductants such as glutathione or tris(2-carboxyethyl)phosphine, with the latter achieving full conversion in acidic media within 20 minutes.[15]
DHA stability is highly pH-dependent, exhibiting rapid hydrolysis at neutral pH while remaining more stable in acidic conditions below pH 4, where solutions can persist for days without significant loss.[12] In aqueous solutions at pH 7, DHA has a half-life of approximately 10–20 minutes at 25–37°C, primarily due to hydrolytic degradation.[13][16]
Environmental factors further influence DHA degradation, including sensitivity to light (particularly UV wavelengths 229–330 nm), elevated temperatures (e.g., accelerated loss above 25°C), and catalytic effects from transition metal ions such as copper(II) and iron(III), which promote autoxidation and hydrolysis via Fenton-like mechanisms.[14][12]
Occurrence and synthesis
Natural occurrence
Dehydroascorbic acid is naturally present in dietary sources, particularly fruits and vegetables, where it typically accounts for 5–20% of the total vitamin C content. Examples include citrus fruits such as oranges, grapefruits, and lemons, as well as broccoli, in which initial ratios of dehydroascorbic acid to total vitamin C often exceed 10% and can rise further during post-harvest storage. This oxidized form arises from the spontaneous or enzymatic conversion of ascorbic acid and contributes to the overall bioavailability of vitamin C in the human diet. Additionally, dehydroascorbic acid is generated in the gastrointestinal tract through the oxidation of ingested ascorbic acid by reactive species in the intestinal lumen, enhancing its absorption potential. In environmental contexts, dehydroascorbic acid forms in plant tissues under stress conditions, such as mechanical wounding or pathogen attacks, where ascorbate oxidase in the apoplastic space catalyzes the oxidation of ascorbic acid to dehydroascorbic acid, facilitating redox signaling and defense responses. For instance, ascorbate oxidase expression increases during biotic stresses like nematode infections, leading to elevated dehydroascorbic acid levels that support reactive oxygen species management and systemic immunity. Concentrations of dehydroascorbic acid in fresh produce are generally low, ranging from 0.5 to 9 mg per 100 g of edible tissue—for example, around 5–7 mg/100 g in fresh yams or less than 3 mg/100 g in citrus juices equivalent to fresh weight—but these levels rise with storage or processing due to progressive oxidation of ascorbic acid. In animal physiology, dehydroascorbic acid accumulates in extracellular fluids, comprising approximately 10% of the total vitamin C pool in human plasma under normal conditions.Biosynthesis
Dehydroascorbic acid (DHA) is primarily synthesized through the oxidation of ascorbic acid (AA) in biological systems, occurring via non-enzymatic reactions with reactive oxygen species (ROS) or transition metals like iron and copper, as well as enzymatic catalysis by oxidases and peroxidases.[12] Non-enzymatic oxidation involves the one- or two-electron transfer from AA, leading to the formation of the ascorbate radical (monodehydroascorbic acid, MDHA) as an intermediate, which can further disproportionate to DHA.[17] Enzymatic pathways, such as those mediated by ascorbate oxidase in plants and ascorbate peroxidase in both plants and animals, accelerate this process under oxidative stress, ensuring rapid conversion to maintain cellular redox homeostasis.[18] In plants, DHA production is a key component of the ascorbate-glutathione cycle, a major antioxidant pathway localized in chloroplasts, mitochondria, and the apoplast. Here, AA is oxidized by ascorbate peroxidase to MDHA using hydrogen peroxide (H₂O₂) as an electron acceptor, and MDHA subsequently forms DHA either through spontaneous dismutation (2 MDHA → AA + DHA) or further oxidation.[19] This cycle integrates DHA formation with glutathione-mediated reduction, allowing plants to scavenge ROS effectively during photosynthesis and environmental stresses like drought or pathogen attack. Ascorbate oxidase, a copper-containing enzyme in the cell wall, further contributes by directly oxidizing AA to DHA, influencing cell wall loosening and growth.[18] In animals and humans, who cannot synthesize AA de novo from glucose due to the loss of gulonolactone oxidase, DHA is generated extracellularly in plasma and tissues, particularly through neutrophil-mediated oxidation during inflammation. Activated neutrophils produce ROS via the NADPH oxidase complex during phagocytosis, oxidizing surrounding AA to DHA in the oxidative microenvironment.[20] This process supports immune function by facilitating DHA uptake into cells via glucose transporters, where it is reduced back to AA. The key oxidase-catalyzed reaction can be represented as:
DHA biosynthesis is regulated by feedback mechanisms to avoid over-oxidation; elevated DHA levels enhance its reduction by dehydroascorbate reductase using glutathione, thereby limiting further AA depletion and preserving antioxidant capacity.[17]
Laboratory synthesis
Dehydroascorbic acid (DHA) was first synthesized in the laboratory shortly after the preparation of L-ascorbic acid in 1933 by Tadeus Reichstein and colleagues through a multi-step process starting from sorbitol derivatives, with DHA obtained via controlled oxidation of the newly synthesized ascorbic acid.[21] This marked the initial chemical production of DHA as the oxidized form of vitamin C, enabling further studies on its properties and reactivity.[22] The classical laboratory method for synthesizing DHA involves the oxidation of L-ascorbic acid using halogens such as iodine or bromine in aqueous solution. In this approach, ascorbic acid is dissolved in water, and a stoichiometric amount of iodine is added, leading to the reduction of iodine to iodide while ascorbic acid is oxidized to DHA through a two-electron transfer process; the reaction is typically conducted at neutral pH and room temperature for efficient conversion.[23] Bromine can be used similarly in the presence of acetic acid to control the reaction rate and prevent side products, yielding DHA in high purity after neutralization and filtration to remove halide salts. Following oxidation, purification is achieved by crystallization from ethanol-water mixtures, where the solution is concentrated and cooled to precipitate DHA, often as its hydrated form, with multiple recrystallizations ensuring removal of unreacted ascorbic acid and inorganic impurities.[24] Modern laboratory approaches have shifted toward milder and more selective methods to improve yield and minimize byproducts. Electrochemical oxidation of ascorbic acid at a controlled potential (typically 0.2–0.6 V vs. Ag/AgCl) on electrodes like platinum or carbon uses an aqueous electrolyte, allowing precise two-electron oxidation to DHA without harsh chemical oxidants, achieving yields of 70–90% under optimized conditions such as pH 4–7 and low temperatures.[25] Alternative mild chemical oxidants, such as potassium ferricyanide or activated charcoal in buffered solutions, facilitate quantitative conversion at ambient conditions, avoiding the need for halogen handling.[22] These methods emphasize scalability and environmental friendliness compared to classical halogen-based techniques. A key challenge in DHA synthesis is preventing over-oxidation or hydrolysis to 2,3-diketogulonic acid, which occurs readily in aqueous media at neutral or basic pH, reducing yields and complicating purification; this is mitigated by maintaining acidic conditions (pH < 4) during oxidation and rapid isolation.[26] Additionally, due to DHA's instability toward further degradation in air and light, synthesized product must be stored under an inert atmosphere, such as nitrogen, at low temperatures to preserve its integrity for subsequent use.[22]Biological transport
Cellular uptake mechanisms
Dehydroascorbic acid (DHA), the oxidized form of ascorbic acid, enters cells primarily through facilitated diffusion mediated by glucose transporters (GLUTs), exploiting its structural mimicry of glucose. The key isoforms involved are GLUT1, GLUT3, and GLUT4, which enable DHA transport across the plasma membrane in various cell types.[27][28] This process contrasts sharply with the uptake of reduced ascorbic acid (AA), which depends on sodium-ascorbate cotransporters (SVCT1 and SVCT2) that operate via sodium-dependent symport mechanisms.[29][30] DHA transport via GLUTs is sodium-independent and energy-independent, relying instead on concentration gradients to drive influx.[31] Upon entry, DHA is rapidly reduced to ascorbic acid by intracellular enzymes such as glutathione-dependent dehydroascorbate reductase, effectively trapping vitamin C within the cell since AA cannot exit through GLUTs.[31] This reduction step enhances net accumulation, with DHA uptake rates often exceeding those of AA by at least 10-fold in many cell types.[29] The kinetics of DHA transport show Michaelis-Menten characteristics, with apparent Km values for GLUT1 around 1.1 mM and for GLUT3 approximately 1.7 mM, indicating moderate affinity compared to glucose.[32] Uptake of DHA is particularly pronounced in erythrocytes, where GLUT1 predominates and facilitates efficient recycling of oxidized vitamin C, and in endothelial cells lining blood vessels, supporting vascular homeostasis.[33][34] In insulin-sensitive tissues such as skeletal muscle and adipose, GLUT4 contributes to DHA influx, with transport stimulated by insulin signaling that translocates GLUT4 to the membrane.[28] These distribution patterns underscore DHA's role in distributing vitamin C to high-demand sites, though competition with glucose can modulate uptake rates in hyperglycemic conditions.[35]Transport to brain
The endothelial cells forming the blood-brain barrier (BBB) express the glucose transporter GLUT1, which facilitates the influx of dehydroascorbic acid (DHA) from the bloodstream into the brain parenchyma.[36] Once inside these cells, DHA is rapidly reduced to ascorbic acid (AA) by enzymes such as glutathione-dependent dehydroascorbate reductase or thioredoxin reductase, allowing accumulation in the reduced form within brain tissue.[36] This mechanism circumvents the BBB's impermeability to AA, enabling effective delivery of vitamin C to neural cells.[37] This transport pathway is physiologically vital, as it supports AA concentrations in the brain that are up to 10-fold higher than in plasma, providing essential protection against oxidative damage to neurons and glia.[36] The elevated AA levels are critical for maintaining neuronal integrity, particularly in regions vulnerable to reactive oxygen species, such as the hippocampus and cortex.[37] Transport efficiency is modulated by competition with glucose for GLUT1 binding sites, where elevated blood glucose levels dose-dependently inhibit DHA uptake across the BBB.[38] Insulin indirectly influences this process by regulating systemic glucose concentrations, though GLUT1 itself remains insulin-independent in brain endothelium.[39] Experimental studies demonstrate that systemic administration of DHA significantly elevates brain AA levels, far more effectively than equivalent doses of AA, which fails to cross the BBB.[36] For instance, intravenous DHA injection in rodent models rapidly increases cerebral AA content and enhances neuroprotection during oxidative challenges.[37] In pathological conditions, such as scurvy resulting from chronic vitamin C deficiency, reduced circulating DHA limits brain accumulation of AA, exacerbating neurological deficits.[40] Similarly, under conditions of heightened oxidative stress, impaired DHA transport can diminish AA replenishment, worsening neuronal vulnerability.[41] Conversely, in ischemia models, DHA delivery is leveraged for therapeutic enhancement, where its rapid BBB penetration reduces infarct size and mitigates reperfusion injury more effectively than AA.[42]Transport to mitochondria
Dehydroascorbic acid (DHA), the oxidized form of ascorbic acid, is transported into mitochondria primarily through facilitative glucose transporters localized to the mitochondrial membrane, such as GLUT1 and GLUT10. GLUT10 serves as a key mitochondrial DHA importer, facilitating its entry into the organelle in cells like smooth muscle cells and adipocytes, where it accumulates and is subsequently reduced to ascorbic acid (AA). Similarly, GLUT1 enables DHA uptake into mitochondria in a sodium-independent, electroneutral manner, allowing the oxidized vitamin to cross the outer mitochondrial membrane. Once inside, DHA is reduced to AA by mitochondrial enzyme systems, including thioredoxin reductase and glutaredoxin, which maintain the redox balance by regenerating the active antioxidant form.[43][44][45]74957-6/fulltext)[46] The primary purpose of DHA transport to mitochondria is to provide reducing equivalents for mitochondrial enzymes and to scavenge reactive oxygen species (ROS), thereby protecting the organelle from oxidative damage. Mitochondrial AA derived from DHA acts as a potent quencher of ROS generated by the electron transport chain, preventing damage to mitochondrial DNA and membrane depolarization under oxidative stress conditions. This process supports overall cellular redox homeostasis, particularly in high-energy-demand tissues where mitochondrial dysfunction could impair energy production.[43][44][45] Evidence for this transport mechanism includes immunoblotting and immunolocalization studies confirming GLUT1 and GLUT10 presence on mitochondrial membranes, alongside in vitro import assays demonstrating DHA accumulation as AA within isolated mitochondria. Inhibition of GLUT10 in mutant models elevates ROS levels and increases oxidative injury, underscoring its protective role, while DHA exposure in cell lines like HEK-293 shows stereo-selective uptake that mitigates ROS-induced damage from respiratory chain inhibitors. Although direct fluorescence imaging of DHA in the mitochondrial matrix under stress is limited, related studies using ROS-sensitive probes highlight enhanced antioxidant activity in mitochondria following DHA supplementation.[45][43][44] Kinetics of mitochondrial DHA uptake are rapid, occurring within seconds to minutes, and are influenced by the mitochondrial membrane potential, with uptake inhibited by competing substrates like D-glucose. This swift transport ensures timely delivery of reducing power during acute oxidative challenges. Deficient DHA transport, such as in GLUT10 loss-of-function models, is associated with mitochondrial dysfunction, elevated oxidative stress, and impaired redox homeostasis, contributing to conditions like arterial tortuosity syndrome and potentially exacerbating mitochondrial impairments in aging and diabetes through reduced ROS scavenging and altered energy metabolism.[45][47][48][44][49]Physiological roles
Oxidation-reduction cycle
Dehydroascorbic acid (DHA) participates in a vital oxidation-reduction cycle in biological systems, where it is reversibly interconverted with ascorbic acid (AA). This cycle enables the recycling of vitamin C, allowing AA to act as an antioxidant by donating electrons to reactive oxygen species (ROS), thereby oxidizing to DHA. Subsequently, DHA is reduced back to AA through enzymatic processes that utilize cellular reducing agents such as glutathione (GSH) or NADPH. Key enzymes involved include glutaredoxin, which facilitates GSH-dependent reduction, and thioredoxin reductase, which employs NADPH to regenerate AA from DHA.[50][46] The reduction of DHA to AA is a two-electron process, often catalyzed by glutaredoxin in a reaction represented by the equation:
where GSSG is oxidized glutathione. This enzymatic step ensures efficient recycling, with monodehydroascorbic acid (MDHA), the ascorbyl semiquinone radical intermediate, playing a role in the overall redox pathway during oxidation from AA to DHA. MDHA forms via one-electron oxidation of AA by ROS and can disproportionate to yield DHA and AA, linking the one- and two-electron steps of the cycle.[51][52][53]
This cycle maintains the cellular pool of vitamin C, with over 90% of plasma vitamin C existing as AA and DHA serving as a short-lived, transient form due to rapid reduction. The efficiency of recycling preserves antioxidant capacity, but imbalances occur under conditions of excessive oxidative stress, where unrelieved oxidation of AA to DHA—and further irreversible degradation of DHA to 2,3-diketogulonic acid—can lead to net depletion of the vitamin C pool.[54][55][13]