title: Levels of 5-methyltetrahydrofolate and ascorbic acid in cerebrospinal fluid are correlated: implications for the accelerated degradation of folate by reactive oxygen species.
abstract: Deficiency of 5-methyltetrahydrofolate (5-MTHF) in cerebrospinal fluid (CSF) is associated with a number of neurometabolic conditions including mitochondrial electron transport chain defects. Whilst failure of the active transport of 5-methyltetrahydrofolate (5-MTHF) into the CSF compartment has been proposed as a potential mechanism responsible for the 5-MTHF deficiency seen in mitochondrial disorders, it is becoming increasingly clear that other mechanisms are involved. Here, we have considered the role of oxidative stress as a contributing mechanism. Concerning, ascorbic acid (AA), we have established a CSF reference range (103-303μM) and demonstrated a significant positive correlation between 5-MTHF and AA. Furthermore, CSF itself was also shown to convey antioxidant properties towards 5-MTHF. However, this protection could be overcome by the introduction of a hydroxyl radical generating system. Using a neuronal model system, inhibition of mitochondrial complex I, by 58%, was associated with a 23% increase in superoxide generation and a significantly increased loss of 5-MTHF from the extracellular medium. Addition of AA (150μM) was able to prevent this increased 5-MTHF catabolism. We conclude that increased generation of reactive oxygen species and/or loss of CSF antioxidants are also factors to consider with regard to the development of a central 5-MTHF deficiency. Co-supplementation of AA together with appropriate folate replacement may be of therapeutic benefit.
authors.affiliation: Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK; Chemical Pathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
authors.forename: Sophie-Beth
authors.initials: SB
authors.lastname: Aylett
authors.forename: Viruna
authors.initials: V
authors.lastname: Neergheen
authors.forename: Iain P
authors.initials: IP
authors.lastname: Hargreaves
authors.forename: Simon
authors.initials: S
authors.lastname: Eaton
authors.forename: John M
authors.initials: JM
authors.lastname: Land
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
authors.forename: Simon J R
authors.initials: SJ
authors.lastname: Heales
mesh_terms: D000293:Adolescent; D000328:Adult; D001205:Ascorbic Acid / Q000134:cerebrospinal fluid*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013763:Tetrahydrofolates / Q000134:cerebrospinal fluid*; D055815:Young Adult
chemical_list: D017382:Reactive Oxygen Species; D013763:Tetrahydrofolates; D005492:Folic Acid; D001205:Ascorbic Acid; C005984:5-methyltetrahydrofolate
keywords: 5-Methyltetrahydrofolate; Folate; Mitochondrial disease; Oxidative stress