Folate deprivation promotes mitochondrial oxidative decay: DNA large deletions, cytochrome c oxidase dysfunction, membrane depolarization and superoxide overproduction in rat liver

• Published in: British journal of nutrition Vol. 97; no. 5; pp. 855 - 863
• Main Authors: Chang, Chun-Min, Yu, Chu-Ching, Lu, Hsin-Te, Chou, Yi-Fang, Huang, Rwei-Fen S.
• Format: Journal Article
• Language: English
• Published: Cambridge, UK Cambridge University Press 01.05.2007
• Subjects: Amino acids; animal disease models; Animals; antioxidant activity; antioxidants; Antioxidants - analysis; Biological and medical sciences; Biological effects; Carbonyl compounds; CcOX activity; Cells; Cells, Cultured; chromosome elimination; Cytochrome; cytochrome c; Decay; deficiency diseases; Deoxyribonucleic acid; Dietary Supplements; Dihydrofolate reductase; DNA; DNA repair; DNA, Mitochondrial - genetics; Electron Transport - physiology; Electron Transport Complex IV - metabolism; Feeding. Feeding behavior; Folate deprivation; Folic acid; Folic Acid - administration & dosage; Folic Acid - metabolism; Folic Acid Deficiency - genetics; Folic Acid Deficiency - metabolism; Folic Acid Deficiency - physiopathology; Fundamental and applied biological sciences. Psychology; Gene Deletion; glutathione peroxidase; hepatocytes; human genetics; Injuries; Life sciences; Liver; Liver - metabolism; Liver - physiopathology; Liver mitochondrial decay; Male; Membrane depolarization; membrane potential; Membrane Potential, Mitochondrial - genetics; Membrane Potential, Mitochondrial - physiology; Membranes; mitochondria; Mitochondria, Liver - metabolism; Mitochondria, Liver - physiology; Mitochondrial DNA; nutrigenomics; Nutrition; oxidation; Oxidative stress; Oxidative Stress - physiology; Oxidizing agents; Peroxidation; Proteins; Rats; Rats, Wistar; superoxide anion; Superoxides - metabolism; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vitamin B; vitamin deficiencies; vitamin supplements; Oxidative stress; Membrane depolarization; Liver mitochondrial decay; Folate deprivation; CcOX activity; Rat; Digestive system; Enzyme; Liver; Rodentia; Cytochrome-c oxidase; Mitochondrial DNA; Folic acid; Folate; Depolarization; Vertebrata; Mitochondria; Mammalia; Dysfunction; Animal; Decay; Deletion; Membrane; Oxidoreductases; Folate deprivation: Liver mitochondrial decay: CcOX activity: Membrane depolarization: Oxidative stress
• ISSN: 0007-1145; 1475-2662
• DOI: 10.1017/S0007114507666410

Little is known about the biological effect of folate in the protection against mitochondrial (mt) oxidative decay. The objective of the present study was to examine the consequence of folate deprivation on mt oxidative degeneration, and the mechanistic link underlying the relationship. Male Wistar rats were fed with an amino acid-defined diet containing either 8 (control) or 0 (folate-deficient, FD) mg folic acid/kg diet. After a 4-week FD feeding period, significant elevation in oxidative stress was observed inside the liver mitochondria with a 77 % decrease in mt folate level (P < 0·001), a 28 % reduction in glutathione peroxidase activity (P = 0·0333), a 1·2-fold increase of mt protein carbonyls (P = 0·0278) and an accumulated 4834 bp large-scale deletion in mtDNA. The elicited oxidative injuries in FD liver mitochondria were associated with 30 % reduction of cytochrome c oxidase (CcOX) activity (P = 0·0264). The defective CcOX activity in FD hepatocytes coincided with mt membrane potential dissipation and intracellular superoxide elevation. Exposure of FD hepatocytes to pro-oxidant challenge (32 μm-copper sulphate for 48 h) led to a further loss in CcOX activity and mt membrane potential with a simultaneous increase in superoxide production. Preincubation of pro-oxidant-treated FD hepatocytes with supplemental folic acid (10–1000 μm) reversed the mt oxidative defects described earlier and diminished superoxide overproduction. Increased supplemented levels of folic acid strongly correlated with decreased lipid peroxidation (γ − 0·824, P = 0·0001) and protein oxidative injuries (γ − 0·865, P = 0·0001) in pro-oxidant-challenged FD liver mitochondria. Taken together, the results demonstrated that folate deprivation induces oxidative stress in liver mitochondria, which is associated with CcOX dysfunction, membrane depolarization and superoxide overproduction. The antioxidant activity of supplemental folic acid may partially, if not fully, contribute to the amelioration of pro-oxidant-elicited mt oxidative decay.