Coenzyme Q(1) depletes NAD(P)H and impairs recycling of ascorbate in astrocytes.
Ascorbate is an important antioxidant in the brain. Astrocytes are capable of recycling ascorbate by taking up and then reducing its oxidation product dehydroascorbic acid (DHAA) using reducing equivalents derived from NAD(P)H. Astrocytes also contain NAD(P)H-dependent quinone reductases, such as NAD(P)H:quinone oxidoreductase (NQO1), which are capable of reducing coenzyme Q and its analogs. Short-chain coenzyme Q analogs have been proposed as therapeutic agents for neurodegenerative illnesses, but they may cause oxidative stress by non-enzymatic redox cycling or enzyme-dependent depletion of NAD(P)H. Therefore, we tested the hypothesis that the short-chain coenzyme Q analog coenzyme Q(1) (CoQ(1), ubiquinone-5) decreases intracellular NAD(P)H levels in astrocytes and impairs the ability of these cells to replace extracellular DHAA with ascorbate (i.e., ascorbate recycling). We observed that CoQ(1) inhibited the production of intra- and extracellular ascorbate by primary rat astrocytes incubated with DHAA in glucose-free medium. Reduction of CoQ(1) to CoQ(1)H(2) by astrocytes was partially blocked by the NQO1 inhibitor dicumarol but was not affected by DHAA. The inhibition of ascorbate recycling by CoQ(1) was attenuated by dicumarol and was abolished by glucose. CoQ(1) lowered intracellular levels of reactive oxygen species, as measured by oxidation of 2',7'-dichlorofluorescin but also produced marked decreases in the concentrations of NADH and NADPH. We conclude that in astrocytes CoQ(1) recycling depletes NAD(P)H and inhibits ascorbate recycling when glucose metabolism is limited. Because DHAA can cause cell-lethal oxidative stress in neurons and ascorbate produced by astrocytes may be neuroprotective, coenzyme Q analogs may adversely affect brain function through this novel mechanism.
Dragan
Magdalena
M
Department of Physiology and Pharmacology, Faculty of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1.
Dixon
S Jeffrey
SJ
Jaworski
Ewa
E
Chan
Tom S
TS
O'brien
Peter J
PJ
Wilson
John X
JX
D000818:Animals; D000831:Animals, Newborn; D001205:Ascorbic Acid / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D003683:Dehydroascorbic Acid / Q000378:metabolism; D001728:Dicumarol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014451:Ubiquinone / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D009243:NAD; D014451:Ubiquinone; D009249:NADP; D001728:Dicumarol; D005947:Glucose; C025203:Ubiquinone Q1; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid