Lithium-induced enhancement of mitochondrial oxidative phosphorylation in human brain tissue.
OBJECTIVE
Extensive preclinical and clinical evidence suggests mitochondrial dysfunction in bipolar disorder. Studies of brain energy metabolism in bipolar disorder suggest an impairment of energy generation by mitochondrial oxidative phosphorylation. Lithium is an effective drug widely used in treating bipolar disorder, but its mechanism of action has remained uncertain. The aim of this study was to clarify the effect of lithium on mitochondrial oxidative phosphorylation.


METHODS
We spectrophotometrically determined the activities of the respiratory chain complexes I + III [antimycin A-sensitive nicotinamide adenine dinucleotide (NADH) cytochrome c oxidorductase], complexes II + III (succinate cytochrome c oxidoreductase), succinate dehydrogenase, and complex IV [cytochrome c oxidase (COX)], and of the mitochondrial matrix enzyme citrate synthase in postmortem human brain cortex homogenates following exposure to lithium (up to 10 mM).


RESULTS
Activities of complexes I + III and of complexes II + III were dose-dependently increased by lithium with maximum values at 1 mM (165%, p = 0.03, and 146%, p = 0.00002, of controls). Activity of succinate dehydrogenase remained unchanged up to 2 mM, but was raised at higher drug concentrations (maximum 220%, p = 0.01, of controls). In contrast, activity of COX was not significantly affected by the drug (decrease of 12% at 1 mM, p = 0.4).


CONCLUSIONS
Our study suggests that lithium stimulates mitochondrial respiratory chain enzyme activities at clinically relevant concentrations. Lithium's effect on the mitochondrial respiratory chain presents further evidence of the pathophysiological significance of mitochondrial dysfunction in bipolar disorder. The effect may be relevant to the therapeutic efficacy of the drug by potentially reversing a disease-related alteration.
Maurer
Iris C
IC
Department of Psychiatry, CCM, University of Berlin, Universitätsmedizin-Charité, Elisabethkirchstrasse 5, 10115 Berlin, Germany. iris.maurer@charite.de
Schippel
Patricia
P
Volz
Hans-Peter
HP
D018692:Antimanic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D011180:Postmortem Changes; D013385:Succinate Dehydrogenase / Q000378:metabolism
D018692:Antimanic Agents; D045222:Electron Transport Chain Complex Proteins; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; D018021:Lithium Chloride