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the widely used mood stabilizer valproate (VpA) causes perturbation of energy metabolism, which is implicated in both the therapeutic mechanism of action of the drug as well as drug toxicity. to gain insight into these mechanisms, we determined the effects of VPA on energy metabolism in yeast. VpA treatment increased levels of glycolytic intermediates, increased expression of glycolysis genes, and increased ethanol production. increased glycolysis was likely a response to perturbation of mitochondrial function, as reflected in decreased membrane potential and oxygen consumption. interestingly, yeast, mouse liver, and isolated bovine cytochrome c oxidase were directly inhibited by the drug, while activities of other oxidative phosphorylation complexes (III and V) were not affected. These findings have implications for mechanisms of therapeutic action and toxicity. Bipolar disorder (BD) is a severe psychiatric illness characterized by shifts in mood, ranging from mania to depression. It affects at least 1% of the population and leads to suicide in 15% of cases 1. BD patients exhibit a higher prevalence of obesity, cardiovascular disease, and diabetes than the general population 2,3. Many studies have shown that the pathophysiology of BD involves altered energy metabolism 4-8. While most of the metabolic markers measured indicate mitochondrial dysfunction in BD 9-12 , some studies have suggested the presence of increased mitochondrial activity in the manic phase of BD 13 , including increased energy generation 14 , basal metabolic rate 15 , uric acid 16 , and calcium ions 17. Valproate (VPA) is one of several mood stabilizers approved by the FDA for the treatment of BD 18,19 , epilepsy 20,21 , and migraine 22. The mechanism of action of VPA is not understood 23. VPA is effective in only 40-60% of cases and can cause serious side effects, including hepatotoxicity and teratogenicity 24. Hepatotoxicity can be life-threatening 25,26 and may occur even at therapeutic doses 27. Although rare, lethal hepatotoxicity associated with VPA has been described in both children 28 and adults 29. The prominent feature of this type of hepatotoxicity is microvesicular steatosis 30 , consistent with mitochondrial dysfunction 31. In agreement with this, patients with congenital defects in mitochondrial metabolism are at a higher risk for susceptibility to VPA toxicity 32-34. VPA exerts numerous documented effects on mitochondrial metabolism. It is metabolized by and inhibits ß-oxidation through several mechanisms 35. VPA and its metabolites sequester coenzyme A (CoA), depleting mitochondrial CoA 36. Furthermore, studies suggest that both unesterified VPA as well as VPA acyl-CoA esters inhibit fatty acid oxidation enzymes 37,38. In addition to affecting ß-oxidation, VPA inhibits α-ketoglutarate dehydrogenase, a key enzyme of the tricarboxylic acid (TCA) cycle 39,40. Inhibition of this enzyme is a proposed mechanism underlying decreased TCA cycle flux in the presence of VPA 41. VPA also decreases levels of carnitine 42,43 , which transpo...

Previous studies have shown that the cardiolipin (CL)-deficient yeast mutant, crd1Δ, has decreased levels of acetyl-CoA and decreased activities of the TCA cycle enzymes aconitase and succinate dehydrogenase. These biochemical phenotypes are expected to lead to defective TCA cycle function. In this study, we report that signaling and anaplerotic metabolic pathways that supplement defects in the TCA cycle are essential in crd1Δ mutant cells. The crd1Δ mutant is synthetically lethal with mutants in the TCA cycle, retrograde (RTG) pathway, glyoxylate cycle, §

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