A pyruvate dehydrogenase complex disorder hypothesis for bipolar disorder

Ketosis is a metabolic state in which the body uses ketones derived from breakdown of fatty acids as the primary mitochondrial fuel source instead of glucose. In recent years an accumulation of evidence for the beneficial effects of the ketotic state on the brain have heightened interest in its potential for use in neurological conditions. The ketogenic diet (KD) induces ketosis and is an effective treatment for medically resistant epilepsy. There is significant comorbidity between epilepsy and bipolar disorder (BD) and both conditions are treated by anti-convulsant drugs. In addition, reports on bipolar disease online fora have highlighted subjective mood stabilization effects associated with the KD. These KD reported effects could be explained if there was a disorder in the conversion of pyruvate into Acetyl-CoA (and subsequent impairment of oxidative phosphorylation) which was bypassed by ketones providing an alternative substrate for oxidative phosphorylation. This is consistent with growing evidence that mitochondrial dysfunction plays a causal role in BD and explains the reported TCA cycle dysfunction and elevated pyruvate levels in BD. Reduced levels of ATP affects the normal operation of the Na, K-ATPase in the brain with differing levels of reduction either leading to reduced neuronal action potential and inhibition of neurotransmitter release (consistent with the depressed state in BD) or increased neuronal resting potential and hyper-excitability (consistent with a [hypo]manic mood state). We hypothesize that the mitochondrial dysfunction is due to a disorder of the Pyruvate Dehydrogenase Complex (PDC) and/or Mitochondrial Carrier Protein (MCP) shuttle which moves intracellular pyruvate into mitochondria. The resultant reduction in ATP generation could explain mood instability and cycling in BD (through mechanisms such as those delineated by Mallakh and Peters). This proposed novel causal pathway could explain mood de-stabilization in BD and the reported positive effects of KD. If true, this hypothesis would suggest that there should be increased research attention to PDC (and in particular the E1 alpha subunit) as potential therapeutic targets and further study of a possible role of KD in BD to improve mood stability. Experimental approaches, such as through a clinical trial of KD on mood stabilization in BD, are required to further investigate this hypothesis.