Alterations in mitochondrial glucose carbon metabolism in epilepsy and targeted metabolic treatments

There is increasing evidence showing that oxidative glucose metabolism in mitochondria is impaired in epilepsy and the involved metabolic mechanisms have been further characterized by recent work. Glucose is the main energy source in brain in people who eat a conventional mixed diet with carbohydrates, fats, and proteins. In the cytoplasm, glucose is metabolized to pyruvate by glycolysis, which produces small amounts of energy. Entry of pyruvate into mitochondria and subsequent metabolism via the tricarboxylic acid cycle generates large amounts of adenosine triphosphate as well as precursors for cellular biosynthesis of lipids and amino acids. Sufficient energy is important for the brain to be able to signal normally and to keep the sodium and potassium gradients stable across cellular membranes. In contrast, insufficient energy can contribute to surges in extracellular potassium levels, which destabilizes membrane potentials and signaling and can result in seizure generation in the chronic epileptic brain. The known biochemical mechanisms leading to mitochondrial impairments of glucose carbon metabolism in epilepsy are summarized in this chapter, including reduced glucose utilization, decreases in enzyme activities, such as pyruvate dehydrogenase, as well as increased anaplerotic demand. Based on this current knowledge, auxiliary brain fuels would be useful to provide extra energy to the epileptic brain. This includes ketones, tricarboxylic acid cycle intermediates, and precursors as well as even medium chain fatty acids and triheptanoin.