Distinct contribution of monocarboxylate transporter 2 to infantile epileptic spasms syndrome

Abstract

Infantile epileptic spasms syndrome (IESS) is the most common refractory epileptic encephalopathy in early brain development, its pathogenesis remains elusive. In the adult brain, glucose serves as the predominant metabolic fuel. However, ketone bodies and lactate are more important in neural energy metabolism during early development. This has been further provided by the effectiveness of ketogenic diet (KD) therapy in IESS. When the circulatory pool of ketone bodies is increased by KD, the brain utilizes ketone bodies preferentially to meet the high energy demand of neurons which is beneficial to mitigate seizure activity and promote prognosis for children with IESS. Neuronal monocarboxylate transporter 2 (MCT2) is crucial in this process, transporting ketone bodies and lactate to mitochondria for adenosine triphosphate (ATP) generation for cellular energy. The inhibition of MCT2 has been linked to mitochondrial dysfunction and its reduction has been found in adult animal epilepsy models. The mitochondrial energy metabolism disorder is a recognized central pathological aspect of epileptogenesis. Therefore, we hypothesize that neuronal MCT2, an essential gatekeeper of energy metabolism, may play a critical role in the genesis and propagation of spasms in IESS by markedly affecting brain metabolic homeostasis and mitochondrial function. We propose to conduct animal studies and clinical studies to investigate the relationship among MCT2, severity of IESS, susceptibility of IESS, and mitochondrial dysfunction from a metabolic perspective.