Grant: Operating Grant

Dietary and nutritional factors are well known to have profound effects on health and disease. However, only recently have physicians and scientists begun to fully appreciate the impact of metabolism on brain function and neurological illnesses. One prominent example of an effective dietary treatment is the ketogenic diet (KD), so named because ingestion of this high-fat, low-carbohydrate diet leads to the production of important chemicals called ketone bodies by the liver. The KD is a proven treatment for epilepsy, and such diets are increasingly being studied for other disorders such as Alzheimer's disease, and even brain cancer. The broad effectiveness of the KD - and in particular, ketone bodies - suggests that important biochemical pathways and affected within cells. Indeed, recent studies have shown that ketone bodies can protect brain cells from various forms of injury, likely through an action on vital cellular components known as mitochondria, which function to produce energy molecules (such as adenosine triphosphate, or ATP) and without which cells would die. The major goal of the proposed studies is to demonstrate that ketone bodies activate a peculiar channel within mitochondria, referred to as the mitochondrial ATP-sensitive potassium channel or mitoKATP - and in so doing enhances mitochondrial function and viability. Thus far, no one has convincingly demonstrated the existence of these channels, let alone characterized their properties in detail. We hypothesize that not only do these mitoKATP channels exist within brain cells, but also that they can be regulated by ketone bodies. Demonstrating a direct action of ketone bodies on mitoKATP channels will pave the way for the development of novel drugs - based on naturally occurring molecules (i.e., ketone bodies) - which could later be tested and validated in a wide range of clinical neurological disorders.