In addition to its role in promoting apoptosis, BAD (BCL-2–associated agonist of cell death) is essential for glucose metabolism in hepatocytes and β cells, a role that requires phosphorylation of Ser155 in BAD (see Ziviani and Scorrano). Because glucose is the primary fuel consumed by neurons, Giménez-Cassina et al. investigated the role of BAD in neuronal metabolism. Primary cultures of cortical neurons and astrocytes from Bad–/– or mice with a knock-in allele encoding a nonphosphorylatable form of BAD (BadS155A) showed lower basal and maximal mitochondrial oxygen consumption rates (indicating lower glucose utilization) and increased consumption of the ketone body β--Dhydroxybutyrate than those from wild-type mice. The ketogenic diet is a high-fat, low-carbohydrate diet that forces the body to burn fat instead of glucose, causes the liver to release ketone bodies instead of glucose, and promotes the utilization of ketone bodies instead of glucose in the brain. This diet can help control forms of epilepsy that are refractory to drug treatment, leading the authors to hypothesize that Bad–/– and BadS155A mice could be protected from seizure activity. The majority of wild-type mice treated with the convulsant kainic acid subsequently suffered the most severe type of seizures (tonic clonic, which involves the entire brain) that were persistent or prolonged (known as status epilepticus). In contrast, Bad–/– and BadS155A mice had less severe seizures and did not reach status epilepticus. KATP channels consist of inwardly rectifying Kir6.2 potassium channels and regulatory Sur (sulfonylurea receptor) subunits, and their activity decreases neuronal excitability. The open probability of KATP channels was higher in Bad–/– neurons than in wild-type neurons, suggesting that increased activity of KATP channels was responsible for the resistance of Bad–/– mice to seizures. Indeed, mice lacking both BAD and Kir6.2 showed the same sensitivity to kainic acid–induced seizures as wild-type mice. Thus, preventing the phosphorylation of Ser155 in BAD causes neurons to use ketone bodies instead of glucose as their primary fuel source, which confers resistance to seizure activity through increased activity of KATP channels.
A. Giménez-Cassina, J. R. Martínez-François, J. K. Fisher, B. Szlyk, K. Polak, J. Wiwczar, G. R. Tanner, A. Lutas, G. Yellen, N. N. Danial, BAD-dependent regulation of fuel metabolism and KATP channel activity confers resistance to epileptic seizures. Neuron 74, 719–730 (2012). [Online Journal]
E. Ziviani, L. Scorrano, In epilepsy, BAD is not really bad. Neuron 74, 600–602 (2012). [Online Journal]