FORUM REVIEW ARTICLE Role of 5 0 -Adenosine Monophosphate-Activated Protein Kinase in Cell Survival and Death Responses in Neurons Petronela Weisova ´ , David Da ´ vila, Liam P. Tuffy, Manus W. Ward, Caoimhı ´n G. Concannon, and Jochen H.M. Prehn Abstract 5 0 -Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of cellular energy status. AMPK signaling regulates energy balance at the cellular, organ, and whole-body level. More recently, it has become apparent that AMPK plays also an important role in long-term decisions that determine cell fate, in particular cell cycle progression and apoptosis activation. Here, we describe the diverse mechanisms of AMPK activation and the role of AMPK in the regulation of cellular energy balance. We summarize recent studies implicating AMPK activation in the regulation of neuronal survival and as a key player during ischemic stroke. We also suggest that AMPK activation may have dual functions in the regulation of neuronal survival: AMPK provides a protective effect during transient energy depletion as exemplified in a model of neuronal Ca 2+ overloading, and this effect is partially mediated by the activation of neuronal glucose transporter 3. Prolonged AMPK activation, on the contrary, can lead to neuronal apoptosis via the transcriptional activation of the proapoptotic Bcl-2 family member, bim. Molecular switches that determine the protective versus cell death- inducing effects of AMPK activation are discussed. Antioxid. Redox Signal. 14, 1863–1876. Compromised Cellular Bioenergetics During Ischemic Conditions T he brain is highly dependent on a continual flow of blood as a main supply of oxygen and glucose with mi- tochondrial oxidative phosphorylation to be the main pro- ducer of the energy in form of adenosine 5 0 -(tetrahydrogen triphosphate) (ATP). Neurons particularly require large amounts of ATP to maintain ionic balance and electrochemical gradi- ents across the plasma and mitochondrial membranes (31, 75). Therefore, any impairment of blood flow leads to a rapid depletion of the energy in affected areas of the brain with neuronal damage ensuing. Neuronal loss as a result of compromised ATP metabolism and=or mitochondrial bio- energetics during ischemic events (such as stroke, cardiac arrest-induced global ischemia, subarachnoid hemorrhage, and traumatic brain injury) is associated with massive release of the excitatory neurotransmitter glutamate. The subsequent overactivation of glutamate receptors (termed glutamate ex- citotoxicity) has been characterized as a major event contrib- uting to neuronal death during ischemia (21). Excitotoxicity has also been described in a range of neurodegenerative dis- orders, including Alzheimer’s disease, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, and Huntington’s dis- ease (8). Several in vitro and in vivo models have been employed to understand the molecular events leading to neuronal injury after prolonged glutamate receptor overactivation, with N-methyl-D-aspartate receptors playing the most prominent role in mediating injury (23, 92, 93). The extent and type of neuronal injury induced by glutamate is dependent on the duration and severity of the glutamate exposure (4, 73, 113– 115) (Fig. 1) with clinical studies linking higher plasma glu- tamate concentrations to larger lesions in stroke patients (19). Prolonged glutamate exposure or high concentrations of synaptic glutamate causes a rapid necrotic injury coupled to irreversible cytosolic Ca 2þ overloading (108, 109). Continual uptake of excessive cytosolic Ca 2þ by mitochondria is linked to a rapid collapse of mitochondrial bioenergetics (ATP de- pletion) with immediate Ca 2þ deregulation, ionic imbalance, and loss of neuronal integrity (4, 12, 22, 73, 108, 111, 113–115) (Fig. 1). In contrast, transient glutamate receptor over- activation results in a delayed apoptotic neuronal injury triggered by a secondary failure in mitochondrial bioener- getics, release of proapoptoptic factors from mitochondria, and a secondary failure of neuronal Ca 2þ homeostasis termed Department of Physiology and Medical Physics, RCSI Neuroscience Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland. ANTIOXIDANTS & REDOX SIGNALING Volume 14, Number 10, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089=ars.2010.3544 1863