Where Is the Oxygen? The Mirage of Non-Oxidative Glucose Consumption During Brain Activity

Ever since the discovery that neuronal tissue can utilize lactate as an aerobic substrate for mitochondrial adenosine triphosphate (ATP) production, a debate has ensued between those who have questioned the importance of lactate in brain energy metabolism and those who argue that lactate plays a central role in this process. The "neuron astrocyte lactate shuttle hypothesis" has sharpened this debate since it postulates lactate to be the oxidative energy substrate for activated neurons. Those who minimize lactate's role insist that a non-oxidative process they termed "aerobic glycolysis" supports brain activation, despite oxygen availability. To explain the paradox that the active brain would utilize the inefficient glycolysis over the much more efficient mitochondrial oxidative phosphorylation (OXPHOS) for ATP production, they suggested the "efficiency tradeoff hypothesis," where the inefficiency of the glycolytic pathway is traded for speed necessary for the information transfer of the active brain. In contrast, other studies reveal that oxidative energy metabolism is the process that supports brain activation, refuting both the "aerobic glycolysis" concept and the premise of the "efficiency tradeoff hypothesis". These studies also shed doubts on the usefulness of the blood oxygenation dependent functional magnetic resonance imaging (BOLD fMRI) method and its signal as an appropriate tool for the estimation of brain oxygen consumption, as it is unable to detect any oxygen present in the extravascular brain tissue.