Brain Energy and Oxygen Metabolism: Emerging Role in Normal Function and Disease

Abstract

Dynamic metabolic changes occurring in neurons are critically important in directing brain plasticity and cognitive function. In other tissue types, disruptions to metabolism and the resultant changes in cellular oxidative state, such as increased reactive oxygen species (ROS) or induction of hypoxia, are associated with cellular stress. In the brain however, where drastic metabolic shifts occur to support physiological processes, subsequent changes to cellular oxidative state and induction of transcriptional sensors of oxidative stress likely play a significant role in regulating physiological neuronal function. Understanding the role of metabolism and metabolically-regulated genes in neuronal function will be critical in elucidating how cognitive functions are disrupted in pathological conditions where neuronal metabolism is affected. Here, we discuss known mechanisms regulating neuronal metabolism as well as the role of hypoxia and oxidative stress during normal and disrupted neuronal function. We also summarize recent studies implicating a role for metabolism in regulating neuronal plasticity as an emerging neuroscience paradigm.

Keywords: hypoxia; neurodegeneration; neurometabolism; oxidative metabolism; plasticity.

Figure 1

Neurovascular and neurometabolic coupling mechanisms. Schematic illustrating neuronal and astrocytic mechanisms responsible for activity-related blood flow and metabolic changes. (a) NMDA receptors (NMDA-R) are linked to neuronal nitric oxide synthase (nNOS) through post-synaptic density protein 95 (PSD-95) and neurovascular coupling during activity is thought to be triggered through the neuronally-produced vasodilator •NO, which can diffuse rapidly and freely through membranes to act on arterioles. (b) Vasodilation is also thought to be controlled at the capillary level through astrocytic Ca⁺ signaling acting on contractile perictyes. (c) In the glutamine-glutamate cycle, glutamate (Glu) released into the synaptic cleft is cleared by Na⁺-dependent astrocytic uptake, primarily through GLT-1. Glutamate is converted to glutamine (Gln) and returned to neurons to replenish neurotransmitter stores. (d,e) The astrocyte-neuron lactate shuttle (ANLS) hypothesis suggests associated increases in astrocytic Na⁺ concentration triggers activation of Na⁺/K⁺ ATPase pumps, promoting glucose uptake and glycolysis. Glycolytically-generated lactate is released and utilized as a substrate for oxidative phosphorylation in neurons during periods of activity. LDH, lactate dehydrogenase; MCT, monocarboxylate transporter. Solid lines indicate enzymatic activity, dashed lines indicate solute movement.

Figure 2

Hypoxia inducible transcription factor regulation. Under normal oxygen conditions hypoxia-inducible factor-1α (HIF-1α) is hydroxylated by prolyl hydroxylase (PHD) enzymes and targeted for ubiquitination by the Von Hippel-Lindau tumor suppresser ubiquitin ligase complex (pVHL). During hypoxia or low oxygen conditions, HIF-1α is stabilized, translocates to the nucleus and associates with HIF-β to promote gene expression, targeting genes containing a hypoxia response element (HRE). HIF-1α acts as a glycolytic enhancer through transcriptional activation of metabolic genes including 6-phosphofructo-2-kinase/fructose-2,6-bisphosphate 3 (PFKFB3) and pyruvate dehydrogenase kinase-1 (PDK1), both positive regulators of glycolysis and monocarboxylate transporter 4 (MCT4), the lactate efflux transporter. Ub, ubiquitin; OH, hydroxyl group.

Figure 3

Disrupted metabolic pathways in neurodegenerative diseases. Hypoxia associated with Alzheimer’s Disease (AD) leads to increases in the HIF-1α target, β-site β-amyloid precursor protein cleavage enzyme 1 (BACE1), which cleaves amyloid precursor protein (APP) to produce Aβ. Aβ accumulates in neuronal mitochondria (MC) early in disease progression and disrupts oxidative metabolism. Acetyl-CoA production and tricaboxcylic acid (TCA) cycle entry is decreased in AD through reduced activity of the pyruvate dehydrogenase complex (PDHC). In all three diseases, activity of α-ketoglutarate dehydrogenase complex (KGDHC) is reduced, reactive oxygen species (ROS) is increased and transglutaminase (TG) activity is increased. TG increases α-synuclein aggregation and reduces oxidative respiration.