Primary Energy Sources

The human brain accounts for approximately 2% of total body mass, yet it is the most energy-intensive organ, consuming nearly 20% of the body’s overall energy expenditure. Remarkably, about 75% of the brain’s energy is dedicated to neurotransmission and essential cellular processes. Adenosine triphosphate (ATP), a nucleoside triphosphate abundant in neurons, is often called the “energy currency” of cells and plays a crucial role in a wide range of cellular functions.

In synaptic transmission, a large amount of ATP is essential for synthesizing and loading neurotransmitters into vesicles and preparing these vesicles for fusion and subsequent recycling. It also plays a vital role in maintaining energy levels and is crucial for preserving the cell’s resting ion gradient, thereby preventing excitotoxicity caused by excess glutamate. Excitotoxicity can result in calcium influx and oxidative stress, ultimately leading to neuronal cell death. Furthermore, ATP powers motor proteins such as kinesin and dynein, which facilitate the transport of cellular materials along long axons. In summary, ATP is a fundamental direct and indirect component of numerous neuronal processes. This significance prompts several questions regarding the creation and regulation of ATP, which we will examine in further detail.

Glucose Metabolism

In summary, ATP is created through several cellular processes: glycolysis, the citric acid cycle, and oxidative phosphorylation. All of these entail the oxidization of glucose, which results in the production of ATP, which occurs through a combination of glycolysis and the citric acid cycle. Glucose is the primary energy source for the adult brain; in other words, our brains have a sweet tooth. The equation for glucose oxidation is as follows: C₆H₁₂O₆ + 6 0₂ ⇒ 6 CO₂ + 6 H₂0. This equation represents the complete oxidation of glucose in which six oxygen molecules are required to oxidize one glucose molecule, resulting in a molar ratio of 6:1.

Nearly all glucose in the brain is oxidized at its resting rate, and during periods of brain activation, glucose utilization increases significantly more than oxygen consumption. The rise in cellular activity associated with specific brain functions heightens the local demand for ATP, stimulating the flux of metabolic pathways, ATP production, and blood flow to the activated tissues. Conversely, decreased activity leads to downregulation of glucose and oxygen consumption and reduced blood flow.

Glucose is transported in the bloodstream through a group of proteins known as glucose transporters (GLUT1-6). Unlike other tissues, glucose transport in the brain operates independently of insulin. The way neuronal cells absorb energy substrates varies depending on the specific type and distribution of transporters unique to each cell type. To enter the brain, GLUT1 is the primary transporter that facilitates the passage of glucose through the endothelial junctions of the blood-brain barrier (BBB) from the bloodstream.

• GLUT3 – neurons

Alternative Energy Sources

• Astrocyte-Neuron Lactate Shuttle Hypothesis
• Ketone Bodies
• Fatty Acids

Key Metabolic Pathways

Glycolysis

Glycolysis, the first stage of cellular respiration consists of 10 enzymatic reactions that extract energy by converting a glucose molecule into two three-carbon molecules known as pyruvate. The initial step involves the irreversible phosphorylation of glucose facilitated by hexokinase. This process occurs in the cytoplasm and results in a net gain of two ATP molecules for each glucose molecule metabolized, even though two ATP molecules are initially consumed. The reactions catalyzed by phosphoglycerate kinase and pyruvate kinase are responsible for the production of ATP in this pathway.

https://www.youtube.com/watch?v=BO0zL03CtDs

Glycolytic enzymes that are membrane-bound, such as hexokinase and phosphoglycerate kinase, operate alongside ion pumps (see chapter on Pumps), including Na+/K+-ATPase, H+-ATPase, and Ca2+-ATPase, all of which are directly powered by ATP. This localized ATP production through the glycolytic pathway is crucial for fulfilling high energy demands rather than relying solely on ATP generated by mitochondria elsewhere in the cell. While glycolysis yields only a tiny amount of energy compared to other metabolic pathways, it is a vital connection to various metabolic processes. For instance, pyruvate, an end product of glycolysis, acts as the starting point for the tricarboxylic acid (TCA) cycle.

• Malate-Aspartate Shuttle: metabolic pathway that moves electrons from the cytosol into the mitochondria

The Tricarboxylic Acid (TCA) Cycle; Citric Acid Cycle

The tricarboxylic acid (TCA) cycle, known as the Krebs cycle, constitutes the second stage of cellular respiration and occurs within the mitochondrial matrix. This localization is a primary reason for the mitochondria’s designation as the “powerhouse of the cell.” The principal function of the TCA cycle is to generate high-energy electron carriers, specifically nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH₂), through a series of enzymatic reactions. These electron carriers subsequently participate in the electron transport chain to facilitate the production of adenosine triphosphate (ATP), the principal energy currency of the cell. Furthermore, the TCA cycle produces various metabolic intermediates, such as α-ketoglutarate and oxaloacetate, which serve as precursors for vital biosynthetic processes. For instance, α-ketoglutarate is a critical precursor for glutamate, the predominant excitatory neurotransmitter in the brain, and its derivative, gamma-aminobutyric acid (GABA), is an important inhibitory neurotransmitter.

https://www.youtube.com/watch?v=rSPUYA3gWK8

The TCA cycle is initiated by the condensation of acetyl-CoA with oxaloacetate to yield citrate, a reaction catalyzed by citrate synthase. Through subsequent enzymatic transformations, citrate is converted sequentially into isocitrate, α-ketoglutarate, succinyl-CoA, succinate, fumarate, malate, and ultimately regenerates oxaloacetate. During this process, two molecules of carbon dioxide are released, alongside the production of three molecules of NADH, one molecule of FADH₂, and one molecule of guanosine triphosphate (GTP) or ATP per cycle turn.

https://www.youtube.com/watch?v=IlSFn0gRyC4

Regulation of the TCA cycle within neurons is critical to align metabolic activity with energy demands. Key regulatory enzymes, including pyruvate dehydrogenase (PDH), isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase, are pivotal control points in this metabolic pathway. PDH, for example, controls the entry of acetyl-CoA into the cycle and is subject to inhibition by elevated levels of ATP, NADH, or acetyl-CoA, thereby signaling sufficient energy availability. Conversely, calcium ions, often released during synaptic activity, activate various TCA cycle enzymes, establishing a link between energy production and neuronal firing.

• Biosynthetic pathways – neurotransmitter synthesis & repair

Oxidative Phosphorylation

The final step in energy production is cellular respiration, the primary source of ATP in neurons. Oxidative phosphorylation can be divided into two key components: the electron transport chain and chemiosmosis. As previously stated, the primary function of the TCA cycle is to generate NADH and FADH₂, which are subsequently transferred through protein complexes in the Electron Transport Chain (ETC) located in the inner mitochondrial membrane. As electrons traverse Complexes I, III, and IV, energy is released, which is then utilized to pump protons into the intermembrane space, establishing an electrochemical gradient. Oxygen acts as the final electron acceptor in Complex IV, resulting in the formation of water. This proton gradient drives ATP synthase, synthesizing ATP as protons flow back into the mitochondrial matrix.

• Reactive Oxygen Species & Antioxidant Defense – HSP70

Pentose Phosphate Shunt (PPS)

Neurons and Glial Cells

• Glycogen Storage
• Astrocytic Lactate
• Microglia
• Oligodendrocytes