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Energy utilization by neurons in the brain and spinal cord. Neurons have a high metabolic rate and use more energy than other cells. Although the brain accounts for 2% of total body weight, it uses 20% of the body's total oxygen consumption. Most energy-requiring processes in cells use either ATP directly or energy stores indirectly derived from ATP such as ion gradients.
Ion pumping accounts for a large part of a neuron's energy requirement. The Na/K pump alone accounts for 25% to 40% of a neuron's ATP utilization. Calcium and the transport of other cations (e.g., H) or anions (Cl or HCO3) also account for significant energy utilization. Some pumping of Ca and H is coupled with Na for an energy source and depletes the Na gradient; thus, Ca and H are indirectly coupled to ATP utilization via the Na/K pump. Energy is required to pump ions from the cytosol to intracellular organelles and to pump molecules across the plasmalemma.
Transport of amino acids and other essential small molecules across the cell membranes requires energy. Glutamate and many other neurotransmitters are removed from the extracellular space by active pumps that require energy. Reduced activity of the glutamate pump can lead to excessive excitability and neuronal damage.
Neuronal structure and function require the synthesis of proteins, lipids, and carbohydrates. These substances are continually being formed, modified, and degraded and require ATP for their synthesis.
The transport of substances within cells also requires energy. Most synthesis takes place in the cell body, and an energy-dependent transport system distributes these substances to the parts of the neuron that require them. The enormity of the task is apparent when one considers the length of the axons and dendrites of a typical neuron; diffusion is not sufficient, and active transport is required.
Energy synthesis by neurons in the brain and spinal cord
Efficient ATP production from glucose requires oxygen (Figure-1).



Figure-1. Energy metabolism in the brain. Dotted lines indicate reactions that occur during ischemia. The dotted line across the oxidative phosphorylation reaction indicates that this reaction is blocked during ischemia. NAD, nicotinamide adenine dinucleotide; ADP, adenosine diphosphate; NADH, nicotinamide adenine dinucleotide, reduced form; ATP, adenosine triphosphate.
 


The major portion of energy is generated by glycolysis (breakdown of glucose), the citric acid cycle (a pathway that generates nicotinamide adenine dinucleotide, reduced form [NADH], from nicotinamide adenine dinucleotide [NAD]), and oxidative phosphorylation (coupling of the regeneration of NAD from NADH to the production of ATP). The mitochondria and oxygen are critical for the efficient production of ATP from glucose. The yield of 1 glucose is a maximum of 38 ATP molecules
C6H12O6 & + 6O2 + 38ADP + 38Pi → 6CO2 + 6H2 + 38ATP
In an actual neuron, other synthesis pathways use some of the energy and biochemical intermediates so that the average yield per glucose is between 30 to 35 ATP molecules.
In the absence of oxygen, the mitochondria cannot convert NADH to NAD and lose much of the energy of glucose oxidation. Each molecule of glucose yields only 2 ATP molecules. This is insufficient to meet the energy demands of the brain. Glucose + 2ADP + 2Pi + 2NAD → 2pyruvate + 2ATP + 2NADH → 2lactate + 2H + 2NAD. The last step is required to regenerate the NAD from NADH; no energy is obtained from this step in the absence of oxygen. The H ion generated can lead to neuronal damage under certain circumstances.
(1) High blood glucose before hypoxia or ischemia has been shown clinically and in animals to increase damage. The excess H ion production could partially explain this.
Emergency sources of energy during metabolic stress
There are two immediate sources of ATP when energy production does not meet the cell's demand for energy.
The enzyme adenylate kinase can convert adenosine diphosphate (ADP) to ATP.
ADP + ADP [left harpoon over right harpoon] ATP + AMP
When energy production recovers, this process is reversed.
Phosphocreatine (PCr) acts as a store of high-energy phosphate that can be rapidly converted to ATP. Normally there are two to three times more PCr than ATP. Nevertheless, PCr levels fall rapidly during ischemia.
PCr + ADP + H [left harpoon over right harpoon] ATP + Cr
The mechanism of energy production and its reduced usage during ischemia:
In addition to the formation of ATP from 2ADP or PCr, anaerobic glycolysis contributes to ATP maintenance. Anaerobic glycolysis leads to acidosis, which may be damaging to neurons. With ischemia that lasts for more than several minutes, ATP formation from 2ADPs and PCr is exhausted and anaerobic glycolysis continues only so long as glucose is available. Some glucose is produced from the breakdown of glycogen.
Shortly after the onset of ischemia (in about 30 seconds), spontaneous neuronal activity stops and the electroencephalogram (EEG) becomes quiet. This reduces the neuron's metabolic rate and ATP utilization.
The overall metabolic rate for the brain
The cerebral metabolic rate of awake young adults is 3.5 mL O2/100 g/minute or 5.5 mg glucose/100 g/minute. This rate is virtually identical in healthy elderly persons. Children have a higher metabolic rate, i.e., 5.2 mL O2/100 g/minute. The reason for the higher metabolic rate in children is unknown, but it may represent continuing growth and development of the nervous system.
Molecular aspects of neuronal metabolism, survival versus apoptosis
Many more neurons are formed during mammalian development than the adult organism needs. In many areas of the brain and spinal cord, 50% of the neurons die as the animal matures.
The target cells of a neuron and those cells a neuron innervates, secrete trophic factors (e.g., nerve growth factor and brain-derived neurotrophic factor) in limited quantities. If the neuron receives enough of these trophic factors, it survives; if not, it dies. Because trophic factors are limited, an average 50% of the neurons do not receive enough trophic factors and die.
Neurons also receive trophic factors from nontarget sources such as glia; this also promotes survival. The combination of trophic factors from all sources determines whether a neuron will survive or die.
The trophic factors work by binding to external receptors on membrane-spanning proteins. When their receptor is bound by a trophic factor, these proteins activate intracellular signals, which in some cases phosphorylate other intracellular proteins and alter cellular processes leading to neuronal survival (Figure-2).
One example of such binding is the tyrosine receptor kinase (trk): it binds nerve growth factor, brain-derived neurotrophic factor, or other neurotrophins, dimerizes (combines two identical molecules), and then becomes active. It adds a phosphate group onto the amino acid tyrosine of certain proteins. This addition alters the activity of these proteins and inhibits cell death pathways.



Figure-2. Trophic factors and apoptosis. A: Absence of trophic factor: caspase activation. B: Presence of trophic factor: inhibition of caspase activation. ATP, adenosine triphosphate; ADP, adenosine diphosphate.

If a cell does not receive enough trophic factor, certain proteins are not phosphorylated and a programmed cell death pathway is activated. This process is called apoptosis and causes cells to die in a way that does not cause inflammation. In the absence of trophic factor induced phosphorylation, a molecule called apoptosis activating factor 1 (Apaf-1) is activated, leading to the proteolysis of inactive procaspases to active caspases, which in turn splits other proteins and signals the cell to undergo programmed cell death (apoptosis).
During and after ischemia, hypoxia Hypoxia, or other injury, neurons can die by one of at least two pathways, necrosis or apoptosis.
Necrosis is caused by severe injury that causes neurons to swell and burst apart. In addition to causing the death of that neuron, inflammation and further cell death occur in that region of the brain.
If the injury is less severe and the neuron can recover its ability to make ATP, the neuron can activate the apoptosis pathway and die in a manner similar to the death of excess neurons during development. The advantage of this apoptosis is that the neuron does not break apart and the neurons around it are preserved, resulting in less overall brain damage.
Apoptosis is triggered by ion flux into the mitochondria through an ion channel formed from the binding of two bax protein molecules together. The ion flux leads to the release of cytochrome c, which binds to Apaf-1, activates it, and initiates the caspase cascade of apoptosis (Figure-2).

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