brain energy metabolism

function of neurons

signal transductions (excitatory/ inhibitory)

function of astrocytes

maintain environment for generation of nerve impulse

function of oligodendrocyte

forming/ maintaining the myelin sheath

function of microglia

function as phagocytes

why brain need energy

1. receive signals (information)

2. integrates incoming signals

3. communicate signals to target cells

Energy consuming Process of the brain

1. Restoration of the membrane gradient following neuronal signal firing

2. Neurotransmitter synthesis/recycling, intracellular signaling and dendritic/axonal transport

explain how Restoration of the membrane gradient following neuronal signal firing consume energy

1. crucial for excitability

2. activity of ionic pumps fueled by ATP

3. Use 50% basal glucose oxidation in the nervous system

how Neurotransmitter synthesis/recycling, intracellular signaling and dendritic/axonal transport consume energy

1. Synthesis of neurotransmitters for communication

2. Reuptake of released neurotransmitter

3. Axonal transport of molecules. synthesised by the nucleus

4. General cellular purposes

Distribution of ATP consumption at neuronal synapses

1. Action potential 47%

2. Postsynaptic receptors 34%

3. Resting potentials 13%

4. Glu recycling 3%

5. Presynaptic Ca2+ 3%

Metabolic substrate that can pass through the blood brain barrier (BBB)

1. Glucose – almost entirely oxidized to CO2 and H2O

2. Metabolic intermediates (lactate, pyruvate)

3. Ketone bodies

Glucose is the main energy substrate for the

brain. How is glucose needed in Energy production

1. Glycolysis

2. TCA Cycle

3. Oxidative phosphorylation

4. Pentose Phosphate pathways

what channel responsible for maintenance of the membrane action potential

Na+/K+ ATPase

ATP consumption by Na+/K+ ATPase

3.2 x 108 ATP/action potential/neuron

Glucose is the main energy substrate for the brain. How is glucose needed for Neurotransmitters synthesis

glucose metabolism intermediate use for

1. GABA

2. glutamate

3. glycine

Glucose is the main energy substrate for the brain. How is glucose needed as Constituent of macromolecules

1. glycolipids

2. glycoproteins in neural cells (e.g Myelin sheath)

Glucose uptake in the brain

1. highly specified process regulated by Glucose Transporter (GLUT) subtypes

2. GLUT1 - transport through BBB into brain extracellular compartment/glial cells (mostly astrocyte)

3. GLUT3 (higher affinity for glucose) – extracellular ==> neurons

4. Astrocyte utilized glucose more than neuron in activated condition

Metabolic profile of Neuron

1. The brain uses a lot of energy through the TCA cycle and oxidative phosphorylation (OxPhos).

2. It mainly uses glucose or lactate for energy (lactate can turn into pyruvate).

3. The enzyme phosphofructokinase (PFK) works slowly because PFKB3 breaks down.

4. The brain avoids using too much glycolysis because high PFKB3 can cause oxidative stress and cell death.

5. Some glucose goes through the pentose phosphate pathway (PPP) to make NADPH for antioxidants.

6. Lactate is actually the preferred fuel.

Metabolic profile of astrocytes

1. Highly glycolytic, lower rates of oxidative metabolism

2. astrocyte is not high-oxygenconsuming cell, most glucose enter anaerobic glycolysis producing lactate

3. Immediate energy produced used for neurotransmitter re-cycling

4. Lactate sent to neurons thru. Monocarboxylate transporter (MCT)

Astrocyte in neurotransmitter recycling & Glycolysis activation

1. Rapid termination of synaptic transmission

2. Glutamate uptake by astrocyte (Na+-dependent)

3. Na+/K+ ATPase activated in astrocyte

4. Glycolysis is stimulated for ATP in astrocyte

5. 1 glutamate uptake = 3 Na+(symporter) ➔ 1 mol. glucose enters

astrocyte => 2 ATP produced

Astrocyte supporting Neuron in Metabolic interaction by

1. reuptake of the neurotransmitter

2. energy (lactate)

Glycogen metabolism

1. Glycogen - stored mainly in astrocytes, not in neuron

2. Glycogen synthase (GS) is inactive in neurone

3. Emergency energy substrate, but very limited

4. Consumed in a few minute

5. Glycogenolysis in astrocyte → produce lactate

The effect of hypoglycemia on brain energy metabolism

Compensatory mechanism

a. utilize glycogen rapidly

b. increase cerebral uptake of lactate (lactate increase 50% during hypoglycemia, MCT upregulated)

c. neuron use lactate for energy, reserve glucose for PPP and for astrocyte neurotransmitter re-uptake

d. lactate –maintain neuronal function

Failure of compensatory mechanism after hypoglycemia

hypoglycemia related consciousness disturbance/coma

can astrocyte use lactate

no

Ketone bodies as alternative energy substrate

• Ketone bodies- product of lipid breakdown

• Metabolized primarily in neurons

• Non-essential fatty acids cannot pass BBB, only essential fatty acid, but thru. special transporter.

• No b-oxidation in brain (no enzyme)

• Astrocyte converts the fatty acid to ketone bodies, while neuron/ oligodendrocytes only use ketone bodies

Particular conditions that Brain prefer ketone bodies as energy substrate:

1. Breastfed neonate

2. Starvation or prolonged exercise

3. Diabetes

explain why Breastfed neonate is one of the conditions that Brain prefer ketone bodies as energy substrate:

▪ maternal milk high in lipids (55%) than carbohydrate

▪ developmentally regulated adaptive mechanism: use ketone bodies acetoacetate & D-3-hydroxybutyrate

▪ Suckling period: ketone bodies used as energy substrate & lipogenesis (myelination)

dorg punya urine and poop bau

Metabolic intermediate as alternative energy substrate

1. Mannose

2. Lactate

how mannose can be alternative energy substrate

• Sustain normal brain function in the absence of glucose.

• Readily crosses the blood-brain barrier

• Converted to fructose-6-phosphate→ glycolysis

• However, not normally present in blood→ not physiological substrate

how lactate can be alternative energy substrate

• Limited permeability on BBB

• enter the cells through specialized monocarboxylate transporters (MCTs)

• Converted to Acetyl-CoA for energy production

• Glycolysis rate > TCA entry →pyruvate to lactate

(neuron activation)

Glucose metabolism & cerebral blood flow regulation

• Tight coupling- energy demand and supply

• Increase neural activity → increase local blood flow & glucose/oxygen utilization

• Basis for functional brain imaging techniques:

a)Positron emission tomography (PET) – metabolic rate of glucose/oxygen consumption/cerebral blood flow

b)Functional magnetic resonance imaging (fMRI)- brain oxygenation & blood volume

Metabolic failure in Alzheimer’s disease

➢Cause unknown, common cause of dementia

➢Neuropathological changes: neurofibrillary tangles(NFTs) in neuronal cytosol, amyloid deposits in extracellular

➢Biochemical characterization:

• pre-symptomatic reduction of brain glucose utilization (PET, MRI for early diagnosis)

• Decrease GLUT1/3 levels, impaired glucose metabolism due to amyloid

• Decrease glycolytic enzymes

• Increase PPP to protects against oxidant

• Mitochondrial dysfunction

carbs met

Metabolic failure in Huntington’s disease

➢autosomal dominant; Polyglutamine (PolyQ) repeat diseases

➢Neuropathological changes: cell loss in striatum, motor & cognitive

dysfunction

➢Biochemical characterization:

• pre-symptomatic reduction of brain glucose metabolism

•Decrease GLUT1/3 levels

•Increase several glycolytic enzymes, but impaired TCA cycle

•Mitochondrial dysfunctions

Metabolic failure in Parkinson’s disease

➢Uncertain etiology; mutation in several genes

➢Neuropathological changes: progressive loss of dopaminergic neurons

➢Biochemical characterization:

•Accumulation of a-synuclein (lewy bodies)

•Hypometabolism of glucose

•Decrease in oxidative phosphorylation (Complex I defect)

•Mitochondrial dysfunction ➔ metabolic failure