Brain Energy Metabolism Quiz

Body Function II, Lecture 1: Brain Metabolism

• Lectures: Tuesdays (13:00-14:00) and Thursdays (13:00-14:00, 15:00)
• Location: Building 4-12 (new building)
• Textbook: Slides and provided materials (check the portal)
• Instructor: George Burjanadze, PhD, TSU Assistant Professor
• Office: TSU Building XI, room 608
• Email: [email protected]
• Office Hours: By appointment
• Prerequisite: General Biochemistry and Cell Biology

Brain Metabolism (Overview)

• Objectives: Understand the primary brain energy source and factors limiting its supply. Recognize key aspects of metabolic pathways.
• Key Points:
  • The brain is a continuously active organ requiring significant energy for operation.
  • Glucose is the primary energy source (80g/day), representing 25% of total body glucose consumption.
  • Glycolysis functions at 20% capacity; TCA cycle operates near maximum capacity.
  • Ketone bodies can be helpful during starvation, but cannot fully replace glucose as an energy source in the brain.

Why Brain Needs Energy

• Maintaining ionic gradients across plasma membranes.
• Supporting various storage and transport processes.
• Producing neurotransmitters.
• Synthesizing other cellular components.

Calculated Energy Use by Brain

• SIGNALING: Consumes 75% of brain's energy. This includes:

  • Action potentials (35.3%).
  • Postsynaptic receptors(25.5%).
  • Resting potentials (9.8%).
  • Glutamate recycling (2.3%).
  • Postsynaptic Ca2+ (2.3%).

• BASIC CELLULAR ACTIVITIES: Consumes 25% of brain's energy. This includes:

  • Phospholipid turnover & membrane distribution (~5%).
  • Turnover of proteins & oligonucleotides (~2%).
  • Axoplasmic transport (*).
  • Mitochondrial proton leak (~20+).

Lipids and Proteins in the Brain

• Lipids are essential for maintaining membrane integrity in the brain, not for metabolic roles.
• Brain proteins are rapidly turned over compared to other body proteins.

Regional Differences in Cerebral Metabolic Rates (CMR)

• Different brain regions display variations in their metabolic rates.
• Metabolic activity in certain brain areas, like cortex and white matter, can be influenced by factors like stimulation or anesthesia.

Carbohydrate Metabolism

• Aerobic oxidation of glucose is the primary energy source for the brain under normal conditions.
• Brain glycogen stores are limited (~1/10th of muscle glycogen).
• Glucose crosses the blood-brain barrier (BBB) via facilitated diffusion (insulin-independent).
• Consequently, the brain is exceedingly susceptible to hypoglycemic conditions.

Glucose Phosphorylation and Glycogen

• If glucose phosphorylation is limited (low glucose concentration), astrocytic glycogenolysis provides glucosyl units to sustain ATP synthesis in glial cells.
• Glycogen can serve as an energy fuel for neurons in cases of hypoglycemia, potentially in the form of lactate. This assists in maintaining neuronal energy levels during glucose deficiency.
• Excess/sufficient glucose in the system is stored in glial glycogen.

Glucose Transport Across BBB

• Glucose transport across the BBB is mediated by specific transporter proteins, specifically Glut 1 and Glut 3.
• Glut 1 is predominantly expressed by glial cells, facilitating glucose transport into endothelial cells.
• Glut 3 is situated on neurons, transporting glucose from the extracellular fluid (ECF) into the neuronal cells.

Ketone Bodies in Starvation

• During extended starvation (more than 48 hours) and in neonates, ketones can serve as a substitute energy source for the brain.
• Specific transporters for ketones are upregulated when blood ketone levels rise.

Pentose Phosphate Pathway (PPS)

• Under basal conditions, about 5% of brain glucose is metabolized through the pentose phosphate pathway.
• PPS activity in brain is high in developing stages, peaking during myelination.
• PPS is crucial for NADPH production needed for lipid synthesis and inactivation of reactive oxygen species.
• PPS contributes to nucleotide synthesis but only minimally.

Glycerol Phosphate Dehydrogenase (GPDH)

• GPDH plays a role in glycolysis, reducing dihydroxyacetone phosphate to glycerol-3-phosphate, thereby oxidizing NADH.
• Under hypoxic conditions, glycerol-3-phosphate and lactate production amounts are initially similar but lactate production substantially surpasses glycerol-3-phosphate production.

Malate-Aspartate Shuttle

• The malate-aspartate shuttle is vital for transferring reducing equivalents from the cytosol to the mitochondria in the brain.
• The malate-aspartate shuttle is more active in neurons compared to astrocytes, reflecting glutamate synthesis and the higher concentration of aralar1 in neuronal mitochondria.
• The activity of this shuttle increases in parallel with synaptogenesis.
• This shuttle system is impacted during pathophysiological conditions like hypoxic/ischemic brain damage.

Lactate Metabolism

• Lactate formation is a characteristic feature of both aerobic and anaerobic brain conditions.
• Conversion of lactate to pyruvate via lactate dehydrogenase supports further metabolic processes of lactate, including complete TCA cycle metabolism.
• Lactate dehydrogenase (LDH) exists in multiple isoforms (LDH1-5), with varied kinetic and affinity properties.
• LDH4 and LDH5 are the primary forms in astrocytes, while LDH1 and LDH2 are dominant in neurons.
• Lactate dehydrogenase plays a role in brain lactate and NADH balance, ensuring glycolysis under hypoxic-anerobic conditions. ATP production from lactate oxidation is necessary to support neuron function.
• Upregulation of LDH in the brain may contribute in instances of thiamine deficiency.

Oxidative Decarboxylation of Pyruvate

• Pyruvate, a glycolysis-derived molecule, must enter the TCA cycle via the pyruvate dehydrogenase complex, which is located in mitochondria.
• The speed of pyruvate moving into the TCA cycle as acetyl-CoA is controlled by the PDH complex.
• The pyruvate dehydrogenase complex (PDH) is a complex-multienzyme entity that includes multiple enzymes (pyruvate decarboxylase, lipoate acetyltransferase, lipoamide dehydrogenase), along with several coenzymes (thiamine pyrophosphate, lipoic acid, CoA, FAD, and NAD+).

Pyruvate Carboxylase

• This reaction is a major anaplerotic pathway in astrocytes, replenishing the TCA cycle intermediates, and supplying the substrates needed by neurons.
• Astrocytes produce a sizable quantity of citrate via this pathway.
• This ensures the continuous production of amino acid neurotransmitters within neurons.

Citrate

• The citrate levels in cerebrospinal fluid (CSF) are comparatively higher than the levels of other TCA cycle intermediates.
• The ability of astrocytes to generate and release considerable amounts of citrate in vitro reflects the activity of pyruvate carboxylase.
• Citrate synthesis in astrocytes produces a readily releasable pool of citrate crucial for neuronal maintenance.
• Bicarbonate significantly influences the release of citrate from cerebellar astrocytes more than from cortical astrocytes, suggesting a potential role in neuronal regional specialization.
• Citrate can modulate the inhibitory effect of zinc ions on NMDA receptors.

TCA Cycle

• TCA cycle activity is intricately regulated through several enzyme steps and influenced by the cellular ADP availability, which acts as a key activator for mitochondrial respiration.
• Multiple isocitrate dehydrogenases are present—a cytoplasmic enzyme using NADP and a mitochondrial enzyme using NAD as cofactors.
• Succinate dehydrogenase is a component of the mitochondrial respiratory chain.
• Isocitrate and succinate concentrations in brain are relatively unaffected by TCA cycle flux changes when sufficient glucose is present.
• Rapid removal of oxaloacetate is maintained by citrate synthase in equilibrium conditions.
• Malate dehydrogenase (MDH). Its activity varies based on the concentration of key metabolites in the mitochondria.

Mitochondria and ATP

• Mitochondria are unevenly distributed through the CNS, predominantly concentrated in regions with high vascularity.
• ATP production in the brain is tightly regulated, especially under metabolic (e.g. hypoglycemic) deficits.
• Glucose isn't the only source of energy; other substrates may be preferentially used under specified conditions.
• Half of the terminal phosphate groups in ATP turn over approximately every 3 seconds in the brain.
• Factors like oxygenation influence the ATP production and phosphocreatine generation in brain tissue.
• The CPK system is involved in transporting and modulating energy levels, particularly notable in neurons with diverse mitochondrial distribution patterns.

Acetyl-CoA

• Acetyl coenzyme A serves as an essential precursor for acetylcholine synthesis, a key neurotransmitter.

• The generation of acetyl-CoA is impacted by glucose supply, and limitations in availability may affect acetylcholine production.

• Citrate plays a crucial export intermediary from mitochondria to the cytosol for subsequent acetyl-CoA production.

• The production of acetyl-CoA is influenced by adverse conditions (hypoglycaemia and hypoxia).

Test your knowledge on brain energy metabolism with questions about glucose transport, alternative energy sources during starvation, and the role of metabolites. This quiz covers essential concepts related to how the brain manages its energy needs under various conditions.