Transcript Zhang Yufeng - USD Biology

Energy Metabolism in
Astrocytes and Neurons
Yufeng Zhang
Fuel selection
• The energy requirements of the brain are very
high
• Lipids contain more energy compare to other
substrate
• Other organs use lipids as fuel
• Fatty acid metabolism has a role in
neurodevelopment, neurotransmission, and
repair processes
Reasons for low FFA oxidation
• (i) a slow passage of fatty acids across the
blood–brain barrier (BBB)
• (ii) a low enzymatic capacity for the fatty acid
degradation
• (iii) side effects of long-chain fatty acids in the
mitochondrial ATP synthesis
BBB Permeability
• In situ perfusion technique demonstrating that
long-chain NEFA are rapidly transported
through the BBB to a large portion and with
similar rates
▫ passive transport or alternatively
▫ protein-mediated diffusion
FFA in mitochondria
• Eightfold lower than that of heart mitochondria
under comparable conditions
• High oxygen consumption with pyruvate or
glutamate as hydrogen donors, as compared
with heart and skeletal muscle mitochondria
• Low-level oxidation of long-chain fatty
attributed to
▫ low translocation rate
▫ low enzymatic capacity of the β-oxidation pathway
Harmful side effect
Other reasons
• Oxidation of Fatty Acids Increases the Tendency
of Neural Tissue to Become Hypoxic
• Increases the Risk of enhanced Oxidative Stress
• Fatty Acid Oxidation is too Slow for Matching
the ATP Requirements
Astrocyte-Neuron Metabolic
Cooperation
• Blood delivery increases with metabolic demand,
• CBF and CMRglc increase more than oxygen
utilization, and
• Both oxidative and nonoxidative processes are
involved to meet the increased metabolic
requirements
Cytoarchitectural organization of brain
• Astrocytes have emerged as active players in
brain energy delivery, production, utilization,
and storage
• Astrocytes possess unique cytoarchitectural and
phenotypic features that ideally position them to
sense their surroundings and dynamically
respond to changes in their microenvironment
Regulation
of Cerebral Blood Flow
• Astrocytes play a key role in neurovascular
coupling
▫ Coupling between neuronal activity and increased
CBF (AKA hyperemia)
▫ Essential contributors to both vasoconstriction
and vasodilation.
1) Increased astrocytic Ca++ concentrations—activation of glycolysis--elevation
of extracellular lactate --- dilation.
2) More oxygen ---astrocytic Ca2+ signals would induce a constricting tone
---keeping CBF at an appropriate lower level
Metabolic Specialization of Neurons
and Glia
• Brain dependent upon the uninterrupted supply
of energy substrates from the circulation.
• In addition to glucose, including lactate,
pyruvate, glutamate, and glutamine can also be
energy substrate
• Lactate used to be considered a metabolic dead
end
Metabolic Profile
• Neurons sustain a high rate of oxidative metabolism
compared to glial cells.
• 6-phosphofructose-2-kinase/fructose-2,6bisphosphatase-3 (Pfkfb3) is virtually absent in
neurons
▫ a potent activator of the glycolytic enzyme
phosphofructokinase-1 (PFK)
• The use of lactate – high ATP, thereby sparing
glucose for the PPP.
• Astrocytes take up glucose and characteristically
present a high glycolytic rate, end with lactate
Neurotransmitter
Recycling and Anaplerosis
• Astrocytes can rapidly remove
neurotransmitters released into the synaptic
cleft
▫ Glutamate: overstimulation of glutamate
receptors is highly toxic to neurons
• Astrocytes also play an important role in
transferring this neurotransmitter back to
neurons
Astrocyte-Neuron Lactate Shuttle
• Amount of glucose that astrocytes take up is higher
to their energy requirements
• (1) neuronal activity increases extracellular
glutamate which is avidly taken up via a Na+dependent mechanism
• (2) increase in Na+ activates the Na+/K+ ATPase
thereby increasing ATP consumption
• (3) leads to a large increase in the production of
lactate in the extracellular space
• (4) lactate can be used as an energy substrate for
neurons
Astrocytic Glycogen Metabolism
• Glycogen is the largest energy reserve of the
brain
• Glycogen has been found to be almost
exclusively localized in astrocytes
Prior to inhibitory avoidance training, rats received intrahippocampal injections of
(DAB, a potent inhibitor of glycogen phosphorylase), lactate, or antisense
oligodeoxynucleotides, as indicated. Short-term memory (STM) was assessed 1 hr
later (experiment 1), while long-term memory (LTM) formation was assessed after 1
and 7 days (experiments 2–7).
Astrocytic glycogen is more than a simple emergency reserve,
and plays an important and active role in complex brain
physiological functions, in particular through an astrocyteto-neuron transfer of energy metabolites in the form of
lactate.
Defense against Oxidative Stress
• The brain is particularly susceptible to oxidative
damage
▫ high rate of oxidative energy metabolism
▫ high unsaturated fatty acids content
▫ Relatively low intrinsic antioxidant capacity
• Astrocytes have higher levels of various
antioxidant molecules
• Neurons are dependent upon the high
antioxidant potential of astrocytes
GSH—the most abundant antioxidant molecule in the brain
neurons are highly dependent on astrocytes for the supply of the precursor amino
acids necessary for their own GSH synthesis
Metabolic Plasticity in Astrocytes
• Astrocytes have a greater metabolic plasticity
than neurons
• Any significant alteration of astrocytic pathways
caused by pathological stimuli could potentially
contribute to neuronal dysfunction
• Enhancing astrocytic functions may represent
therapeutic avenues for neurodegenerative
disease
Neuronal Excitability
• Glucose-sensing neurons increase their firing
rate in response to elevation of central glucose
levels, ultimately resulting in decreased blood
glucose and insulin levels and the suppression of
hepatic gluconeogenesis
• Orexin neurons also function as lactate sensors
• Salt-intake behavior is also influenced by
extracellular astrocyte-derived lactate
What extent neurons are fed directly
by glucose or by lactate?
• Method:
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Mixed culture of neuronal and glial cells
Probes 2-NBDG and 6-NBDG
Optical measurements
Protein extraction and Immunoblot
Conclusion
• Neural cells don’t use Fatty Acid as fuel, which
helps to protect neural cells against enhanced
oxidative stress
• Neuroenergetics has evolved from a
neurocentric view into a more integrated one in
which complementarities and cooperativities
between astrocytes and neurons.
▫ lactate shuttling from astrocytes to neurons
Thank you