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Editor | xi In the human brain, approximately 86 billion neurons form a complex neural network to communicate information through synapses
.
When the nerve impulse is transmitted to the presynaptic terminal, the presynaptic membrane excites the action potential to generate and cause calcium ion influx, which triggers the fusion of synaptic vesicles with the cell membrane and releases neurotransmitters
.
This process needs to consume a lot of cellular energy in the form of ATP molecules
.
Due to the highly polarized structure of neurons, the ATP produced in the cell body cannot be transmitted to the distal synapse through molecular diffusion to provide energy for nerve conduction
.
Therefore, presynaptic local energy metabolism plays an important role in maintaining nerve conduction function
.
In addition, synaptic function will change according to the intensity of different nerve stimulation
.
In order to adapt to the increased energy demand caused by changes in synaptic function, presynaptic energy metabolism must be adjusted rapidly to maintain the effectiveness and plasticity of nerve conduction
.
Therefore, studying local energy metabolism at presynapses is an important frontier research field
.
However, this field is often overlooked in classic neuroscience textbooks
.
On November 15, 2021, Sunan Li and Zu-Hang Sheng from the National Institutes of Health published a long review on Nature Reviews Neuroscience entitled Energy matters: presynaptic metabolism and the maintenance of synaptic transmission
.
This article discusses in depth the mechanism of local energy metabolism (glycolysis and mitochondrial oxidative phosphorylation), and the important role of energy levels in maintaining and regulating the effectiveness and plasticity of synaptic transmission, and proposes synaptic energy for the first time A new concept of metabolism (Synaptoenergetics)
.
1.
During the presynaptic local energy metabolism process, neuronal energy is provided by approximately 7% glycolysis and 93% mitochondrial oxidative phosphorylation
.
Glycolysis converts glucose, the main energy source of the brain, into pyruvate and produces two ATP molecules
.
Pyruvate is then transported to the mitochondria and generates ~32 ATP molecules through an oxidative phosphorylation reaction
.
In the resting state, the rapid but inefficient ATP production method of glycolysis is sufficient to maintain basic action potentials and synaptic functions
.
When neurons are stimulated more strongly, high-intensity neural activity imposes a heavier presynaptic local energy metabolism burden
.
At this time, neurons increase the level of glycolysis by increasing presynaptic glucose uptake and forming a metabolon on the surface of synaptic vesicles rich in key enzymes of the glycolysis pathway
.
Glycolysis, as a rapid energy supply pathway, is an important way for neurons to cope with local presynaptic energy metabolism pressure
.
However, the rapid but inefficient production of ATP by glycolysis determines that it cannot independently support the stable energy supply required for high-intensity nerve conduction activities
.
Mitochondrial oxidative phosphorylation, as an efficient ATP synthesis pathway, can provide a stable energy source to ensure high-intensity nerve conduction activities
.
When neurons are stimulated with high intensity, the presynaptic nodules (boutons) without mitochondria support will have more obvious energy deficiency and synaptic vesicle circulation disorders, which reflects the importance of mitochondria in maintaining stable presynaptic energy metabolism.
Role
.
Neurons meet the energy requirements of high-intensity synaptic activity by increasing the function of mitochondria and their density in the presynaptic nodules
.
On the one hand, the influx of calcium ions caused by high-intensity stimulation into the mitochondrial matrix leads to increased mitochondrial protein expression levels and ultrastructural changes (the surface area, density, and number of crest membranes)
.
These changes can increase oxygen intake and cytochrome oxidase activity, and increase the efficiency of mitochondrial energy production
.
On the other hand, synaptic activity can enrich more mitochondria to the presynaptic nodules to participate in local energy supply
.
High-intensity neural activity activates calcium signals and energy metabolism pathways, and then combines tubulin and microfilament proteins to anchor the moving mitochondria to the presynaptic nodules to support local energy metabolism, thereby ensuring sufficient ATP energy supply to maintain high-intensity synapses Transmission and plasticity
.
2.
Energy metabolism regulating synaptic transmission function AMPK is one of the core molecules regulating bioenergy metabolism in cells
.
High-intensity synaptic activity consumes a lot of energy, leading to an increase in the local AMP/ATP ratio before synapses and activating the AMPK signaling pathway
.
AMPK pathway activation can increase the translocation of glucose transporters to the surface of the presynaptic membrane to promote glucose uptake, and it also recruits glycolytic metabolism compartments to increase the level of presynaptic local glycolysis
.
At the same time, activation of AMPK and downstream kinases can promote tubulin and microfilament-mediated anchoring of presynaptic mitochondria, thereby increasing the density of mitochondria in the presynaptic nodules
.
In addition, the increase in glucose levels caused by AMPK activation can also glycosylate microtubule-mediated molecules to regulate presynaptic mitochondrial localization
.
By regulating the three aspects of glucose, glycolysis and mitochondria, the activation of the AMPK signaling pathway guarantees the presynaptic local energy demand under high-intensity neural activity to the greatest extent
.
3.
The important role of presynaptic local energy metabolism disorders in neurological diseases.
In recent years, energy metabolism has played an important role in major neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
An important role in the course of the disease is gradually being discovered
.
Although there is evidence that glucose intake and glycolysis efficiency are significantly reduced in neurodegenerative brain regions, it is limited to the technical bottleneck of real-time imaging and quantitative analysis of ATP dynamics in vivo to observe local presynaptic glycolysis levels The role in disease development remains a major challenge
.
At present, a large amount of experimental evidence is centered on the role of mitochondrial-related metabolic regulation in the early development of the disease
.
Both clinical and laboratory evidence indicate that disease-causing gene mutations can lead to abnormalities in the morphology and function of presynaptic mitochondria, as well as the loss of presynaptic mitochondrial positioning caused by abnormal mitochondrial axon transport
.
In addition, a number of studies have revealed that abnormal presynaptic energy metabolism is also related to the development of neurodevelopmental disorders and psychiatric diseases
.
These research evidences laid the foundation for the development of new treatment strategies related to energy metabolism in the future
.
Concluding remarks In summary, presynaptic local energy metabolism is closely related to the maintenance of nerve conduction activities, and energy metabolism disorders play an important role in the development of neurological diseases
.
This review lays the foundation for the in-depth study of presynaptic energy metabolism (Synaptoenergetics), and also opens up new research directions for synaptic conduction and plasticity, as well as the regulation and maintenance of brain neural network activities
.
The laboratory is currently recruiting postdoctoral fellows.
For specific research content and application methods, please visit https://research.
ninds.
nih.
gov/sheng-lab/postdoctoral-fellowship-opening attached to the recent work of the Sheng Zuhang team: 1.
(2020) Cell Metabolism | Xu Xiaoming/Sheng Zuhang team's joint research results improve energy supply and help spinal cord injury recovery 2.
(2020) Nat Metab | Sheng Zuhang team reveals a new mechanism for mitochondria to participate in the regulation of presynaptic energy metabolism 3.
(2021) Dev Cell | Sheng Zuhang team reveals nerve cells The neurodegenerative pathogenic mechanism of lysosomal transport disorder in Niemann-Pick disease type C 4.
(2021) Current Biology | Sheng Zuhang's team reveals that neuronal axon injury response signals regulate energy metabolism and promote survival and regeneration after injury Mechanism 5.
(2021) Neuron | Sheng Zuhang's team focuses on a new mechanism of energy metabolism in the central nervous system: revealing the cross-cellular transmission pathway of metabolic signals between oligodendrocytes and neuron axons.
Original link: https:// /articles/s41583-021-00535-8 Plate maker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated.
.
.
When the nerve impulse is transmitted to the presynaptic terminal, the presynaptic membrane excites the action potential to generate and cause calcium ion influx, which triggers the fusion of synaptic vesicles with the cell membrane and releases neurotransmitters
.
This process needs to consume a lot of cellular energy in the form of ATP molecules
.
Due to the highly polarized structure of neurons, the ATP produced in the cell body cannot be transmitted to the distal synapse through molecular diffusion to provide energy for nerve conduction
.
Therefore, presynaptic local energy metabolism plays an important role in maintaining nerve conduction function
.
In addition, synaptic function will change according to the intensity of different nerve stimulation
.
In order to adapt to the increased energy demand caused by changes in synaptic function, presynaptic energy metabolism must be adjusted rapidly to maintain the effectiveness and plasticity of nerve conduction
.
Therefore, studying local energy metabolism at presynapses is an important frontier research field
.
However, this field is often overlooked in classic neuroscience textbooks
.
On November 15, 2021, Sunan Li and Zu-Hang Sheng from the National Institutes of Health published a long review on Nature Reviews Neuroscience entitled Energy matters: presynaptic metabolism and the maintenance of synaptic transmission
.
This article discusses in depth the mechanism of local energy metabolism (glycolysis and mitochondrial oxidative phosphorylation), and the important role of energy levels in maintaining and regulating the effectiveness and plasticity of synaptic transmission, and proposes synaptic energy for the first time A new concept of metabolism (Synaptoenergetics)
.
1.
During the presynaptic local energy metabolism process, neuronal energy is provided by approximately 7% glycolysis and 93% mitochondrial oxidative phosphorylation
.
Glycolysis converts glucose, the main energy source of the brain, into pyruvate and produces two ATP molecules
.
Pyruvate is then transported to the mitochondria and generates ~32 ATP molecules through an oxidative phosphorylation reaction
.
In the resting state, the rapid but inefficient ATP production method of glycolysis is sufficient to maintain basic action potentials and synaptic functions
.
When neurons are stimulated more strongly, high-intensity neural activity imposes a heavier presynaptic local energy metabolism burden
.
At this time, neurons increase the level of glycolysis by increasing presynaptic glucose uptake and forming a metabolon on the surface of synaptic vesicles rich in key enzymes of the glycolysis pathway
.
Glycolysis, as a rapid energy supply pathway, is an important way for neurons to cope with local presynaptic energy metabolism pressure
.
However, the rapid but inefficient production of ATP by glycolysis determines that it cannot independently support the stable energy supply required for high-intensity nerve conduction activities
.
Mitochondrial oxidative phosphorylation, as an efficient ATP synthesis pathway, can provide a stable energy source to ensure high-intensity nerve conduction activities
.
When neurons are stimulated with high intensity, the presynaptic nodules (boutons) without mitochondria support will have more obvious energy deficiency and synaptic vesicle circulation disorders, which reflects the importance of mitochondria in maintaining stable presynaptic energy metabolism.
Role
.
Neurons meet the energy requirements of high-intensity synaptic activity by increasing the function of mitochondria and their density in the presynaptic nodules
.
On the one hand, the influx of calcium ions caused by high-intensity stimulation into the mitochondrial matrix leads to increased mitochondrial protein expression levels and ultrastructural changes (the surface area, density, and number of crest membranes)
.
These changes can increase oxygen intake and cytochrome oxidase activity, and increase the efficiency of mitochondrial energy production
.
On the other hand, synaptic activity can enrich more mitochondria to the presynaptic nodules to participate in local energy supply
.
High-intensity neural activity activates calcium signals and energy metabolism pathways, and then combines tubulin and microfilament proteins to anchor the moving mitochondria to the presynaptic nodules to support local energy metabolism, thereby ensuring sufficient ATP energy supply to maintain high-intensity synapses Transmission and plasticity
.
2.
Energy metabolism regulating synaptic transmission function AMPK is one of the core molecules regulating bioenergy metabolism in cells
.
High-intensity synaptic activity consumes a lot of energy, leading to an increase in the local AMP/ATP ratio before synapses and activating the AMPK signaling pathway
.
AMPK pathway activation can increase the translocation of glucose transporters to the surface of the presynaptic membrane to promote glucose uptake, and it also recruits glycolytic metabolism compartments to increase the level of presynaptic local glycolysis
.
At the same time, activation of AMPK and downstream kinases can promote tubulin and microfilament-mediated anchoring of presynaptic mitochondria, thereby increasing the density of mitochondria in the presynaptic nodules
.
In addition, the increase in glucose levels caused by AMPK activation can also glycosylate microtubule-mediated molecules to regulate presynaptic mitochondrial localization
.
By regulating the three aspects of glucose, glycolysis and mitochondria, the activation of the AMPK signaling pathway guarantees the presynaptic local energy demand under high-intensity neural activity to the greatest extent
.
3.
The important role of presynaptic local energy metabolism disorders in neurological diseases.
In recent years, energy metabolism has played an important role in major neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
An important role in the course of the disease is gradually being discovered
.
Although there is evidence that glucose intake and glycolysis efficiency are significantly reduced in neurodegenerative brain regions, it is limited to the technical bottleneck of real-time imaging and quantitative analysis of ATP dynamics in vivo to observe local presynaptic glycolysis levels The role in disease development remains a major challenge
.
At present, a large amount of experimental evidence is centered on the role of mitochondrial-related metabolic regulation in the early development of the disease
.
Both clinical and laboratory evidence indicate that disease-causing gene mutations can lead to abnormalities in the morphology and function of presynaptic mitochondria, as well as the loss of presynaptic mitochondrial positioning caused by abnormal mitochondrial axon transport
.
In addition, a number of studies have revealed that abnormal presynaptic energy metabolism is also related to the development of neurodevelopmental disorders and psychiatric diseases
.
These research evidences laid the foundation for the development of new treatment strategies related to energy metabolism in the future
.
Concluding remarks In summary, presynaptic local energy metabolism is closely related to the maintenance of nerve conduction activities, and energy metabolism disorders play an important role in the development of neurological diseases
.
This review lays the foundation for the in-depth study of presynaptic energy metabolism (Synaptoenergetics), and also opens up new research directions for synaptic conduction and plasticity, as well as the regulation and maintenance of brain neural network activities
.
The laboratory is currently recruiting postdoctoral fellows.
For specific research content and application methods, please visit https://research.
ninds.
nih.
gov/sheng-lab/postdoctoral-fellowship-opening attached to the recent work of the Sheng Zuhang team: 1.
(2020) Cell Metabolism | Xu Xiaoming/Sheng Zuhang team's joint research results improve energy supply and help spinal cord injury recovery 2.
(2020) Nat Metab | Sheng Zuhang team reveals a new mechanism for mitochondria to participate in the regulation of presynaptic energy metabolism 3.
(2021) Dev Cell | Sheng Zuhang team reveals nerve cells The neurodegenerative pathogenic mechanism of lysosomal transport disorder in Niemann-Pick disease type C 4.
(2021) Current Biology | Sheng Zuhang's team reveals that neuronal axon injury response signals regulate energy metabolism and promote survival and regeneration after injury Mechanism 5.
(2021) Neuron | Sheng Zuhang's team focuses on a new mechanism of energy metabolism in the central nervous system: revealing the cross-cellular transmission pathway of metabolic signals between oligodendrocytes and neuron axons.
Original link: https:// /articles/s41583-021-00535-8 Plate maker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated.
.
