Neuron Sheng Zuhang's team focuses on a new mechanism of energy metabolism in the central nervous system: revealing the transcellular transmission pathway of metabolic signals between oligodendrocytes and neuron axons

Responsibility Editor | The brain needs to consume a lot of energy in the process of maintaining normal physiological activities, which accounts for about 20%-25% of the total daily energy consumption of an individual
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Once the brain's energy supply is abnormal, it will affect basic functions such as cognition and memory in the short term, and cause irreversible nervous system damage and even nervous system diseases in the long term
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As the most basic structure of the nervous system, neuronal cells are highly dependent on ATP produced by mitochondrial oxidative phosphorylation as a source of energy due to their highly specialized structure and complex physiological functions
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Due to the slow diffusion of ATP in the long and narrow structure of axons, the energy production (bioenergetics) of axon mitochondria is essential for maintaining the energy homeostasis and physiological functions of axon ends
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The occurrence and development of a variety of neurodegenerative diseases are accompanied by abnormal axon mitochondrial energy production.
Therefore, the maintenance of neuronal axon energy supply mechanism has gradually become a frontier hotspot in the prevention and treatment of axon degeneration
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The composition of the central nervous system network is extremely complex.
Taking the human brain as an example, it contains about 86 billion neuronal cells and about 84 billion glial cells (Glial cells), which means that the energy metabolism of neuronal axons is not limited to nerves.
The regulation of the yuan itself is also affected by the surrounding glial cells
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Oligodendrocytes, as a type of glial cells, can form Myelin sheath to protect the axons of the central nervous system
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Under the condition of aglycemia, oligodendrocytes can deliver lactic acid (Lactate) to the axon as a metabolic substrate to maintain the normal energy balance in the axon
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However, under physiological conditions, oligodendrocytes regulate the production efficiency of axon mitochondria, and the way and mechanism of maintaining energy metabolism in axons are still unclear
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On September 9, 2021, the National Institutes of Health (NIH) Sheng Zuhang team published a research paper titled Oligodendrocytes Enhance Axonal Energy Metabolism by Deacetylation of Mitochondrial Proteins Through Transcellular Delivery of SIRT2 in Neuron
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This study reveals for the first time that oligodendrocytes release exosomes to transduce the deacetylase SIRT2 into mature neuron axons, regulate the acetylation level of the axon mitochondrial protein ANT1/2, and then affect axons The biological process of internal energy metabolism
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The study first used microfluidic devices to co-culture oligodendrocytes and neuronal axons in vitro
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Using the fluorescent probe GO-ATeam2 to label the ATP levels in axons in real time, it was found that the ATP levels in neuronal axons increased significantly after co-culture
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A previous article reported that oligodendrocytes can release exosomes and neurons for signal transduction.
In order to study whether oligodendrocytes regulate energy metabolism in axons by releasing exosomes, this study will purify less.
The exosomes of dendritic cells were incubated with neuronal axons, and it was found that the mitochondrial membrane potential (Mitochondrial membrane potential) and productivity efficiency of axon mitochondria increased significantly after incubation.
When exosomes were added to oligodendrocytes, the inhibition After treatment, this phenomenon was inhibited, which proved that oligodendrocytes participate in the regulation of axon mitochondrial productivity efficiency through exosomes
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By comparing the expression profiles of neurons and oligodendrocytes, it is found that the deacetylase SIRT2 is expressed at a high level in oligodendrocytes, but is almost not expressed in neurons
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Through immunoelectron microscopy (Immuno-EM) observation, the exosomes released by oligodendrocytes cultured in vitro contained SIRT2
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When oligodendrocytes knockdown (Knockdown) or knockout (Knockout, KO) SIRT2, their function of regulating neuronal axon energy metabolism is lost
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In order to find out the possible substrates of SIRT2 derived from exosomes in neuronal axon mitochondria, this study found that the acetylation levels of a series of mitochondrial energy-related proteins were different before and after incubation of exosomes through mass spectrometry analysis
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After further verification by immunoprecipitation experiments, it was found that the acetylation level of mitochondrial protein ANT1/2 (adenine nucleotide translocase 1/2) was significantly reduced after treatment with wild-type (WT)-derived exosomes
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A previous article pointed out that the deacetylated form of ANT1 can significantly improve its ADP binding ability and promote the conversion of ADP to ATP
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Therefore, this study believes that SIRT2 transported by oligodendrocyte exosomes specifically regulates the acetylation level of the axon mitochondrial protein ANT1/2, thereby increasing the efficiency of axon mitochondrial productivity
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In the spinal cord axon bundle, oligodendrocytes release exosomes containing the deacetylase SIRT2 into the gap between the myelin sheath and axons, and then into the axons
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SIRT2 derived from exosomes reduces the acetylation level of the axon mitochondrial protein ANT1/2, thereby increasing the energy production efficiency of axon mitochondria
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Finally, the study verified the important functions of exosomes released by oligodendrocytes in the body
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Immunoelectron microscopic observations showed that in wild-type mouse spinal cord axon bundles, oligodendrocytes can release SIRT2-containing exosomes into the gap between myelin sheath and axon, and then enter the axon, for the first time in the in vivo environment Prove the adjustment mechanism
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Previous studies have shown that mitochondria in the central nervous system of Sirt2 knockout mice have dysfunction
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After injecting purified oligodendrocyte exosomes into the spinal cord of Sirt2 knockout mice, it was found that wild-type exosomes can significantly increase the membrane potential of mitochondria in the spinal cord axon bundles of Sirt2 knockout mice, while Sirt2 knockout mice Except for the source of exosomes, there is no significant difference
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In addition, through immunoprecipitation testing, it was found that after injection of wild-type exosomes, the acetylation level of ANT1/2 in the spinal cord tissue of mice was significantly lower than that in the control group, further indicating that the oligodendrocytes in the central nervous system Cells play an important role in regulating the function of neuronal axons and mitochondria
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In summary, the study found that oligodendrocytes release exosomes to regulate a new model of neuronal axon mitochondrial energy production and metabolism
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As a highly efficient biological carrier, exosomes have received extensive attention in the field of cancer treatment, and their application in the field of neuro-related diseases is still in its infancy
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The research results also provide new targets and ideas for intervening the energy defects and degeneration of axons in the early stages of neurodegenerative diseases
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Researcher Sheng Zuhang is the corresponding author of the study.
The co-first authors are Dr.
Kelly Chamberlain and Dr.
Huang Ning in the laboratory of Sheng Zuhang.
Dr.
Yuxiang Xie and Dr.
Sunan Li in the laboratory also participated in this research
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The Sheng Zuhang laboratory has systematically studied the connection between neuronal axon mitochondrial transport and neurodegenerative diseases for a long time, and published a number of original works (Kang et al.
, Cell 2008; Cai et al.
, Current Biology 2012; Sun & Qiao et al.
, Cell Reports 2013; Chen & Sheng JCB 2013; Cai et al.
, Neuron 2010; Sheng & Cai, Nature Reviews Neuroscience 2012; Xie & Zhou et al.
, Neuron 2015; Lin & Cheng et al.
, Neuron 2017; Puri et al.
, Nature Communications, 2019; Roney et al.
, Developmental Cell, 2021)
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In recent years, the laboratory has taken the energy metabolism in mature neuron axons as an entry point, revealing that axonal energy homeostasis and mitochondrial transport promote neuron regeneration (Zhou et al.
, JCB 2016; Han et al.
, Cell Metabolism 2020; Huang et al.
, Current Biology 2021), an important role in maintaining synaptic function (Li et al.
, Nature Metabolism 2020)
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This time, focusing on the role of oligodendrocytes in regulating axon energy balance is another pioneering research direction in the laboratory
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To learn more about Sheng Zuhang Laboratory, please visit the laboratory homepage https://research.
ninds.
nih.
gov/sheng-lab
.

The laboratory currently recruits 2 post-doctoral fellows, and the applicants have highly motivated, independent, and career-oriented doctorate, with good academic communication and English writing skills
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Research experience with organelles and cell membrane transport; energy metabolism; mitochondrial and lysosome biology; nerve regeneration, aging, degeneration, etc.
will be given priority
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For specific research content and application methods, please visit https://research.
ninds.
nih.
gov/sheng-lab/postdoctoral-fellowship-opening
.

Original link: https://doi.
org/10.
1016/j.
neuron.
2021.
08.
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