Effects of O-GlcNAcylation on functional mitochondrial transfer from astrocytes
Open accessAbstract
Mitochondria may be transferred from cell to cell in the central nervous system and this process may help defend neurons against injury and disease. But how mitochondria maintain their functionality during the process of release into extracellular space remains unknown. Here, we report that mitochondrial protein O-GlcNAcylation is a critical process to support extracellular mitochondrial functionality. Activation of CD38-cADPR signaling in astrocytes robustly induced protein O-GlcNAcylation in mitochondria, while oxygen-glucose deprivation and reoxygenation showed transient and mild protein modification. Blocking the endoplasmic reticulum – Golgi trafficking with Brefeldin A or slc35B4 siRNA reduced O-GlcNAcylation, and resulted in the secretion of mitochondria with decreased membrane potential and mtDNA. Finally, loss-of-function studies verified that O-GlcNAc-modified mitochondria demonstrated higher levels of neuroprotection after astrocyte-to-neuron mitochondrial transfer. Collectively, these findings suggest that post-translational modification by O-GlcNAc may be required for supporting the functionality and neuroprotective properties of mitochondria released from astrocytes.
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The CD38-cADPR-Ca2+ signaling pathway mediates the release of extracellular vesicles containing mitochondria from astrocytes, rescuing neurons from apoptosis after oxygen-glucose deprivation.
“Furthermore, the CD38‐cADPR‐Ca2+ signaling pathway mediates the release of extracellular vesicles containing mitochondria from astrocytes, rescuing neurons from apoptosis after oxygen–glucose deprivation [60].”
From Aerobic exercise improves astrocyte mitochondrial quality and transfer to neurons in a mouse model of Alzheimer's disease (2025) · cites this paper as [60]
The O-GlcNA cycle is involved in maintaining extracellular mitochondrial function during and after intercellular mitochondrial transfer.
“It has been reported that the O‐GlcNA cycle is involved in maintaining extracellular mitochondrial function during and after intercellular mitochondrial transfer [60].”
From Aerobic exercise improves astrocyte mitochondrial quality and transfer to neurons in a mouse model of Alzheimer's disease (2025) · cites this paper as [60]
CD38 plays a crucial role in mediating mitochondrial release and enhances the expression of the O-GlcNA cycle.
“CD38 plays a crucial role in mediating mitochondrial release and also enhances the expression of the O‐GlcNA cycle [60].”
From Aerobic exercise improves astrocyte mitochondrial quality and transfer to neurons in a mouse model of Alzheimer's disease (2025) · cites this paper as [60]
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Self-citationNeuronal O-GlcNAcylation Improves Cognitive Function in the Aged Mouse Brain
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Cai, J., Chen, Y., She, Y., He, X., Feng, H., Sun, H., Yin, M., Gao, J., Sheng, C., Li, Q., et al. (2025) · Brain Pathology · doi:10.1111/bpa.13316 · Cited by 30 · see citing works
- Authors
- Park, J.-H., Nakamura, Y., Li, W., Hamanaka, G., Arai, K., Lo, E. H., & Hayakawa, K.
- Affiliations
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
- Harvard University (US)
- Corresponding author
- Hayakawa, Kazuhide
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2020-11-05
- Volume
- 41
- Issue
- 7
- Pages
- 1523-1535
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC8221762
- OpenAlex
- W3097355334
- Cited by
- 42
- References
- 7
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 5 · 2023: 6 · 2022: 7 · 2021: 5 · 2020: 1
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS094756)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- O-GlcNAcylation, mitochondrial transfer, astrocytes, extracellular mitochondria, mitochondrial membrane potential, mitochondrial DNA, brefeldin A, neuroprotection, oxygen-glucose deprivation, reoxygenation, post-translational modification
- MeSH terms
- Neuroprotection, Acetylglucosamine, Animals, Astrocytes, Membrane Potentials, Mice, Inbred C57BL, Mitochondria, Protein Processing, Post-Translational, Rats, Sprague-Dawley, N-Acetylglucosaminyltransferases, Mitochondrial Proteins, Mice, Rats
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