Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging

Gopal V. Velmurugan; Hemendra J. Vekaria; Samir P. Patel; Patrick G. Sullivan; W. Brad Hubbard

doi:10.1177/0271678X241306054

Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

Intercellular mitochondrial transfer (IMT) is an intriguing biological phenomenon where mitochondria are transferred between different cells and notably, cell types. IMT is physiological, occurring in normal conditions, but also is utilized to deliver healthy mitochondria to cells in distress. Transferred mitochondria can be integrated to improve cellular metabolism, and mitochondrial function. Research on the mitochondrial transfer axis between astrocytes and brain capillaries in vivo is limited by the cellular heterogeneity of the neurovascular unit. To this end, we developed an inducible mouse model that expresses mitochondrial Dendra2 only in astrocytes and then isolated brain capillaries to remove all intact astrocytes. This method allows the visualization of in vivo astrocyte- endothelial cell (EC) and astrocyte-pericyte IMT. We demonstrate evidence of astrocyte-EC and astrocyte-pericyte mitochondrial transfer within brain capillaries. We also show that healthy aging enhances mitochondrial transfer from astrocytes to brain capillaries, revealing a potential link between brain aging and cellular mitochondrial dynamics. Finally, we observe that astrocyte-derived extracellular vesicles transfer mitochondria to brain microvascular endothelial cells, showing the potential route of in vivo IMT. These results represent a breakthrough in our understanding of IMT in the brain and a new target in brain aging and neurovascular metabolism.

Original language	English
Pages (from-to)	418-429
Number of pages	12
Journal	Journal of Cerebral Blood Flow and Metabolism
Volume	46
Issue number	2 Special Issue: Extracellular vesicles and mitochondria in C...
DOIs	https://doi.org/10.1177/0271678X241306054
State	Published - Feb 2026

Bibliographical note

Publisher Copyright:
© The Author(s) 2024. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The studies were supported by NIH P20 GM148326 (PGS/WBH). This research was supported in part by IK2 BX004618 (WBH) from BLR&D of the Department of Veterans Affairs and HT9425-24-1-0301 from the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense Epilepsy Research Program. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States government. We would like to thank Dr. Josh Morganti (University of Kentucky) for kindly providing pair of Aldh 1l1 Cre-ER mice to cross with our mtD2f/fmice. We would also like to acknowledge Dr. Alexander Rabchevsky for his intellectual input in this research. Also, we would like to thank Spinal Cord and Brain Injury Research Center (SCoBIRC) and Light Microscopy Core, University of Kentucky for providing confocal imaging and image processing facility. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The studies were supported by NIH P20 GM148326 (PGS/WBH). This research was supported in part by IK2 BX004618 (WBH) from BLR&D of the Department of Veterans Affairs and HT9425-24-1-0301 from the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense Epilepsy Research Program. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States government. Acknowledgements

Funders	Funder number
University of Kentucky
Department of Defense Epilepsy Research Program
Brain Injury Research Center Endowment
National Institutes of Health (NIH)	P20 GM148326, IK2 BX004618
U.S. Department of Veterans Affairs	HT9425-24-1-0301

Keywords

Mitochondrial transfer
aging
astrocyte EV-mito
brain capillaries
capillary isolation

ASJC Scopus subject areas

Neurology
Clinical Neurology
Cardiology and Cardiovascular Medicine

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10.1177/0271678X241306054

Cite this

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title = "Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging",

abstract = "Intercellular mitochondrial transfer (IMT) is an intriguing biological phenomenon where mitochondria are transferred between different cells and notably, cell types. IMT is physiological, occurring in normal conditions, but also is utilized to deliver healthy mitochondria to cells in distress. Transferred mitochondria can be integrated to improve cellular metabolism, and mitochondrial function. Research on the mitochondrial transfer axis between astrocytes and brain capillaries in vivo is limited by the cellular heterogeneity of the neurovascular unit. To this end, we developed an inducible mouse model that expresses mitochondrial Dendra2 only in astrocytes and then isolated brain capillaries to remove all intact astrocytes. This method allows the visualization of in vivo astrocyte- endothelial cell (EC) and astrocyte-pericyte IMT. We demonstrate evidence of astrocyte-EC and astrocyte-pericyte mitochondrial transfer within brain capillaries. We also show that healthy aging enhances mitochondrial transfer from astrocytes to brain capillaries, revealing a potential link between brain aging and cellular mitochondrial dynamics. Finally, we observe that astrocyte-derived extracellular vesicles transfer mitochondria to brain microvascular endothelial cells, showing the potential route of in vivo IMT. These results represent a breakthrough in our understanding of IMT in the brain and a new target in brain aging and neurovascular metabolism.",

keywords = "Mitochondrial transfer, aging, astrocyte EV-mito, brain capillaries, capillary isolation",

author = "Velmurugan, \{Gopal V.\} and Vekaria, \{Hemendra J.\} and Patel, \{Samir P.\} and Sullivan, \{Patrick G.\} and Hubbard, \{W. Brad\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).",

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Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging. / Velmurugan, Gopal V.; Vekaria, Hemendra J.; Patel, Samir P. et al.
In: Journal of Cerebral Blood Flow and Metabolism, Vol. 46, No. 2 Special Issue: Extracellular vesicles and mitochondria in C..., 02.2026, p. 418-429.

Research output: Contribution to journal › Article › peer-review

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T1 - Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging

AU - Velmurugan, Gopal V.

AU - Vekaria, Hemendra J.

AU - Patel, Samir P.

AU - Sullivan, Patrick G.

AU - Hubbard, W. Brad

N1 - Publisher Copyright: © The Author(s) 2024. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).

PY - 2026/2

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N2 - Intercellular mitochondrial transfer (IMT) is an intriguing biological phenomenon where mitochondria are transferred between different cells and notably, cell types. IMT is physiological, occurring in normal conditions, but also is utilized to deliver healthy mitochondria to cells in distress. Transferred mitochondria can be integrated to improve cellular metabolism, and mitochondrial function. Research on the mitochondrial transfer axis between astrocytes and brain capillaries in vivo is limited by the cellular heterogeneity of the neurovascular unit. To this end, we developed an inducible mouse model that expresses mitochondrial Dendra2 only in astrocytes and then isolated brain capillaries to remove all intact astrocytes. This method allows the visualization of in vivo astrocyte- endothelial cell (EC) and astrocyte-pericyte IMT. We demonstrate evidence of astrocyte-EC and astrocyte-pericyte mitochondrial transfer within brain capillaries. We also show that healthy aging enhances mitochondrial transfer from astrocytes to brain capillaries, revealing a potential link between brain aging and cellular mitochondrial dynamics. Finally, we observe that astrocyte-derived extracellular vesicles transfer mitochondria to brain microvascular endothelial cells, showing the potential route of in vivo IMT. These results represent a breakthrough in our understanding of IMT in the brain and a new target in brain aging and neurovascular metabolism.

AB - Intercellular mitochondrial transfer (IMT) is an intriguing biological phenomenon where mitochondria are transferred between different cells and notably, cell types. IMT is physiological, occurring in normal conditions, but also is utilized to deliver healthy mitochondria to cells in distress. Transferred mitochondria can be integrated to improve cellular metabolism, and mitochondrial function. Research on the mitochondrial transfer axis between astrocytes and brain capillaries in vivo is limited by the cellular heterogeneity of the neurovascular unit. To this end, we developed an inducible mouse model that expresses mitochondrial Dendra2 only in astrocytes and then isolated brain capillaries to remove all intact astrocytes. This method allows the visualization of in vivo astrocyte- endothelial cell (EC) and astrocyte-pericyte IMT. We demonstrate evidence of astrocyte-EC and astrocyte-pericyte mitochondrial transfer within brain capillaries. We also show that healthy aging enhances mitochondrial transfer from astrocytes to brain capillaries, revealing a potential link between brain aging and cellular mitochondrial dynamics. Finally, we observe that astrocyte-derived extracellular vesicles transfer mitochondria to brain microvascular endothelial cells, showing the potential route of in vivo IMT. These results represent a breakthrough in our understanding of IMT in the brain and a new target in brain aging and neurovascular metabolism.

KW - Mitochondrial transfer

KW - aging

KW - astrocyte EV-mito

KW - brain capillaries

KW - capillary isolation

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JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

IS - 2 Special Issue: Extracellular vesicles and mitochondria in C...

ER -

Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging

Abstract

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