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Mitochondria-ER contacts in reactive astrocytes coordinate local perivascular domains to promote vascular remodelling

Jana Goebel, Esther Engelhardt, Patric Pelzer, Vignesh Sakthivelu, Hannah M. Jahn, Milica Jevtic, Kat Folz-Donahue, Christian Kukat, Astrid Schauss, Christian K. Frese, Patrick Giavalisco, Alexander Ghanem, Karl-Klaus Conzelmann, Elisa Motori, Matteo Bergami
doi: https://doi.org/10.1101/657999
Jana Goebel
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University Hospital Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany
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Esther Engelhardt
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University Hospital Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany
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Patric Pelzer
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University Hospital Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany
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Vignesh Sakthivelu
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University Hospital Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany
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Hannah M. Jahn
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University Hospital Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany
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Milica Jevtic
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University Hospital Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany
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Kat Folz-Donahue
2Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany
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Christian Kukat
2Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany
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Astrid Schauss
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University Hospital Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany
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Christian K. Frese
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University Hospital Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany
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Patrick Giavalisco
2Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany
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Alexander Ghanem
3Max von Pettenkofer-Institute Virology, Faculty of Medicine and Gene Center, Ludwig Maximilians University Munich, Feodor-Lynen-Str. 25, D-81377 Munich, Germany
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Karl-Klaus Conzelmann
3Max von Pettenkofer-Institute Virology, Faculty of Medicine and Gene Center, Ludwig Maximilians University Munich, Feodor-Lynen-Str. 25, D-81377 Munich, Germany
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Elisa Motori
2Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany
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  • For correspondence: elisa.motori@age.mpg.de matteo.bergami@uk-koeln.de
Matteo Bergami
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University Hospital Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany
4Institute of Genetics, Zülpicher Str. 47a, D-50674, University of Cologne, Germany
5Center for Molecular Medicine, Robert-Koch-Str. 21, 50931 Cologne, Germany
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  • For correspondence: elisa.motori@age.mpg.de matteo.bergami@uk-koeln.de
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Summary

Astrocytes have emerged for playing important roles in brain tissue repair, however the underlying mechanisms remain poorly understood. We show that acute injury and blood-brain barrier disruption trigger the formation of a prominent mitochondrial-enriched compartment in astrocytic end-feet which enables vascular remodeling. Integrated imaging approaches revealed that this mitochondrial clustering is part of an adaptive response regulated by fusion dynamics. Astrocyte-specific conditional deletion of Mitofusin 2 (Mfn2) suppressed perivascular mitochondrial clustering and disrupted mitochondria-ER contact sites. Functionally, two-photon imaging experiments showed that these structural changes were mirrored by impaired mitochondrial Ca2+ uptake leading to abnormal cytosolic transients within end-feet in vivo. At the tissue level, a compromised vascular complexity in the lesioned area was restored by boosting mitochondrial-ER perivascular tethering in MFN2-deficient astrocytes. These data unmask a crucial role for mitochondrial dynamics in coordinating astrocytic local domains and have important implications for repairing the injured brain.

Footnotes

  • Figures and text have been revised to take into account new data. In addition, the title was updated.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 13, 2020.
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Mitochondria-ER contacts in reactive astrocytes coordinate local perivascular domains to promote vascular remodelling
Jana Goebel, Esther Engelhardt, Patric Pelzer, Vignesh Sakthivelu, Hannah M. Jahn, Milica Jevtic, Kat Folz-Donahue, Christian Kukat, Astrid Schauss, Christian K. Frese, Patrick Giavalisco, Alexander Ghanem, Karl-Klaus Conzelmann, Elisa Motori, Matteo Bergami
bioRxiv 657999; doi: https://doi.org/10.1101/657999
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Mitochondria-ER contacts in reactive astrocytes coordinate local perivascular domains to promote vascular remodelling
Jana Goebel, Esther Engelhardt, Patric Pelzer, Vignesh Sakthivelu, Hannah M. Jahn, Milica Jevtic, Kat Folz-Donahue, Christian Kukat, Astrid Schauss, Christian K. Frese, Patrick Giavalisco, Alexander Ghanem, Karl-Klaus Conzelmann, Elisa Motori, Matteo Bergami
bioRxiv 657999; doi: https://doi.org/10.1101/657999

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