Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth

L. M. Schiffmann; J. P. Werthenbach; F. Heintges-Kleinhofer; J. M. Seeger; M. Fritsch; S. D. Günther; S. Willenborg; S. Brodesser; C. Lucas; C. Jüngst; M. C. Albert; F. Schorn; A. Witt; C. T. Moraes; C. J. Bruns; M. Pasparakis; M. Krönke; S. A. Eming; O. Coutelle; H. Kashkar

doi:10.1038/s41467-020-17472-2

Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth

L. M. Schiffmann, J. P. Werthenbach, F. Heintges-Kleinhofer, J. M. Seeger, M. Fritsch, S. D. Günther, S. Willenborg, S. Brodesser, C. Lucas, C. Jüngst, M. C. Albert, F. Schorn, A. Witt, C. T. Moraes, C. J. Bruns, M. Pasparakis, M. Krönke, S. A. Eming, O. Coutelle, H. Kashkar

Neurology

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

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Abstract

The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer.

Original language	English (US)
Article number	3653
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17472-2
State	Published - Dec 1 2020

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Schiffmann, L. M., Werthenbach, J. P., Heintges-Kleinhofer, F., Seeger, J. M., Fritsch, M., Günther, S. D., Willenborg, S., Brodesser, S., Lucas, C., Jüngst, C., Albert, M. C., Schorn, F., Witt, A., Moraes, C. T., Bruns, C. J., Pasparakis, M., Krönke, M., Eming, S. A., Coutelle, O., & Kashkar, H. (2020). Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth. Nature communications, 11(1), [3653]. https://doi.org/10.1038/s41467-020-17472-2

Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth. / Schiffmann, L. M.; Werthenbach, J. P.; Heintges-Kleinhofer, F.; Seeger, J. M.; Fritsch, M.; Günther, S. D.; Willenborg, S.; Brodesser, S.; Lucas, C.; Jüngst, C.; Albert, M. C.; Schorn, F.; Witt, A.; Moraes, C. T.; Bruns, C. J.; Pasparakis, M.; Krönke, M.; Eming, S. A.; Coutelle, O.; Kashkar, H.

In: Nature communications, Vol. 11, No. 1, 3653, 01.12.2020.

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

Schiffmann, LM, Werthenbach, JP, Heintges-Kleinhofer, F, Seeger, JM, Fritsch, M, Günther, SD, Willenborg, S, Brodesser, S, Lucas, C, Jüngst, C, Albert, MC, Schorn, F, Witt, A, Moraes, CT, Bruns, CJ, Pasparakis, M, Krönke, M, Eming, SA, Coutelle, O & Kashkar, H 2020, 'Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth', Nature communications, vol. 11, no. 1, 3653. https://doi.org/10.1038/s41467-020-17472-2

Schiffmann, L. M. ; Werthenbach, J. P. ; Heintges-Kleinhofer, F. ; Seeger, J. M. ; Fritsch, M. ; Günther, S. D. ; Willenborg, S. ; Brodesser, S. ; Lucas, C. ; Jüngst, C. ; Albert, M. C. ; Schorn, F. ; Witt, A. ; Moraes, C. T. ; Bruns, C. J. ; Pasparakis, M. ; Krönke, M. ; Eming, S. A. ; Coutelle, O. ; Kashkar, H. / Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth. In: Nature communications. 2020 ; Vol. 11, No. 1.

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abstract = "The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer.",

author = "Schiffmann, {L. M.} and Werthenbach, {J. P.} and F. Heintges-Kleinhofer and Seeger, {J. M.} and M. Fritsch and G{\"u}nther, {S. D.} and S. Willenborg and S. Brodesser and C. Lucas and C. J{\"u}ngst and Albert, {M. C.} and F. Schorn and A. Witt and Moraes, {C. T.} and Bruns, {C. J.} and M. Pasparakis and M. Kr{\"o}nke and Eming, {S. A.} and O. Coutelle and H. Kashkar",

note = "Funding Information: H.K. acknowledges funding from the Deutsche Krebshilfe (70112113) and the Deutsche Forschungsgemeinschaft SFB1218 (project number 269925409) and SFB1403 (project number 414786233). L.M.S and F.H.K. are supported by the Koeln Fortune Programme, Faculty of Medicine, University of Cologne. S.A.E. acknowledges funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation Project ID 73111208-SFB829, FOR2240, FOR2599 and DEBRA International). We thank Joachim G{\"o}thert (University Hospital Essen, Germany) and the Telethon Kids Institute (Subiaco, Australia) for providing the EndSCLCreERT transgenic mice and Dirk Wohlleber (Technical University of Munich, Germany) for providing the Tie2-Cre mice. We thank the CECAD Imaging Facility, University of Cologne (Head: Dr. Astrid Schauss). We thank Tanja Roth, Ali Manav, Maureen Menning and Michael Piekarek for great technical assistance. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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AU - Werthenbach, J. P.

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AU - Seeger, J. M.

AU - Fritsch, M.

AU - Günther, S. D.

AU - Willenborg, S.

AU - Brodesser, S.

AU - Lucas, C.

AU - Jüngst, C.

AU - Albert, M. C.

AU - Schorn, F.

AU - Witt, A.

AU - Moraes, C. T.

AU - Bruns, C. J.

AU - Pasparakis, M.

AU - Krönke, M.

AU - Eming, S. A.

AU - Coutelle, O.

AU - Kashkar, H.

N1 - Funding Information: H.K. acknowledges funding from the Deutsche Krebshilfe (70112113) and the Deutsche Forschungsgemeinschaft SFB1218 (project number 269925409) and SFB1403 (project number 414786233). L.M.S and F.H.K. are supported by the Koeln Fortune Programme, Faculty of Medicine, University of Cologne. S.A.E. acknowledges funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation Project ID 73111208-SFB829, FOR2240, FOR2599 and DEBRA International). We thank Joachim Göthert (University Hospital Essen, Germany) and the Telethon Kids Institute (Subiaco, Australia) for providing the EndSCLCreERT transgenic mice and Dirk Wohlleber (Technical University of Munich, Germany) for providing the Tie2-Cre mice. We thank the CECAD Imaging Facility, University of Cologne (Head: Dr. Astrid Schauss). We thank Tanja Roth, Ali Manav, Maureen Menning and Michael Piekarek for great technical assistance. Publisher Copyright: © 2020, The Author(s).

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N2 - The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer.

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Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth

Abstract

ASJC Scopus subject areas

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