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  Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation

Schlegel, A., Muller, X., Mueller, M., Stepanova, A., Kron, P., de Rougemont, O., et al. (2020). Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation. EBioMedicine, 60: 103014. doi:10.1016/j.ebiom.2020.103014.

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© 2020 The Author(s)

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 Creators:
Schlegel, Andrea, Author
Muller, Xavier , Author
Mueller, Matteo , Author
Stepanova, Anna, Author
Kron, Philipp , Author
de Rougemont, Olivier, Author
Muiesan, Paolo , Author
Clavien, Pierre-Alain , Author
Galkin, Alexander , Author
Meierhofer, David1, Author           
Dutkowski, Philipp , Author
Affiliations:
1Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              

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Free keywords: FMN Complex I Hypothermic oxygenated perfusion Normothermic oxygenated perfusion Liver transplantation
 Abstract: Background:
Mitochondrial succinate accumulation has been suggested as key event for ischemia reperfusioninjury in mice. No specific data are however available on behavior of liver mitochondria duringex situmachine perfusion in clinical transplant models.
Methods:
We investigated mitochondrial metabolism of isolated perfused rat livers before transplantation.Livers were exposed to warm and cold ischemia to simulate donation after circulatory death (DCD) and organtransport. Subsequently, livers were perfused with oxygenated Belzer-MPS for 1h, at hypothermic or normo-thermic conditions. Various experiments were performed with supplemented succinate and/or mitochon-drial inhibitors. The perfusate, liver tissues, and isolated mitochondria were analyzed by mass-spectroscopyandfluorimetry. Additionally, rat DCD livers were transplanted after 1h hypothermic or normothermic oxy-genated perfusion. In parallel, perfusate samples were analysed during HOPE-treatment of human DCD liversbefore transplantation.
Findings:
Succinate exposure during rat liver perfusion triggered a dose-dependent release of mitochondrialFlavin-Mononucleotide (FMN) and NADH in perfusates under normothermic conditions. In contrast, perfus-ate FMN was 3-8 fold lower under hypothermic conditions, suggesting less mitochondrial injury during coldre-oxygenation compared to normothermic conditions. HOPE-treatment induced a mitochondrial reprog-ramming with uploading of the nucleotide pool and effective succinate metabolism. This resulted in a clearsuperiority after liver transplantation compared to normothermic perfusion. Finally, the degree of mitochon-drial injury during HOPE of human DCD livers, quantified by perfusate FMN and NADH, was predictive forliver function.
Interpretation:
Mitochondrial injury determines outcome of transplanted rodent and human livers. Hypothermicoxygenated perfusion improves mitochondrial function, and allows viability assessment of liver grafts beforeimplantation.
Funding:
detailed information can be found in Acknowledgments.

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Language(s): eng - English
 Dates: 2020-09-072020-09-24
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1016/j.ebiom.2020.103014
 Degree: -

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Title: EBioMedicine
Source Genre: Journal
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Publ. Info: Amsterdam : Elsevier
Pages: - Volume / Issue: 60 Sequence Number: 103014 Start / End Page: - Identifier: ISSN: 2352-3964
CoNE: https://pure.mpg.de/cone/journals/resource/2352-3964