Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation.
- Schlegel A Department of Surgery and Transplantation, University Hospital Zurich, Switzerland; Liver Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, UK; NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, UK.
- Muller X Department of Surgery and Transplantation, University Hospital Zurich, Switzerland.
- Mueller M Department of Surgery and Transplantation, University Hospital Zurich, Switzerland.
- Stepanova A Columbia University, Department of Pediatrics, 650 W 168th St, New York, NY 10032, U.S.A.
- Kron P Department of Surgery and Transplantation, University Hospital Zurich, Switzerland.
- de Rougemont O Department of Surgery and Transplantation, University Hospital Zurich, Switzerland.
- Muiesan P Liver Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, UK; NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, UK.
- Clavien PA Department of Surgery and Transplantation, University Hospital Zurich, Switzerland.
- Galkin A Columbia University, Department of Pediatrics, 650 W 168th St, New York, NY 10032, U.S.A.
- Meierhofer D Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Berlin, Germany.
- Dutkowski P Department of Surgery and Transplantation, University Hospital Zurich, Switzerland. Electronic address: philipp.dutkowski@usz.ch.
- 2020-09-26
Published in:
- EBioMedicine. - 2020
Complex I
FMN
Hypothermic oxygenated perfusion
Liver transplantation
Normothermic oxygenated perfusion
English
BACKGROUND
Mitochondrial succinate accumulation has been suggested as key event for ischemia reperfusion injury in mice. No specific data are however available on behavior of liver mitochondria during ex situ machine 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 organ transport. Subsequently, livers were perfused with oxygenated Belzer-MPS for 1h, at hypothermic or normothermic conditions. Various experiments were performed with supplemented succinate and/or mitochondrial inhibitors. The perfusate, liver tissues, and isolated mitochondria were analyzed by mass-spectroscopy and fluorimetry. Additionally, rat DCD livers were transplanted after 1h hypothermic or normothermic oxygenated perfusion. In parallel, perfusate samples were analysed during HOPE-treatment of human DCD livers before transplantation.
FINDINGS
Succinate exposure during rat liver perfusion triggered a dose-dependent release of mitochondrial Flavin-Mononucleotide (FMN) and NADH in perfusates under normothermic conditions. In contrast, perfusate FMN was 3-8 fold lower under hypothermic conditions, suggesting less mitochondrial injury during cold re-oxygenation compared to normothermic conditions. HOPE-treatment induced a mitochondrial reprogramming with uploading of the nucleotide pool and effective succinate metabolism. This resulted in a clear superiority after liver transplantation compared to normothermic perfusion. Finally, the degree of mitochondrial injury during HOPE of human DCD livers, quantified by perfusate FMN and NADH, was predictive for liver function.
INTERPRETATION
Mitochondrial injury determines outcome of transplanted rodent and human livers. Hypothermic oxygenated perfusion improves mitochondrial function, and allows viability assessment of liver grafts before implantation.
FUNDING
detailed information can be found in Acknowledgments.
Mitochondrial succinate accumulation has been suggested as key event for ischemia reperfusion injury in mice. No specific data are however available on behavior of liver mitochondria during ex situ machine 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 organ transport. Subsequently, livers were perfused with oxygenated Belzer-MPS for 1h, at hypothermic or normothermic conditions. Various experiments were performed with supplemented succinate and/or mitochondrial inhibitors. The perfusate, liver tissues, and isolated mitochondria were analyzed by mass-spectroscopy and fluorimetry. Additionally, rat DCD livers were transplanted after 1h hypothermic or normothermic oxygenated perfusion. In parallel, perfusate samples were analysed during HOPE-treatment of human DCD livers before transplantation.
FINDINGS
Succinate exposure during rat liver perfusion triggered a dose-dependent release of mitochondrial Flavin-Mononucleotide (FMN) and NADH in perfusates under normothermic conditions. In contrast, perfusate FMN was 3-8 fold lower under hypothermic conditions, suggesting less mitochondrial injury during cold re-oxygenation compared to normothermic conditions. HOPE-treatment induced a mitochondrial reprogramming with uploading of the nucleotide pool and effective succinate metabolism. This resulted in a clear superiority after liver transplantation compared to normothermic perfusion. Finally, the degree of mitochondrial injury during HOPE of human DCD livers, quantified by perfusate FMN and NADH, was predictive for liver function.
INTERPRETATION
Mitochondrial injury determines outcome of transplanted rodent and human livers. Hypothermic oxygenated perfusion improves mitochondrial function, and allows viability assessment of liver grafts before implantation.
FUNDING
detailed information can be found in Acknowledgments.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1016/j.ebiom.2020.103014
- PMID 32979838
- Persistent URL
- https://sonar.ch/global/documents/226323
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