Succinate accumulation drives ischaemia-reperfusion injury during organ transplantation.
Martin, Jack L
Gruszczyk, Anja V
Beach, Timothy E
Allen, Fay M
Hinchy, Elizabeth C
Springer Science and Business Media LLC
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Martin, J. L., Costa, A. S., Gruszczyk, A. V., Beach, T. E., Allen, F. M., Prag, H., Hinchy, E. C., et al. (2019). Succinate accumulation drives ischaemia-reperfusion injury during organ transplantation.. Nature metabolism, 1 966-974. https://doi.org/10.1038/s42255-019-0115-y
During heart transplantation, storage in cold preservation solution is thought to protect the organ by slowing metabolism, providing osmotic support and minimizing ischaemia–reperfusion (IR) injury following transplantation in the recipient1,2. Despite its widespread use, our understanding of the metabolic changes prevented by cold storage and how warm ischaemia leads to damage is surprisingly poor. Here, we compare the metabolic changes during warm ischaemia (WI) and cold ischaemia (CI) in mouse, pig and human hearts. We identify common metabolic alterations during WI and CI, thereby elucidating mechanisms underlying the benefits of CI and how WI causes damage. Succinate accumulation is a major feature within ischaemic hearts across species, and CI slows succinate generation, thereby reducing tissue damage upon reperfusion caused by the production of mitochondrial reactive oxygen species (ROS)3,4. Importantly, the inevitable periods of WI during organ procurement lead to the accumulation of damaging levels of succinate during transplantation, despite cooling organs as rapidly as possible. This damage is ameliorated by metabolic inhibitors that prevent succinate accumulation and oxidation. Our findings suggest how WI and CI contribute to transplant outcome and indicate new therapies for improving the quality of transplanted organs.
Animals, Swine, Humans, Mice, Reperfusion Injury, Succinic Acid, Organ Transplantation
Work in the M.P.M. laboratory was supported by the Medical Research Council UK (MC_U105663142) and by a Wellcome Trust Investigator award (110159/Z/15/Z) to M.P.M. Work in the C.F. laboratory was supported by the Medical Research Council (MRC_MC_UU_12022/6). Work in the K.S.P. laboratory was supported by the Medical Research Council UK. Work in the RCH lab laboratory was supported by a Wellcome Trust Investigator award (110158/Z/15/Z) and a PhD studentship for .L.P from the University of Glasgow. A.V.G. was supported by a PhD studentship funded by the National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Organ Donation and Transplantation at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT).
Department of Health (via National Institute for Health Research (NIHR)) (NIHR BTRU-2014-10027)
Wellcome Trust (110159/Z/15/Z)
Medical Research Council (MC_UU_12022/6)
External DOI: https://doi.org/10.1038/s42255-019-0115-y
This record's URL: https://www.repository.cam.ac.uk/handle/1810/299513
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