Succinate accumulation drives ischaemia-reperfusion injury during organ transplantation

Martin, J. et al. (2019) Succinate accumulation drives ischaemia-reperfusion injury during organ transplantation. Nature Metabolism, 1(10), pp. 966-974. (doi: 10.1038/s42255-019-0115-y)

193791.pdf - Accepted Version



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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Caldwell, Dr Stuart and Pala, Ms Laura and Hartley, Professor Richard
Authors: Martin, J., Costa, A., Gruszczyk, A., Beach, T., Allen, F., Prag, H., Hinchy, E., Mahbubani, K., Hamed, M., James, A., Krieg, T., Robinson, A., Pala, L., Hartley, R., Frezza, C., Saeb-Parsy, K., Logan, A., Caldwell, S., Huang, M., Tronci, L., Nikitopoulou, E., and Murphy, M.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Nature Metabolism
Publisher:Nature Research
ISSN (Online):2522-5812
Published Online:30 September 2019
Copyright Holders:Copyright © 2019 Springer Nature
First Published:First published in Nature Metabolism 1(10): 966-974
Publisher Policy:Reproduced in accordance with the publisher copyright policy
Data DOI:10.5525/gla.researchdata.646

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
710821'Exploring mitochondrial metabolism in health and disease using targeted biological chemistryRichard HartleyWellcome Trust (WELLCOTR)110158/Z/15/ZCHEM - CHEMISTRY