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dc.contributor.authorMartin, Jack Len
dc.contributor.authorCosta, Ana SHen
dc.contributor.authorGruszczyk, Anja Ven
dc.contributor.authorBeach, Timothy Een
dc.contributor.authorAllen, Fay Men
dc.contributor.authorPrag, Hiranen
dc.contributor.authorHinchy, Elizabeth Cen
dc.contributor.authorMahbubani, Krishnaaen
dc.contributor.authorHamed, Mazinen
dc.contributor.authorTronci, Lauraen
dc.contributor.authorNikitopoulou, Efterpien
dc.contributor.authorJames, Andrewen
dc.contributor.authorKrieg, Thomasen
dc.contributor.authorRobinson, Alanen
dc.contributor.authorHuang, Margaret Men
dc.contributor.authorCaldwell, Stuart Ten
dc.contributor.authorLogan, Angelaen
dc.contributor.authorPala, Lauraen
dc.contributor.authorHartley, Richard Cen
dc.contributor.authorFrezza, Christianen
dc.contributor.authorSaeb-Parsy, Kouroshen
dc.contributor.authorMurphy, Mikeen
dc.date.accessioned2019-12-04T00:30:23Z
dc.date.available2019-12-04T00:30:23Z
dc.date.issued2019-09en
dc.identifier.issn2522-5812
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/299513
dc.description.abstractDuring 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.
dc.description.sponsorshipWork 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).
dc.format.mediumPrinten
dc.languageengen
dc.publisherSpringer Science and Business Media LLC
dc.rightsAll rights reserved
dc.rights.uri
dc.subjectAnimalsen
dc.subjectSwineen
dc.subjectHumansen
dc.subjectMiceen
dc.subjectReperfusion Injuryen
dc.subjectSuccinic Aciden
dc.subjectOrgan Transplantationen
dc.titleSuccinate accumulation drives ischaemia-reperfusion injury during organ transplantation.en
dc.typeArticle
prism.endingPage974
prism.publicationDate2019en
prism.publicationNameNature metabolismen
prism.startingPage966
prism.volume1en
dc.identifier.doi10.17863/CAM.46586
dcterms.dateAccepted2019-08-16en
rioxxterms.versionofrecord10.1038/s42255-019-0115-yen
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-09en
dc.contributor.orcidCosta, Ana SH [0000-0001-8932-6370]
dc.contributor.orcidPrag, Hiran [0000-0002-4753-8567]
dc.contributor.orcidMahbubani, Krishnaa [0000-0002-1327-2334]
dc.contributor.orcidKrieg, Thomas [0000-0002-5192-580X]
dc.contributor.orcidRobinson, Alan [0000-0001-9943-0059]
dc.contributor.orcidHuang, Margaret M [0000-0001-5277-863X]
dc.contributor.orcidCaldwell, Stuart T [0000-0003-1604-3462]
dc.contributor.orcidHartley, Richard C [0000-0003-1033-5405]
dc.contributor.orcidFrezza, Christian [0000-0002-3293-7397]
dc.contributor.orcidSaeb-Parsy, Kourosh [0000-0002-0633-3696]
dc.contributor.orcidMurphy, Michael [0000-0003-1115-9618]
dc.identifier.eissn2522-5812
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NIHR BTRU-2014-10027)
pubs.funder-project-idMRC (MC_U105663142)
pubs.funder-project-idMRC (MC_EX_MR/M015769/1)
pubs.funder-project-idMRC (MC_UU_00015/3)
pubs.funder-project-idWellcome Trust (110159/Z/15/Z)
pubs.funder-project-idMRC (MR/M015769/1)
pubs.funder-project-idMedical Research Council (MC_UU_12022/6)
pubs.funder-project-idMRC (MC_U105674181)
cam.orpheus.counter2*
rioxxterms.freetoread.startdate2020-03-30


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