Academic Journal
Succinate accumulation drives ischaemia-reperfusion injury during organ transplantation.
| Τίτλος: | Succinate accumulation drives ischaemia-reperfusion injury during organ transplantation. |
|---|---|
| Συγγραφείς: | Martin JL; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, UK., Costa ASH; MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK., Gruszczyk AV; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, UK.; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK., Beach TE; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, UK., Allen FM; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK., Prag HA; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK., Hinchy EC; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK., Mahbubani K; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, UK., Hamed M; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, UK., Tronci L; MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK., Nikitopoulou E; MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK., James AM; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK., Krieg T; Department of Medicine, University of Cambridge, Cambridge, UK., Robinson AJ; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK., Huang MM; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, UK.; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK., Caldwell ST; School of Chemistry, University of Glasgow, Glasgow, UK., Logan A; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK., Pala L; School of Chemistry, University of Glasgow, Glasgow, UK., Hartley RC; School of Chemistry, University of Glasgow, Glasgow, UK., Frezza C; MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK., Saeb-Parsy K; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, UK., Murphy MP; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK. mpm@mrc-mbu.cam.ac.uk.; Department of Medicine, University of Cambridge, Cambridge, UK. mpm@mrc-mbu.cam.ac.uk. |
| Πηγή: | Nature metabolism [Nat Metab] 2019 Sep 30; Vol. 1, pp. 966-974. |
| Τύπος έκδοσης: | Journal Article; Research Support, Non-U.S. Gov't |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Springer Nature Country of Publication: Germany NLM ID: 101736592 Publication Model: Print Cited Medium: Internet ISSN: 2522-5812 (Electronic) Linking ISSN: 25225812 NLM ISO Abbreviation: Nat Metab |
| Imprint Name(s): | Original Publication: Berlin : Springer Nature, [2019]- |
| Ιατρικοί όροι (MeSH): | Organ Transplantation*, Reperfusion Injury/*metabolism , Succinic Acid/*metabolism, Animals ; Humans ; Mice ; Swine |
| Περίληψη: | During heart transplantation, storage in cold preservation solution is thought to protect the organ by slowing metabolism; by providing osmotic support; and by minimising ischaemia-reperfusion (IR) injury upon transplantation into 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 hearts from mouse, pig, and human. We identify common metabolic alterations during WI and those affected by 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. |
| Competing Interests: | Competing interests The authors declare competing interests. MPM, TK AND RCH have submitted a patent application on the use of dimethyl malonate to prevent ischaemia reperfusion injury. |
| References: | Jahania, M. S., Sanchez, J. A., Narayan, P., Lasley, R. D. & Mentzer, R. M. Jr. Heart preservation for transplantation: principles and strategies. Ann. Thorac. Surg. 68, 1983–1987 (1999). (PMID: 10.1016/S0003-4975(99)01028-0) Southard, J. H. & Belzer, F. O. Organ preservation. Annu. Rev. Med. 46, 235–247 (1995). (PMID: 10.1146/annurev.med.46.1.235) Chouchani, E. T. et al. A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury. Cell Metab. 23, 254–263 (2016). (PMID: 10.1016/j.cmet.2015.12.009) Chouchani, E. T. et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431–435 (2014). (PMID: 10.1038/nature13909) Pagani, F. D. Use of heart donors following circulatory death: a viable addition to the heart donor pool. J. Am. Coll. Cardiol. 73, 1460–1462 (2019). (PMID: 10.1016/j.jacc.2018.12.068) Johnson, R. J., Bradbury, L. L., Martin, K. & Neuberger, J. Organ donation and transplantation in the UK-the last decade: a report from the UK national transplant registry. Transplantation 97, S1–S27 (2014). (PMID: 10.1097/01.TP.0000438215.16737.68) Chew, H. C. et al. Outcomes of donation after circulatory death heart transplantation in australia. J. Am. Coll. Cardiol. 73, 1447–1459 (2019). (PMID: 10.1016/j.jacc.2018.12.067) Dhital, K. K. et al. Adult heart transplantation with distant procurement and ex-vivo preservation of donor hearts after circulatory death: a case series. Lancet 385, 2585–2591 (2015). (PMID: 10.1016/S0140-6736(15)60038-1) Nasralla, D. et al. A randomized trial of normothermic preservation in liver transplantation. Nature 557, 50–56 (2018). (PMID: 10.1038/s41586-018-0047-9) Coffey, J. C. et al. The influence of functional warm ischemia time on DCD liver transplant recipients’ outcomes. Clin. Transplant. 31, e13068 (2017). (PMID: 10.1111/ctr.13068) Blok, J. J. et al. Longterm results of liver transplantation from donation after circulatory death. Liver Transplant. 22, 1107–1114 (2016). (PMID: 10.1002/lt.24449) Eltzschig, H. K. & Eckle, T. Ischemia and reperfusion—from mechanism to translation. Nat. Med. 17, 1391–1401 (2011). (PMID: 10.1038/nm.2507) Liu, F. & Kang, S. M. Heterotopic heart transplantation in mice. J. Vis. Exp. 6, 238 (2007). Niimi, M. The technique for heterotopic cardiac transplantation in mice: experience of 3000 operations by one surgeon. J. Heart Lung Transplant. 20, 1123–1128 (2001). (PMID: 10.1016/S1053-2498(01)00309-6) Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010). (PMID: 10.1038/nature08780) Nakahira, K. et al. Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation. PLoS Med. 10, e1001577 (2013). (PMID: 10.1371/journal.pmed.1001577) Ehinger, J. K. et al. Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency. Nat. Commun. 7, 12317 (2016). (PMID: 10.1038/ncomms12317) Valls-Lacalle, L. et al. Selective inhibition of succinate dehydrogenase in reperfused myocardium with intracoronary malonate reduces infarct size. Sci. Rep. 8, 2442 (2018). (PMID: 10.1038/s41598-018-20866-4) Valls-Lacalle, L. et al. Succinate dehydrogenase inhibition with malonate during reperfusion reduces infarct size by preventing mitochondrial permeability transition. Cardiovasc. Res. 109, 374–384 (2016). (PMID: 10.1093/cvr/cvv279) Bundgaard, A. et al. Metabolic adaptations during extreme anoxia in the turtle heart and their implications for ischemia-reperfusion injury. Sci. Rep. 9, 2850 (2019). (PMID: 10.1038/s41598-019-39836-5) Zhang, J. et al. Accumulation of succinate in cardiac ischemia primarily occurs via canonical krebs cycle activity. Cell Rep. 23, 2617–2628 (2018). (PMID: 10.1016/j.celrep.2018.04.104) Dare, A. J. et al. The mitochondria-targeted anti-oxidant MitoQ decreases ischemia-reperfusion injury in a murine syngeneic heart transplant model. J. Heart Lung Transplant. 34, 1471–1480 (2015). (PMID: 10.1016/j.healun.2015.05.007) Mackay, G. M., Zheng, L., van den Broek, N. J. & Gottlieb, E. Analysis of cell metabolism using LC-MS and isotope tracers. Meth. Enzymol. 561, 171–196 (2015). (PMID: 10.1016/bs.mie.2015.05.016) Strehler, B. L. in Methods in Enzymatic Analysis (ed. Bergmeyer, U.) 2112–2126 (Academic Press, 1974). Passonneau, J. V. & Lauderdale, V. R. A comparison of three methods of glycogen measurement in tissues. Anal. Biochem. 60, 405–412 (1974). (PMID: 10.1016/0003-2697(74)90248-6) Santos, J. H., Meyer, J. N., Mandavilli, B. S. & Van Houten, B. Quantitative PCR-based measurement of nuclear and mitochondrial DNA damage and repair in mammalian cells. Methods Mol. Biol. 314, 183–199 (2006). (PMID: 10.1385/1-59259-973-7:183) Ritchie, M. E. et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nuc. Acids Res. 43, e47 (2015). (PMID: 10.1093/nar/gkv007) |
| Grant Information: | MC_UU_12022/6 United Kingdom MRC_ Medical Research Council; 110158 United Kingdom WT_ Wellcome Trust; MC_EX_MR/M015769/1 United Kingdom MRC_ Medical Research Council; United Kingdom DH_ Department of Health; MC_U105663142 United Kingdom MRC_ Medical Research Council; MC_U105674181 United Kingdom MRC_ Medical Research Council; 110158/Z/15/Z United Kingdom WT_ Wellcome Trust; 110159 United Kingdom WT_ Wellcome Trust; MC_UU_00015/3 United Kingdom MRC_ Medical Research Council |
| Substance Nomenclature: | AB6MNQ6J6L (Succinic Acid) |
| Entry Date(s): | Date Created: 20200513 Date Completed: 20210106 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC7212038 |
| DOI: | 10.1038/s42255-019-0115-y |
| PMID: | 32395697 |
| Βάση Δεδομένων: | MEDLINE |
καταχωρήστε σχόλιο πρώτοι!