Publication Date:
2014-11-11
Description:
Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255242/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255242/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chouchani, Edward T -- Pell, Victoria R -- Gaude, Edoardo -- Aksentijevic, Dunja -- Sundier, Stephanie Y -- Robb, Ellen L -- Logan, Angela -- Nadtochiy, Sergiy M -- Ord, Emily N J -- Smith, Anthony C -- Eyassu, Filmon -- Shirley, Rachel -- Hu, Chou-Hui -- Dare, Anna J -- James, Andrew M -- Rogatti, Sebastian -- Hartley, Richard C -- Eaton, Simon -- Costa, Ana S H -- Brookes, Paul S -- Davidson, Sean M -- Duchen, Michael R -- Saeb-Parsy, Kourosh -- Shattock, Michael J -- Robinson, Alan J -- Work, Lorraine M -- Frezza, Christian -- Krieg, Thomas -- Murphy, Michael P -- G1100562/Medical Research Council/United Kingdom -- MC_U105663142/Medical Research Council/United Kingdom -- MC_U105674181/Medical Research Council/United Kingdom -- MC_UP_1101/3/Medical Research Council/United Kingdom -- MC_UU_12022/6/Medical Research Council/United Kingdom -- PG/07/126/24223/British Heart Foundation/United Kingdom -- PG/12/42/29655/British Heart Foundation/United Kingdom -- R01 HL071158/HL/NHLBI NIH HHS/ -- RG/12/4/29426/British Heart Foundation/United Kingdom -- British Heart Foundation/United Kingdom -- Canadian Institutes of Health Research/Canada -- Medical Research Council/United Kingdom -- England -- Nature. 2014 Nov 20;515(7527):431-5. doi: 10.1038/nature13909. Epub 2014 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK [2] Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. ; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. ; MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK. ; King's College London, British Heart Foundation Centre of Research Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK. ; Department of Cell and Developmental Biology and UCL Consortium for Mitochondrial Biology, University College London, Gower Street, London WC1E 6BT, UK. ; MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK. ; Department of Anesthesiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA. ; Institute of Cardiovascular &Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK. ; School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK. ; Unit of Paediatric Surgery, UCL Institute of Child Health, London WC1N 1EH, UK. ; Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK. ; University Department of Surgery and Cambridge NIHR Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383517" target="_blank"〉PubMed〈/a〉
Keywords:
Adenosine Monophosphate/metabolism
;
Animals
;
Aspartic Acid/metabolism
;
Citric Acid Cycle
;
Disease Models, Animal
;
Electron Transport
;
Electron Transport Complex I/metabolism
;
Fumarates/metabolism
;
Ischemia/enzymology/*metabolism
;
Malates/metabolism
;
Male
;
Metabolomics
;
Mice
;
Mitochondria/enzymology/*metabolism
;
Myocardial Infarction/enzymology/metabolism
;
Myocardium/cytology/enzymology/metabolism
;
Myocytes, Cardiac/enzymology/metabolism
;
NAD/metabolism
;
Reactive Oxygen Species/*metabolism
;
Reperfusion Injury/enzymology/*metabolism
;
Stroke/enzymology/metabolism
;
Succinate Dehydrogenase/metabolism
;
Succinic Acid/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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