Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.
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.
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.|Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
Edward T
ET
Chouchani
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
Victoria R
VR
Pell
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.
Edoardo
E
Gaude
King's College London, British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
Dunja
D
Aksentijević
Department of Cell and Developmental Biology and UCL Consortium for Mitochondrial Biology, University College London, Gower Street, London WC1E 6BT, UK.
Stephanie Y
SY
Sundier
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
Ellen L
EL
Robb
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
Angela
A
Logan
Department of Anesthesiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Sergiy M
SM
Nadtochiy
Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
Emily N J
ENJ
Ord
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
Anthony C
AC
Smith
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
Filmon
F
Eyassu
Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
Rachel
R
Shirley
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
Chou-Hui
CH
Hu
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
Anna J
AJ
Dare
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
Andrew M
AM
James
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
Sebastian
S
Rogatti
School of Chemistry, University of Glasgow, Glasgow, G12 8TA, UK.
Richard C
RC
Hartley
Unit of Paediatric Surgery, UCL Institute of Child Health, London, WC1N 1EH, UK.
Simon
S
Eaton
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.
Ana S H
ASH
Costa
Department of Anesthesiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Paul S
PS
Brookes
Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.
Sean M
SM
Davidson
Department of Cell and Developmental Biology and UCL Consortium for Mitochondrial Biology, University College London, Gower Street, London WC1E 6BT, UK.
Michael R
MR
Duchen
University Department of Surgery and Cambridge NIHR Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
Kourosh
K
Saeb-Parsy
King's College London, British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
Michael J
MJ
Shattock
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
Alan J
AJ
Robinson
Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
Lorraine M
LM
Work
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.
Christian
C
Frezza
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
Thomas
T
Krieg
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
Michael P
MP
Murphy
D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D002952:Citric Acid Cycle; D004195:Disease Models, Animal; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000378:metabolism; D005650:Fumarates / Q000378:metabolism; D007511:Ischemia / Q000201:enzymology / Q000378:metabolism*; D008293:Malates / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D009203:Myocardial Infarction / Q000201:enzymology / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000201:enzymology / Q000378:metabolism*; D020521:Stroke / Q000201:enzymology / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism*
D005650:Fumarates; D008293:Malates; D017382:Reactive Oxygen Species; D009243:NAD; D001224:Aspartic Acid; D000249:Adenosine Monophosphate; C030298:malic acid; C032005:fumaric acid; D019802:Succinic Acid; D013385:Succinate Dehydrogenase; D042967:Electron Transport Complex I