title: Succinate metabolism: a new therapeutic target for myocardial reperfusion injury.
abstract: Myocardial ischaemia/reperfusion (IR) injury is a major cause of death worldwide and remains a disease for which current clinical therapies are strikingly deficient. While the production of mitochondrial reactive oxygen species (ROS) is a critical driver of tissue damage upon reperfusion, the precise mechanisms underlying ROS production have remained elusive. More recently, it has been demonstrated that a specific metabolic mechanism occurs during ischaemia that underlies elevated ROS at reperfusion, suggesting a unifying model as to why so many different compounds have been found to be cardioprotective against IR injury. This review will discuss the role of the citric acid cycle intermediate succinate in IR pathology focusing on the mechanism by which this metabolite accumulates during ischaemia and how it can drive ROS production at Complex I via reverse electron transport. We will then examine the potential for manipulating succinate accumulation and metabolism during IR injury in order to protect the heart against IR damage and discuss targets for novel therapeutics designed to reduce reperfusion injury in patients.
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Pell
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Chouchani
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Frezza
authors.affiliation: MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK tk382@medschl.cam.ac.uk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D019802:Succinic Acid / Q000378:metabolism*
chemical_list: D002317:Cardiovascular Agents; D017382:Reactive Oxygen Species; D019802:Succinic Acid; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I
keywords: Ischaemia/reperfusion; Mitochondria; Reactive oxygen species; Succinate