Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.

TitleIschaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.
Publication TypeJournal Article
Year of Publication2014
AuthorsChouchani, ET, Pell, VR, Gaude, E, Aksentijevińá, D, Sundier, SY, Robb, EL, Logan, A, Nadtochiy, SM, Ord, ENJ, Smith, AC, Eyassu, F, Shirley, R, Hu, C-H, Dare, AJ, James, AM, Rogatti, S, Hartley, RC, Eaton, S, Costa, ASH, Brookes, PS, Davidson, SM, Duchen, MR, Saeb-Parsy, K, Shattock, MJ, Robinson, AJ, Work, LM, Frezza, C, Krieg, T, Murphy, MP
JournalNature
Volume515
Issue7527
Pagination431-5
Date Published2014 Nov 20
ISSN1476-4687
KeywordsAdenosine Monophosphate, Animals, Aspartic Acid, Citric Acid Cycle, Disease Models, Animal, Electron Transport, Electron Transport Complex I, Fumarates, Ischemia, Malates, Male, Metabolomics, Mice, Mitochondria, Myocardial Infarction, Myocardium, Myocytes, Cardiac, NAD, Reactive Oxygen Species, Reperfusion Injury, Stroke, Succinate Dehydrogenase, Succinic Acid
Abstract

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.

DOI10.1038/nature13909
Alternate JournalNature
Citation Key10.1038/nature13909
PubMed ID25383517
PubMed Central IDPMC4255242
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
MC_U105674181 / / Medical Research Council / United Kingdom
PG/12/42/29655 / / British Heart Foundation / United Kingdom
R01 HL071158 / HL / NHLBI NIH HHS / United States
/ / British Heart Foundation / United Kingdom
/ / Canadian Institutes of Health Research / Canada
/ / Medical Research Council / United Kingdom