Journal Article

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS

Ord, Emily N. J., Shattock, Michael J., Shirley, Rachel, Eaton, Simon, Chouchani, Edward T., James, Andrew M., Costa, Ana S. H., Hu, Chou-Hui, Murphy, Michael P., Brookes, Paul S., Gaude, Edoardo, Robb, Ellen L., Nadtochiy, Sergiy M., Davidson, Sean M., Frezza, Christian, Rogatti, Sebastian, Smith, Anthony C., Work, Lorraine M., Aksentijević, Dunja, Saeb-Parsy, Kourosh, Duchen, Michael R., Sundier, Stephanie Y., Eyassu, Filmon, Hartley, Richard C., Krieg, Thomas, Robinson, Alan J., Pell, Victoria R., Logan, Angela, Dare, Anna J.

2014

Overview

A metabolomics study on the ischaemic heart identifies succinate as a metabolite that drives the production of reactive oxygen species and contributes to ischaemia-reperfusion injury; pharmacological inhibition of succinate accumulation ameliorates ischaemia-reperfusion injury in a mouse model of heart attack and a rat model of stroke. Succinate a heart breaker In this metabolomics study of the ischaemic heart, Michael Murphy and colleagues identify a metabolite that drives the production of reactive oxygen species and contributes to ischaemia reperfusion injury. They show that succinate is a conserved metabolic signature of ischaemia in several tissues. Succinate accumulates during ischaemia due to a reversal of the enzyme succinate dehydrogenase. Upon reperfusion the accumulated succinate is rapidly oxidized and drives reactive oxygen species production through reverse electron transport at mitochondrial complex I. Pharmacological blockade of succinate accumulation ameliorates ischaemia reperfusion injury in mouse models of heart attack and stroke. 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) 1 , 2 , 3 , 4 , 5 . Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion 1 , 3 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/45/320 / 64 / 64/60 / Accumulation / Adenosine Monophosphate - metabolism / Analysis / Animals / Aspartic Acid - metabolism / Carbon / Citric Acid Cycle / Dehydrogenase / Disease Models, Animal / Electron Transport / Electron Transport Complex I - metabolism / Fumarates - metabolism / Glucose / Health aspects / Heart / Humanities and Social Sciences / Ischemia - enzymology / Ischemia - metabolism / letter / Malates - metabolism / Male / Metabolism / Metabolites / Metabolomics / Mice / Mitochondria - enzymology / Mitochondria - metabolism / multidisciplinary / Myocardial Infarction - enzymology / Myocardial Infarction - metabolism / Myocardium - cytology / Myocardium - enzymology / Myocardium - metabolism / Myocytes, Cardiac - enzymology / Myocytes, Cardiac - metabolism / NAD - metabolism / Overflow / Reactive oxygen species / Reactive Oxygen Species - metabolism / Reperfusion injury / Reperfusion Injury - enzymology / Reperfusion Injury - metabolism / Science / Stroke / Stroke - enzymology / Stroke - metabolism / Succinate Dehydrogenase - metabolism / Succinates / Succinic Acid - metabolism