Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS

By Edward T. Chouchani, V. Pell, E. Gaude, D. Aksentijević, Stephanie Y. Sundier, Ellen L. Robb, A. Logan, S. Nadtochiy, E. N. Ord, Anthony C. Smith and 19 more. Nature, 2014

2,574 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/1fc086b68113dde931901a5c8b20405d7e6f413d

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In Molecular Biology

1. D. Granger
2. P. Kvietys
3. Rong Tian
4. Thomas Braun
5. David S. Wishart
6. Eyal Gottlieb
7. M. Murphy
8. M. Santoro

Citations in the corpus

• A randomized trial of normothermic preservation in liver transplantation (2018, background): “This has been demonstrated through the replenishment of ATP levels [11] which in turn contributes to a reduction in the severity of ischaemia-reperfusion injury experienced after transplantation [5, 10].”
• CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis (2016, background): “perfusion injury (53)dconverge on insufficient mitochondrial energy output and contractile failure as the basic mechanism.”
• ROS homeostasis and metabolism: a dangerous liason in cancer cells (2016, background): “More recent evidence indicates that this pathway is also crucial for redox balance.(115,116) With this respect, the mitochondria have been shown to have a prominent role.”
• Metabolomics for Investigating Physiological and Pathophysiological Processes. (2019, background): “This has led to a number of targeted metabolomic studies aimed at identifying previously unsuspected roles for these organic acid hormones in thermogenesis (325), macrophage activation (282), T cell proliferation (63), ischemic injury (85), and obesity (525).”
• T cell metabolism drives immunity (2015, background): “This leads to overreduction of the electron carrier coenzyme Q, causing reverse electron transport through mitochondrial complex I and, subsequently, excessive ROS production (Chouchani et al., 2014; O’Neill, 2014).”
• Mitochondrial dysfunction in pathophysiology of heart failure (2018, background): “Inhibition of ATP synthase activity not only impedes ATP production but also impairs electron flow and enhances ROS emission (128, 129).”
• Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1α/Glycolysis-Dependent Axis (2020, positive): “These data indicate that RET is an important source of mtROS in CoV-2-infected monocytes.”
• Reperfusion injury and reactive oxygen species: The evolution of a concept (2015, background): “Additional support for a primary role for ETC complexes in initiating mitochondrial ROS production stems from a metabolomic analysis of various tissues subjected to ischemia [149].”
• Ischemia/Reperfusion (2016, neutral): “electron transport at mitochondrial complex I (145, 146).”
• Mitochondrial dysfunction: mechanisms and advances in therapy (2024, background): “17,213 In the ischemic state, there is a reversal in the function of the succinate dehydrogenase complex (Complex II), which, by utilizing aspartate as a carbon source, increases the biosynthesis of succinate.”