Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.
Edward T. Chouchani,Edward T. Chouchani,Victoria R. Pell,Edoardo Gaude,Dunja Aksentijevic,Stephanie Y. Sundier,Ellen L. Robb,Angela Logan,Sergiy M. Nadtochiy,Emily N.J. Ord,Anthony C. Smith,Filmon Eyassu,Rachel Shirley,Chou Hui Hu,Anna J. Dare,Andrew M. James,Sebastian Rogatti,Richard C. Hartley,Simon Eaton,Ana S. H. Costa,Paul S. Brookes,Sean M. Davidson,Michael R. Duchen,Kourosh Saeb-Parsy,Michael J. Shattock,Alan J. Robinson,Lorraine M. Work,Christian Frezza,Thomas Krieg,Michael P. Murphy +29 more
TLDR
In this article, a comparative in vivo metabolomic analysis was conducted to identify widely conserved metabolic pathways responsible for mitochondrial reactive oxygen species (ROS) production during ischaemia reperfusion.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.read more
Citations
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Metabolomics: beyond biomarkers and towards mechanisms
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TL;DR: In this article, the intrinsic biochemical properties of reactive oxygen species (ROS) underlie the mechanisms that regulate various physiological functions of living organisms, and they play an essential role in regulating various physiological function.
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Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages
Evanna L. Mills,Beth Kelly,Angela Logan,Ana S. H. Costa,Mukund Varma,Clare E. Bryant,Panagiotis Tourlomousis,J. Henry M. Däbritz,Eyal Gottlieb,Isabel J. Latorre,Sinéad C. Corr,Gavin J. McManus,Dylan G. Ryan,Howard T. Jacobs,Howard T. Jacobs,Marten Szibor,Marten Szibor,Marten Szibor,Ramnik J. Xavier,Thomas Braun,Christian Frezza,Michael P. Murphy,Luke A. J. O'Neill +22 more
TL;DR: It is demonstrated that upon lipopolysaccharide stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels, and repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state.
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Metabolic reprogramming in macrophages and dendritic cells in innate immunity
Beth Kelly,Luke A. J. O'Neill +1 more
TL;DR: New insights are providing a deeper understanding of the role of metabolic reprogramming in innate immunity, and another TCA cycle intermediate, succinate, activates HIF-1α and promotes inflammatory gene expression.
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Mitochondrial TCA cycle metabolites control physiology and disease.
TL;DR: This review summarizes the mechanisms by which the abundance of different TCA cycle metabolites controls cellular function and fate in different contexts and focuses on how these metabolites mediated signaling can affect physiology and disease.
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