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Ferrata Storti Foundation
Multiple faces of succinate beyond metabolism in blood
Franco Grimolizzi1 and Lorena Arranz1,2,3
1Stem Cell Aging and Cancer Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of Norway; 2Department of Hematology, University Hospital of North Norway and 3Young Associate Investigator, Norwegian Center for Molecular Medicine (NCMM), Tromsø, Norway
ABSTRACT
Succinate is an essential intermediate of the tricarboxylic acid cycle that exerts pleiotropic roles beyond metabolism in both physiologi- cal and pathological conditions. Recent evidence obtained in mouse models shows its essential role regulating blood cell function through var- ious mechanisms that include pseudohypoxia responses by hypoxia- inducible factor-1α activation, post-translational modifications like suc- cinylation, and communication mediated by succinate receptor 1. Hence, succinate links metabolism to processes like gene expression and intercel- lular communication. Interestingly, succinate plays key dual roles during inflammatory responses, leading to net inflammation or anti-inflamma- tion depending on factors like the cellular context. Here, we further dis- cuss current suggestions of the possible contribution of succinate to blood stem cell function and blood formation. Further study will be required in the future to better understand succinate biology in blood cells. This promising field may open new avenues to modulate inflammatory responses and to preserve blood cell homeostasis in the clinical setting.
Introduction: roles of succinate beyond metabolism
The metabolite succinate or succinic acid is at the hub of the tricarboxylic acid (TCA) cycle, and it is mainly produced by succinyl coenzyme A synthetase from succinyl coenzyme A, in a reversible reaction that generally occurs under aerobic conditions (Figure 1). Nonetheless, when cells rely on anaerobic glycolysis, like can- cer cells and certain innate immune cells upon activation, other metabolic pathways sustain succinate levels, including glutamine-dependent anerplerosis to α-ketoglu- tarate, and eventually citrate by reductive carboxylation.1 Similarly, succinate may derive from the γ-aminobutyric acid shunt pathway that correlates with levels of expression of the γ-aminobutyric acid transporters solute carrier family 6 members 12 and 13 (SLC6A12, SLC6A13).2,3 Under physiological hypoxia, low oxygen levels lead to reduced activity of succinate dehydrogenase (SDH), which metabolizes suc- cinate, and other oxygen-dependent enzymes in the electron transport chain, caus- ing succinate accumulation.4,5 Succinate functions as a competitive inhibitor for pro- lyl hydroxylase domain (PHD) proteins that are central to degradation of hypoxia- inducible factor (HIF)-1α subunit.3-6 In fact, one of the first pieces of evidence for a role of succinate in cancer development was provided by the discovery of pseudo- hypoxia, which refers to activation of hypoxia signaling pathways under normal oxygen levels. Pseudohypoxia is a typical event in tumors with mutated SDH.7
Hence, succinate functions may be classified as metabolic or non-metabolic. In mitochondria, succinate plays a crucial role in metabolism and operates in both anabolic and catabolic pathways.2,3 Mitochondria are the physiological source for succinate, but accumulated succinate may be transported to the cytosol through the dicarboxylic acid translocator in the mitochondrial inner membrane and the voltage-dependent anion channel in the outer membrane (Figure 1).6 In the cytosol, succinate plays regulatory roles beyond primary metabolism. Elevated cytosolic succinate levels may promote protein post-translational modifications by addition of succinyl groups to lysine residues.8,9 A remarkable effect of succinylation is to
Haematologica 2018 Volume 103(10):1586-1592
Correspondence:
lorena.arranz@uit.no
Received: April 19, 2018. Accepted: June 27, 2018. Pre-published: June 28, 2018.
doi:10.3324/haematol.2018.196097
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/10/1586
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