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Succinate beyond metabolism in blood
alter the net charge of the protein by up to two charge units.8,9 Further, lysine succinylation is abundant and it induces significant structural changes in proteins,10 but its functional effects on protein and cellular functions have yet to be elucidated.
Interestingly, succinate connects intracellular metabolic status and intercellular communication, as it may be released to the extracellular space through plasma mem- brane transporters of the SLC13 family (Figure 1).11 Nevertheless, expression of these transporters on blood cells has not been well characterized. In the extracellular environment, succinate contributes to intercellular signal- ing by a receptor-mediated mechanism.12 Under steady- state conditions, circulating levels of succinate vary from 2 to 20 mM, and pro-inflammatory stimuli such as lipopolysaccharide (LPS), interleukin (IL)-8 and tumor necrosis factor (TNF)-α boost its concentration.13,14 In addi- tion, activation of succinate receptor (Figure 1) was shown to be a critical mediator of inflammatory responses acting in synergy with toll-like receptors (TLR), thereby enhanc- ing TNF-α and IL-1b expression in myeloid cells.12 Succinate further functions as chemoattractant, driving immune cell precursors from site of generation to place of
maturation.12 In humans, circulating levels of succinate increase exponentially under certain circumstances like endurance exercise (93 mM)15 and pathological conditions such as type 2 diabetes (~47 to 125 mM),16,17 obesity (~80 mM),17 and ischemia-reperfusion injury following myocar- dial infarction.18 In addition, elevated levels of circulating succinate relate to development of solid tumors and poor prognosis in a variety of hematologic malignancies.6,19 Conversely, activation of succinate receptor on neural stem cells was recently shown to promote their anti-inflamma- tory activity in an experimental model of autoimmune encephalomyelitis.20
Here, we critically assess recent advances on the role of succinate, beyond its metabolic functions, at the intersec- tion between inflammatory responses and blood cell activ- ity with the aim of identifying gaps in the literature and proposing perspectives for further research.
Succinylation and its potential immunomodulatory effects
For some time now, succinate has been known to pro-
Figure 1. Succinate production and mechanisms of action. Succinate is an intermediate of several metabolic pathways, i.e. tricarboxylic acid (TCA) cycle under nor- moxic conditions (blue lines), and glutamine-dependent anerplerosis and γ-aminobutyric acid (GABA) shunt under anaerobic conditions (red lines). Accumulation of succinate associates with succinylation, i.e. addition of succinyl group to a lysine residue of a protein. Succinate inhibits action of prolyl hydroxylases (PHD) and there- by causes stabilization of hypoxia-inducible factor-1α (HIF-1α). Succinate further inhibits several dioxygenases involved in epigenetic regulation like ten-eleven translocation methylcytosine dioxygenase (TET) and jumonji C domain-containing histone lysine demethylases (JMJD3). Dicarboxylate carriers (DIC) and voltage- dependent anion channels (VDAC) control succinate release from mitochondria to cytosol. Succinate is released to the extracellular space through sodium-coupled citrate transporters (SLC13). GPR91 is a G protein–coupled cell surface receptor for extracellular succinate (Sucnr1). ACO: aconitase; IDH: isocitrate dehydrogenase; ODC: oxoglutarate dehydrogenase; SCS: α-succinyl-CoA synthetase; SDH: succinate dehydrogenase; FUM: fumarase; MDH: malate dehydrogenase; CSY: citrate syn- thase; GS: glutamine synthetase; GOGAT: glutamine oxoglutarate aminotransferase.
haematologica | 2018; 103(10)
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