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Global Translational Medicine Succinate metabolism in CVD

When a tissue is hypoxic, there will be SDH activity pyruvate, to cells. Recent studies have shown that MCT1
reversal; that is, it mediates the reverse production of can transfer succinate to the extracellular space through
succinate from fumarate. Following myocardial ischemia the plasma membrane of myocardium, skeletal muscle,
and hypoxia, the SDH activity in cardiomyocytes is and retina [28,29] . In addition to succinate produced by
reversed. Fumaric acid produced by aspartic acid and cells themselves, extracellular succinate uptake is another
adenosine monophosphate (AMP) metabolism generates a major source of intracellular succinate. Extracellular
large amount of succinate under the action of SDH, resulting succinate can also be absorbed and recovered by sodium-
in the accumulation of succinate in hypoxic myocardial dependent dicarboxylic acid transporters. The plasma
tissues. Following reperfusion, the accumulated succinate membrane transporter of the SLC13 family is responsible
is rapidly oxidized by normally active SDH to produce for transporting succinate from the circulation into cells
excess ROS, resulting in further damage to myocardial and regulating succinate homeostasis.
tissues .
[24]
2.6. Succinate receptor 1 (SUCNR1)
When macrophages undergo pro-inflammatory
M1 polarization, the glutamine metabolic pathway is SUCNR1 (also known as GPR91) is a G protein-coupled
activated and the expression of glutamate dehydrogenase receptor responsible for succinate signaling and is widely
is upregulated. The latter catalyzes glutamine to produce expressed in systemic cell types [30,31] . Emerging evidence
a-ketoglutarate and provides the substrate for OGDH to suggests that the succinate-SUCNR1 pathway plays an
produce succinate. Meanwhile, lipopolysaccharide (LPS) important role in regulating immune homeostasis. In
stimulation also leads to an increase in GABA levels different microenvironments, succinate activates SUCNR1,
and GABA transferase activity in macrophages. GABA which leads to different immune cell responses. Therefore,
is catalyzed by GABA transferase to produce succinic the SUCNR1 pathway can help reduce inflammatory
semialdehyde (SSA), which is subsequently converted into damage in diseased tissues. In chronic inflammation,
succinate by SSA dehydrogenase . succinate is released into the extracellular matrix as a
[25]
signaling molecule to regulate the function of other cells
2.5. Transport of succinate through the interaction with receptors.
Intracellular succinate is involved in mitochondrial TCA SUCNR1 is expressed in various cells of the immune
cycle and is incapable of crossing the cell membrane. system and plays an important role in regulating cellular
However, when there is an abrupt increase in energy demand immune homeostasis and inflammatory response.
and the energy supply cannot be maintained, the anaerobic SUCNR1 is also widely expressed in the adaptive immune
pathway will be activated, resulting in excessive lactic acid system, such as T-cells (including CD4 and CD8 T-cells)
+
+
production and cell acidification. The decrease in pH value and B-cells. Large amounts of interleukin (IL)-10 and
will lead to the protonation of succinate, which involves succinate are released as a result of the activation of
the transformation of dicarboxylate trapped in the cell into T-cells in patients with systemic lupus erythematosus.
monocarboxylate so that it can cross the cell membrane and When cocultured with B-cells, the activation of T-cells is
[32]
escape into the extracellular matrix. A specific membrane inhibited by the neutralization of SUCNR1 on B-cells .
carrier transport is required for succinate to pass through However, it remains unclear whether succinate acts
the cell membrane . The solute carrier (SLC) family synergistically with other cytokines to regulate adaptive
[26]
is composed of a large class of transmembrane solute immunity. The effect of SUCNR1 activation in innate
transporters. SLC25A10 is a mitochondrial dicarboxylate immune cells is environment dependent. For example,
carrier located on the mitochondrial membrane. It in human immature dendritic cells, SUCNR1 controls
mainly transports dicarboxylic acids, such as malic acid its chemotaxis in a succinate concentration-dependent
and succinate, from the mitochondria to the cytoplasm manner . SUCNR1 and toll-like receptor-3 (TLR-3) or
[33]
for the exchange of phosphate, sulfate, and thiosulfate, TLR-7, independent of TLR-2 or TLR-4, act in synergy,
thus providing substrates for gluconeogenesis and urea increasing the expression of pro-inflammatory cytokines,
synthesis, as well as maintaining the distribution and such as tumor necrosis factor (TNF)-α and IL-1β, leading
homeostasis of intermediate products in and out of to the enhancement of antigen presentation ability and the
the mitochondria during the TCA cycle . SLC25A10 activation of CD4 T-cells . However, the activation of
[27]
[33]
+
transports succinate from the mitochondrial matrix to SUCNR1 pathway seems to occur only in the acute phase
the cytosol, which is the first step of succinate transport to of stimulation, since SUCNR1 is rapidly downregulated
the extracellular space. Monocarboxylic acid transporter 1 following the activation of dendritic cells. In a mouse
(MCT1), a member of the SLC16 family, is a protein that experimental arthritis model, SUCNR1-mediated
transports monocarboxylic acids, such as lactic acid and chemotaxis of dendritic cells into lymph nodes in vivo

Volume 1 Issue 2 (2022) 3 https://doi.org/10.36922/gtm.v1i2.160