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Global Translational Medicine Succinate metabolism in CVD

to its receptor and regulating metabolism and immune such as succinylation, acetylation, deacetylation, and
homeostasis in various pathophysiological activities . phosphorylation, to cope with various external stimuli [12-14] .
[6]
However, the exact underlying mechanism of succinate
in CVD has not been elucidated. As a potential biomarker 2.3. Intestinal flora as a source
for CVD, succinate plays an important role in the early The intestinal flora is also an important source of succinate,
diagnosis and treatment. The role of succinate in CVD and especially in the fermentation of polysaccharides and
the available evidence, including some mechanisms, recent oligosaccharides. Microbiota-derived succinate is generally
progress, and clinical significance of succinate in CVD, is considered an intermediate product of propionate
outlined in this review. synthesis, and it accumulates less in bacteria in view of its
high utilization rate.
2. Source and metabolism of succinate
Since succinate is produced by microbiota, there are
Succinate is an important metabolic intermediate that low levels of succinate in the intestinal contents of specific
participates in various metabolic pathways, such as pathogen-free (SPF) mice and almost none in sterile
the TCA cycle and glutamine metabolism. Succinate is mice . Succinate concentrations range from 1 to 3 mM
[15]
an intermediate metabolite of the TCA cycle, located in human intestinal contents and feces, accounting for
downstream of α-ketoglutarate. The α-ketoglutarate 2 – 4% of the total organic anions in feces, which are much
dehydrogenase complex (OGDH) catalyzes the oxidative higher than the level of succinate in plasma. The high level
decarboxylation of α-ketoglutarate into succinyl-CoA. of succinate in feces implies that succinate is produced by
Under the catalysis of succinyl-CoA synthase, the sulfur microorganisms and then absorbed into the blood through
lipid bond of succinyl-CoA is broken to form succinate, the intestinal epithelium, participating in host-microbiota
in which this reaction is reversible. Subsequently, the interactions and host cell metabolism. The main source
generated succinate is oxidized into fumaric acid under of succinate in the intestine is Bacteroidetes. Bacteroides
the action of the succinate dehydrogenase complex fragilis, Prevotella copri, and Enterococcus faecalis
(SDH) . Succinate generates a large number of reactive produce succinate through the fermentation of dietary
[7]
oxygen species (ROS) in the oxidation process. This is a fiber [16,17] . Dietary fiber supplements can significantly
crucial step in the production of ATP in the TCA cycle . increase the concentration of succinate in the cecum of
[8]
mice and participate in the process of small intestinal
2.1. α-ketoglutarate dehydrogenase complex
gluconeogenesis, thus playing an important role in
OGDH is a rate-limiting enzyme in the TCA cycle. It maintaining glucose homeostasis . Succinate levels in the
[17]
consists of three enzymes (α-ketoglutarate dehydrogenase, cecum may also increase with dietary fiber supplements
dihydrolipoamide succinyltransferase, and dihydrolipoyl during a high-fat diet (HFD) . In the intestinal flora,
[18]
dehydrogenase) . While the secretion of inflammatory there are also some succinate-consuming bacteria, such
[9]
factors increases in an inflammatory milieu, the increase as P. faecium and Ruminococcus, which convert succinate
in OGDH activity in macrophages promotes the into propionate . An imbalance in intestinal homeostasis
[19]
decarboxylation of a-ketoglutarate into succinate, resulting may occur as a result of antibiotics and intestinal
in a decrease in the ratio of α-ketoglutarate to succinate. inflammation, where there is an increase in succinate-
The addition of α-ketoglutarate increases the ratio and secreting bacteria, but a decrease in succinate-consuming
[10]
decreases the level of cellular inflammation . bacteria, thus resulting in the accumulation of succinate in
the intestine . In a study, the concentration of succinate
[20]
2.2. SDH in the feces of patients with inflammatory bowel disease
The SDH, also known as mitochondrial respiratory was significantly higher than that of the control group;
complex II, is located within the inner mitochondrial in a dextran sulfate sodium (DSS)-induced colitis mouse
membrane. It consists of six subunits, namely, SDHA, model, there was also an increase in the concentration of
SDHB, SDHC, SDHD, SDHAF1, and SDHAF2. SDH is succinate in feces [21,22] .
also involved in the TCA cycle and electron transport
chain . In the TCA cycle, SDH oxidizes succinate into 2.4. Other pathways of succinate production
[11]
fumaric acid, and subsequently, as a part of oxidative In addition to the formation of succinate from
phosphorylation, SDH transfers electrons from succinate a-ketoglutarate through the decarboxylation of OGDH,
to coenzyme Q. SDH is located at the intersection of two many metabolic pathways are also involved in the
important metabolic pathways: The TCA cycle and electron production of succinate, such as reverse SDH activity,
transport chain. Growing evidence reveals that the activity γ-aminobutyric acid (GABA) shunt, and glutamine
of SDH is regulated by post-translational modifications, metabolism .
[23]

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