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Global Translational Medicine Succinate metabolism in CVD

accumulation and inducing cardiomyocyte proliferation through the phosphatidylinositol 3-kinase/protein kinase
and heart regeneration . SDH is the most crucial enzyme B (PI3K/Akt) signaling pathway . In a previous study, a
[63]
[56]
for succinate accumulation and oxidation to produce ROS patient who presented with congestive heart failure was
during ischemia-reperfusion. Dimethyl malonate has a found deficient in succinate dehydrogenase, which caused
protective effect on ischemia-reperfusion injury in pre- succinate to accumulate extracellularly . Succinate
[64]
ischemia or ischemia . In a porcine ischemia-reperfusion activates the cardiomyocyte PKA pathway, regulates
[24]
2+
model, coronary administration of dimethyl malonate was cardiomyocyte Ca transients through SUCNR1, reduces
found to be cardioprotective . In addition to its role in ventricular cardiomyocyte viability, increases caspase-3
[57]
[65]
myocardial infarction, SDH inhibitors can also be used in activity, and leads to cardiomyocyte apoptosis . The
2+
predictable ischemic processes, such as ischemic stroke, Ca transient is an important indicator of myocardial
kidney disease, and organ transplantation. Dimethyl hypertrophy . These results suggest that succinate
[66]
malonate has been shown to reduce brain damage after promotes cardiomyocyte apoptosis and Ca transients,
2+
[58]
cardiac arrest in rats . Malonic acid may emerge as a resulting in myocardial hypertrophy and heart failure.
potential treatment for reducing injuries during organ 3.6. Succinate and metabolic cardiomyopathy
transplantation.
Metabolic cardiomyopathy is a type of cardiomyopathy
Isolated organs are in a state of hypoxia, which leads
to the accumulation of succinate in the organs and caused by metabolic disorders, primarily glucose, and lipid
metabolism disorders, some of which include heart failure
oxidation after reperfusion, resulting in tissue injury and with preserved ejection fraction, diabetic cardiomyopathy,
inflammation. The cold storage solution can slow down the and Takotsubo syndrome. [67,68] Obesity, body fat, and
metabolism and the production of succinate, thus reducing body mass index are significant risk factors for these
the production of mitochondrial ROS during reperfusion cardiomyopathies, and succinate may this condition.
and in reperfusion injury . In a recent study related to
[59]
organ transplantation, a new storage method was designed Obesity may lead to metabolic disorders of adipose
to preserve the heart for transplantation. Hypothermia tissue, leading to macrophage infiltration and chronic
oxygenation was used to raise the level of adenosine inflammation. Succinate-SUCNR1 mediates adipose
triphosphate/adenosine diphosphate (ATP/ADP) in tissue macrophage infiltration and glucose intolerance in
[37]
the perfusion tissue, which reduced the level of cardiac obesity . The knockout of SUCNR1 results in a significant
[37]
succinate and cell injury, thus achieving a protective effect reduction in macrophage infiltration in adipose tissues .
on the heart . A large amount of succinate tends to In addition to worsening obesity, inflammation and glucose
[60]
accumulate in ischemic tissue, but following reperfusion, intolerance may occur as a result of macrophage-specific
[69]
succinate is rapidly oxidized by SDH, and excess ROS are deficiency of SUCNR1 . The elevated plasma level of
produced through mitochondrial respiratory complex I, succinate is related to metabolic abnormalities. In obese
resulting in calcium imbalance and ATP depletion, which people, the level of succinate in the circulation increases,
lead to further damage and myocardial cell death . while the expression of SUCNR1 in adipose tissue-resident
[24]
[70]
macrophages decreases . The thermogenic activity of
3.5. Succinate and myocardial hypertrophy and brown adipose tissue (BAT) plays a significant role in obesity.
heart failure Uncoupling protein 1 (UCP1), which is a key thermogenic
Cardiac overload is the primary cause of heart failure. protein expressed in brown and beige adipocytes, regulates
Myocardial hypertrophy is the main compensatory the removal of succinate from the circulation of brown
mechanism with an increase in cardiac afterload. The and beige fat. High levels of succinate are rapidly absorbed
apoptosis of cardiomyocytes has a significant role in the by adipocyte mitochondria, producing ROS through
SDH-mediated succinate oxidation, driving UCP1-
transition from myocardial hypertrophy to heart failure . dependent thermogenic respiration, and then regulating
[61]
Pathological myocardial hypertrophy is a major risk liver inflammation and glucose intolerance under obesity
factor for various CVDs and sudden death, but there is no conditions [71,72] . In a cold exposure mouse model, succinate
effective treatment strategy at present.
accumulated in brown adipocytes, reduced HFD-induced
Succinate triggers ERK1/2 phosphorylation, Ca / obesity, and enhanced thermogenesis in BAT through
2+
calmodulin-dependent protein kinase II delta (CaMKIIδ) non-adrenergic signaling pathways . Therefore, succinate
[71]
expression, and intracellular histone deacetylase 5 (HDAC5 can be regarded as an activator of BAT thermogenesis.
translocation) through SUCNR1, leading to cardiomyocyte Interestingly, the exogenous supplementation of succinate
[62]
hypertrophy . Succinate-SUCNR1 is involved in right to pregnant and lactating female mice was found to
ventricular hypertrophy induced by pressure overload promote the development of brown fat in newborn mice

Volume 1 Issue 2 (2022) 6 https://doi.org/10.36922/gtm.v1i2.160