SMPDB

Pathway Description

Succinate Signalling

Homo sapiens

Protein Pathway

Created: 2018-08-07

Last Updated: 2019-09-20

The Krebs cycle, also known as the citric acid cycle (CAC) or tricarboxylic acid cycle (TCA cycle) occurs in the mitochondria, and it involves the oxidation of acetyl-CoA from glycolysis to form molecules of ATP, as well as NADH, which will later be used to form more ATP. Intermediates from the Krebs cycle can be used as inflammatory signals in the body, specifically in immune cells such as macrophages. Succinic acid, or its anion succinate, can leave the mitochondria and can directly inhibit the prolyl 4-hydroxylase subunit alpha-3 protein, which then allows for additional activation of the hypoxia-inducible factor 1-alpha (HF-1α). The higher levels of HF-1α enhance the expression of genes, including those for interleukin-1 beta (IL-1β). Succinic acid is also necessary for the succinylation of proteins, leading to changes in their structure and function. Another intermediate of the Krebs cycle, NAD, activates the NAD-dependent protein deacetylase sirtuin-3, which is involved in the deacetylase of proteins in the cell, regulating ATP levels and promoting mtDNA transcription when needed. Activated sirtuin-3 inhibits NACHT, LRR and PYD domains-containing protein 3, which works to activate the inflammasome, and thus the increase in NAD+ leads to anti-inflammatory actions in the body. Citric acid is another intermediate of the Krebs cycle, and it activates the production of reactive oxygen species, nitric oxide, which is the precursor for reactive nitrogen species, and prostaglandins. Prostaglandins can act as vasodilators, and as such are involved in the inflammation response. Finally, glutamine is important for immune cells to carry out their functions, and when LPS binds to the Toll-like receptor 4 (TLR4) on the cell surface, activating this response, extra L-glutamine can be transported into the cell to fill this need. The L-glutamine can then be converted to oxoglutaric acid, which is important in the Krebs cycle, leading to the effects from its intermediates on the rest of the inflammatory response.

References

Succinate Signalling References

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	Citric acid
	L-Glutamine
	LPS core
	NAD
	Nitric oxide
	Oxoglutaric acid
	Succinic acid

	Hypoxia-inducible factor 1-alpha
	Interleukin-1 beta
	NACHT, LRR and PYD domains-containing protein 3
	NAD-dependent protein deacetylase sirtuin-3, mitochondrial
	Prolyl 4-hydroxylase subunit alpha-3
	Toll-like receptor 4

		Citric acid
		L-Glutamine
		LPS core
		NAD
		Nitric oxide
		Oxoglutaric acid
		Succinic acid

		Hypoxia-inducible factor 1-alpha
		Interleukin-1 beta
		NACHT, LRR and PYD domains-containing protein 3
		NAD-dependent protein deacetylase sirtuin-3, mitochondrial
		Prolyl 4-hydroxylase subunit alpha-3
		Toll-like receptor 4

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Succinate Signalling

Succinate Signalling References