Reactome | SDH complex dehydrogenates succinate

SDH complex dehydrogenates succinate

Stable Identifier

R-HSA-70994

Type

Reaction [transition]

Species

Homo sapiens

Compartment

mitochondrial matrix, mitochondrial inner membrane

Synonyms

Succinate + Q10 => Fumarate + Q10H2

ReviewStatus

5/5

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The succinate dehydrogenase complex (SDH, complex II), associated with the inner mitochondrial membrane, catalyzes the dehydrogenation of succinate to fumarate, reducing ubiquinone (Q10) to ubiquinol (Q10H2) on the membrane part of the enzyme. FAD is covalently bound to His-99 of the SDHA subunit (PDB 6VAX; Sharma et al., 2020). The redox potential of Q10H2 is then used in the electron transfer chain to drive a proton motive force to generate ATP (Devertanian et al., 1964; Renkema et al., 2015)

The endogenous metabolite itaconate has been shown to bind and inhibit Complex II, leading to an accumulation of succinate. Elevated succinate levels modulate immune, hypoxic and metabolic reprogramming pathways, including during oncogenesis (Booth et al, 1952; Selak et al., 2005; Cordes et al., 2016; reviewed by Hayash et al., 2018; Peace & O'Neill, 2022). The mitochondrial heat shock protein 75 kDa (TRAP1) inhibits Complex II which elicits respiratory downregulation, leading to a pseudohypoxic state. This state is caused by succinate-dependent HIF1-alpha stabilisation which, in turn, can promote tumorigenesis (Sciacovelli et al. 2013, Yoshida et al. 2013, Guzzo et al. 2014).

Mutations in all four SDH subunits (SDHA, SDHB, SDHC, SDHD) have been reported, leading to distinct phenotypes of SDH deficiency and tumors (reviewed by Briere et al., 2005).

Literature References

PubMed ID	Title	Journal	Year
14946179	The inhibitory effects of itaconic acid in vitro and in vivo DEEDS, F, BOOTH, AN, WILSON, RH, Taylor, J	J Biol Chem	1952
23564345	Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis Lee, MJ, Miyajima, N, Picard, D, Trepel, J, Tsutsumi, S, Tatokoro, M, Hasumi, H, Koga, F, Muhlebach, G, Kihara, K, Beebe, K, Yoshida, S, Nakamura, K, Sourbier, C, Neckers, L, Fukushima, H, Chen, Y, Lee, S, Mohney, RP, Xu, W, Vartholomaiou, E	Proc. Natl. Acad. Sci. U.S.A.	2013
15652751	Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase MacKenzie, ED, Boulahbel, H, Selak, MA, Pan, Y, Armour, SM, Watson, DG, Gottlieb, E, Mansfield, KD, Simon, MC, Thompson, CB	Cancer Cell	2005
25564869	Inhibition of succinate dehydrogenase by the mitochondrial chaperone TRAP1 has anti-oxidant and anti-apoptotic effects on tumor cells Rasola, A, Bernardi, P, Guzzo, G, Sciacovelli, M	Oncotarget	2014
27374498	Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation Jones, RG, Sergushichev, A, Khader, S, Lampropoulou, V, Pearce, EJ, Cervantes-Barragan, L, Diamond, MS, Ma, X, Loginicheva, E, Bambouskova, M, Griss, T, Artyomov, MN, Vincent, EE, Diwan, A, Randolph, GJ, Weinheimer, CJ, Nair, S, Huang, SC	Cell Metab	2016
15987702	Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations Wortham, NC, Griffiths, JR, Moat, SJ, Pollard, PJ, Barclay, E, Barwell, J, Mitchell, M, Tomlinson, IP, Alam, NA, Hargreaves, IP, Poulsom, R, Dalgleish, A, Heales, SJ, Hodgson, SV, Hunt, T, Gleeson, MJ, McGrath, JA, Brière, JJ, Rustin, P, Chung, YL, Olpin, S	Hum Mol Genet	2005
17182618	Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF Myllyharju, J, Remes, AM, Hirsilä, M, Hassinen, IE, Kivirikko, KI, Koivunen, P	J Biol Chem	2007
14249115	STUDIES ON SUCCINATE DEHYDROGENASE. I. SPECTRAL PROPERTIES OF THE PURIFIED ENZYME AND FORMATION OF ENZYME-COMPETITIVE INHIBITOR COMPLEXES DERVARTANIAN, DV, VEEGER, C	Biochim Biophys Acta	1964
27189937	Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels Metallo, CM, Wallace, M, Cordes, T, Murphy, AN, Koseki, H, Divakaruni, AS, Michelucci, A, Sapcariu, SC, Cabrales, P, Hiller, K, Sousa, C	J Biol Chem	2016
30844107	Hypoxia/pseudohypoxia-mediated activation of hypoxia-inducible factor-1α in cancer Harada, H, Yokota, A, Hayashi, Y, Huang, G	Cancer Sci	2019
23747254	The mitochondrial chaperone TRAP1 promotes neoplastic growth by inhibiting succinate dehydrogenase Defilippi, P, Nannini, N, Calabrese, F, Rasola, A, Laudiero, G, Bernardi, P, Guzzo, G, Frezza, C, Zheng, L, Esposito, F, Landriscina, M, Morello, V, Sciacovelli, M	Cell Metab.	2013
16143825	Succinate dehydrogenase deficiency in human Djouadi, F, Gimenez, AP, El Ghouzzi, V, Favier, J, Briere, JJ, Rustin, P, Benit, P	Cell Mol Life Sci	2005