SUCLA2

SUCLA2
Identifiers
Aliases SUCLA2, A-BETA, MTDPS5, SCS-betaA, succinate-CoA ligase ADP-forming beta subunit
External IDs MGI: 1306775 HomoloGene: 2856 GeneCards: SUCLA2
Orthologs
Species Human Mouse
Entrez

8803

20916

Ensembl

ENSG00000136143

ENSMUSG00000022110

UniProt

Q9P2R7
Q5T9Q8

Q9Z2I9

RefSeq (mRNA)

NM_003850

NM_011506

RefSeq (protein)

NP_003841.1

NP_035636.1

Location (UCSC) Chr 13: 47.94 – 48 Mb Chr 14: 73.53 – 73.6 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse

Succinyl-CoA ligase [ADP-forming] subunit beta, mitochondrial (SUCLA2), also known as ADP-forming succinyl-CoA synthetase (SCS-A), is an enzyme that in humans is encoded by the SUCLA2 gene on chromosome 13.[3][4][5]

Succinyl-CoA synthetase (SCS) is a mitochondrial matrix enzyme that acts as a heterodimer, being composed of an invariant alpha subunit and a substrate-specific beta subunit. The protein encoded by this gene is an ATP-specific SCS beta subunit that dimerizes with the SCS alpha subunit to form SCS-A, an essential component of the tricarboxylic acid cycle. SCS-A hydrolyzes ATP to convert succinate to succinyl-CoA. Defects in this gene are a cause of myopathic mitochondrial DNA depletion syndrome. A pseudogene of this gene has been found on chromosome 6. [provided by RefSeq, Jul 2008][4]

Structure

SCS, also known as succinyl CoA ligase (SUCL), is a heterodimer composed of a catalytic α subunit encoded by the SUCLG1 gene and a β subunit encoded by either the SUCLA2 gene or the SUCLG2 gene, which determines the enzyme specificity for either ADP or GDP. SUCLA2 is the SCS variant containing the SUCLA2-encoded β subunit.[6][7][8] Amino acid sequence alignment of the two β subunit types reveals a homology of ~50% identity, with specific regions conserved throughout the sequences.[3]

SUCLA2 is located on chromosome 13 and contains 13 exons.[4]

Function

As a subunit of SCS, SUCLA2 is a mitochondrial matrix enzyme that catalyzes the reversible conversion of succinyl-CoA to succinate and acetoacetyl CoA, accompanied by the substrate-level phosphorylation of ADP to ATP, as a step in the tricarboxylic acid (TCA) cycle.[6][7][8] The ATP generated is then consumed in catabolic pathways.[7] Since substrate-level phosphorylation does not require oxygen for ATP production, this reaction can rescue cells from cytosolic ATP depletion during ischemia.[8] The reverse reaction generates succinyl-CoA from succinate to fuel ketone body and heme synthesis.[6][8]

While SCS is ubiquitously expressed, SUCLA2 is predominantly expressed in catabolic tissues reliant on ATP as their main energy source, including heart, brain, and skeletal muscle.[3][5][8] Within the brain, SUCLA2 is found exclusively in neurons; meanwhile, both SUCLA2 and SUCLG2 are absent in astrocytes, microglia, and oligodendrocytes. In order to acquire succinate to continue the TCA cycle, these cells may instead synthesize succinate through GABA metabolism of α-ketoglutarate or ketone body metabolism of succinyl-CoA.[7][8]

Clinical significance

Mutations in the SUCLA2 gene are associated with mitochondrial DNA (mtDNA) depletion syndrome.[9][10] Symptoms include early onset low muscle tone, severe muscular atrophy, scoliosis, movement disorders such as dystonia and hyperkinesia, epilepsy, and growth retardation. There currently is no curative therapy. Treatment is restricted to managing symptoms and includes exercises to promote mobility, respiratory assistance, baclofen to treat dystonia and hyperkinesia, and antiepileptic drugs for seizures.[9][11]

There is a relatively high incidence of a specific SUCLA2 mutation in the Faroe Island due to a founder effect. This particular mutation is often associated with early lethality.[12] Two additional founder mutations in have been discovered in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.[13] These patients show a higher variability in outcomes with a number of patients with SUCLA2 missense mutation surviving into adulthood. This variability suggests that SUCLA2 missense mutations may be associated with residual enzyme activity.[13]

Coenzyme Q10 and antioxidants have been used to treat mitochondrial DNA depletion syndrome but there is currently no evidence that these treatments result in clinical benefit.[11][14]

Mutations in the SUCLA2 gene leading to SUCLA2 deficiency result in Leigh's or a Leigh-like syndrome with onset of severe hypotonia, muscular atrophy, sensorineural hearing impairment, and often death in early childhood.[6][8]

See also

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. 1 2 3 Johnson JD, Mehus JG, Tews K, Milavetz BI, Lambeth DO (Oct 1998). "Genetic evidence for the expression of ATP- and GTP-specific succinyl-CoA synthetases in multicellular eucaryotes". The Journal of Biological Chemistry. 273 (42): 27580–6. doi:10.1074/jbc.273.42.27580. PMID 9765291.
  4. 1 2 3 "Entrez Gene: SUCLA2 succinate-CoA ligase, ADP-forming, beta subunit".
  5. 1 2 Matilainen, S; Isohanni, P; Euro, L; Lönnqvist, T; Pihko, H; Kivelä, T; Knuutila, S; Suomalainen, A (March 2015). "Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion.". European Journal of Human Genetics. 23 (3): 325–30. doi:10.1038/ejhg.2014.128. PMC 4326715Freely accessible. PMID 24986829.
  6. 1 2 3 4 Miller, C; Wang, L; Ostergaard, E; Dan, P; Saada, A (May 2011). "The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion.". Biochimica et Biophysica Acta. 1812 (5): 625–9. doi:10.1016/j.bbadis.2011.01.013. PMID 21295139.
  7. 1 2 3 4 Dobolyi, A; Bagó, AG; Gál, A; Molnár, MJ; Palkovits, M; Adam-Vizi, V; Chinopoulos, C (April 2015). "Localization of SUCLA2 and SUCLG2 subunits of succinyl CoA ligase within the cerebral cortex suggests the absence of matrix substrate-level phosphorylation in glial cells of the human brain.". Journal of bioenergetics and biomembranes. 47 (1-2): 33–41. doi:10.1007/s10863-014-9586-4. PMID 25370487.
  8. 1 2 3 4 5 6 7 Dobolyi, A; Ostergaard, E; Bagó, AG; Dóczi, T; Palkovits, M; Gál, A; Molnár, MJ; Adam-Vizi, V; Chinopoulos, C (January 2015). "Exclusive neuronal expression of SUCLA2 in the human brain.". Brain structure & function. 220 (1): 135–51. doi:10.1007/s00429-013-0643-2. PMID 24085565.
  9. 1 2 Ostergaard E (May 2009). Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Fong CT, Mefford HC, Smith RJ, Stephens K, eds. "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Acuduria". review. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle.
  10. ↑ El-Hattab AW, Scaglia F (2013). "Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options". review. Neurotherapeutics. 10 (2): 186–98. doi:10.1007/s13311-013-0177-6. PMC 3625391Freely accessible. PMID 23385875.
  11. 1 2 Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R, Medicine Society TM (Nov 2009). "A modern approach to the treatment of mitochondrial disease". primary source. Current Treatment Options in Neurology. 11 (6): 414–30. doi:10.1007/s11940-009-0046-0. PMC 3561461Freely accessible. PMID 19891905.
  12. ↑ Ostergaard E, Hansen FJ, Sorensen N, Duno M, Vissing J, Larsen PL, Faeroe O, Thorgrimsson S, Wibrand F, Christensen E, Schwartz M (Mar 2007). "Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations". primary source. Brain. 130 (Pt 3): 853–61. doi:10.1093/brain/awl383. PMID 17287286.
  13. 1 2 Carrozzo R, Verrigni D, Rasmussen M, de Coo R, Amartino H, Bianchi M, et al. (Oct 2015). "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients". primary source. Journal of Inherited Metabolic Disease. 39: 243–52. doi:10.1007/s10545-015-9894-9. PMID 26475597.
  14. ↑ Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF (2012). "Treatment for mitochondrial disorders". review. The Cochrane Database of Systematic Reviews. 4: CD004426. doi:10.1002/14651858.CD004426.pub3. PMID 22513923.

Further reading

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