Succinyl-CoA ligase [ADP-forming] subunit beta, mitochondrial (SUCLA2), also known as ADP-forming succinyl-CoA synthetase (SCS-A), is anenzyme that in humans is encoded by theSUCLA2gene on chromosome 13.[5][6][7]
SCS, also known as succinyl CoA ligase (SUCL), is a heterodimer composed of a catalytic α subunit encoded by theSUCLG1 gene and a β subunit encoded by either theSUCLA2 gene or theSUCLG2 gene, which determines the enzyme specificity for either ADP or GDP. SUCLA2 is the SCS variant containing theSUCLA2-encoded β subunit.[8][9][10]Amino acid sequence alignment of the two β subunit types reveals a homology of ~50% identity, with specific regions conserved throughout the sequences.[5]
SUCLA2 is located on chromosome 13 and contains 13exons.[6]
As a subunit of SCS, SUCLA2 is a mitochondrial matrix enzyme that catalyzes the reversible conversion of succinyl-CoA to succinate andAcetoacetyl CoA, accompanied by thesubstrate-level phosphorylation of ADP to ATP, as a step in the tricarboxylic acid (TCA) cycle.[8][9][10] The ATP generated is then consumed incatabolic pathways.[9] Since substrate-level phosphorylation does not require oxygen for ATP production, this reaction can rescue cells from cytosolic ATP depletion duringischemia.[10] The reverse reaction generates succinyl-CoA from succinate to fuelketone body andheme synthesis.[8][10]
While SCS is ubiquitously expressed, SUCLA2 is predominantly expressed in catabolic tissues reliant on ATP as their main energy source, including theheart,brain, andskeletal muscle.[5][7][10] Within the brain, SUCLA2 is found exclusively inneurons; meanwhile, both SUCLA2 and SUCLG2 are absent inastrocytes,microglia, andoligodendrocytes. In order to acquire succinate to continue the TCA cycle, these cells may instead synthesize succinate throughGABAmetabolism ofα-ketoglutarate or ketone body metabolism of succinyl-CoA.[9][10]
Mutations in the SUCLA2 gene are associated withmitochondrial DNA (mtDNA) depletion syndrome.[11][12] Symptoms include early-onsetlow muscle tone, severe muscular atrophy,scoliosis, movement disorders such asdystonia andhyperkinesia,epilepsy, and growth retardation. Because succinic acid cannot be made from succinyl coa, treatment is with oral succinic acid, which allows the Krebs cycle and electron transport chain to function correctly. Other treatments for managing symptoms include exercises to promote mobility and respiratory assistance,baclofen to treatdystonia andhyperkinesia, and antiepileptic drugs for seizures.[11][13]
There is a relatively high incidence of a specific SUCLA2 mutation in theFaroe Islands due to afounder effect. This particular mutation is often associated with early lethality.[14] Two additional founder mutations have been discovered in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.[15] These patients show a higher variability in outcomes with several patients with SUCLA2missense mutation surviving into adulthood. This variability suggests that SUCLA2 missense mutations may be associated with residual enzyme activity.[15]
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.[13][16]
Mutations in theSUCLA2 gene leading to SUCLA2 deficiency result inLeigh's or a Leigh-like syndrome with the onset of severehypotonia,muscular atrophy, sensorineural hearing impairment, and often death in early childhood.[8][10]
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