SUCLG2

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. SUCLG2 is the SCS variant containing the SUCLG2-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.^[9]

SUCLG2 is located on chromosome 3 and contains 14 exons.^[5]

As a subunit of SCS, SUCLG2 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 GDP to GTP, as a step in the tricarboxylic acid (TCA) cycle.^{[6][7][8][10]} The GTP generated is then consumed in anabolic pathways.^[7][9] However, since GTP is not transported through the inner mitochondrial membrane in mammals and other higher organisms, it must be recycled within the matrix.^[8] In addition, SUCLG2 may function in ATP generation in the absence of SUCLA2 by complexing with the mitochondrial nucleotide diphosphate kinase, nm23-H4, and thus compensate for SUCLA2 deficiency.^[6][8] The reverse reaction generates succinyl-CoA from succinate to fuel ketone body and heme synthesis.^[6][8]

While SCS is ubiquitously expressed, SUCLG2 is predominantly expressed in tissues involved in biosynthesis, including liver and kidney.^[8][9][11] SUCLG2 has also been detected in the microvasculature of the brain, likely to support its growth.^[7] Notably, both SUCLA2 and SUCLG2 are absent in astrocytes, microglia, and oligodendrocytes in the brain; thus, 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]

Though mitochondrial DNA (mtDNA) depletion syndrome has been largely attributed to SUCLA2 deficiency, SUCLG2 may play a more crucial role in mtDNA maintenance, as it functions to compensate for SUCLA2 deficiency and its absence results in decreased mtDNA and OXPHOS-dependent growth.^[6] Moreover, no mutations in the SUCLG2 gene have been reported, indicating that such mutations are lethal and selected against.^[8]

SUCLG2 may also play a role in clearing cerebrospinal fluid amyloid-beta 1–42 (Aβ1–42) in Alzheimer's disease (AD) and, thus, reducing neuronal death.^[10]

• Succinyl-CoA synthetase
• SUCLG1
• SUCLA2