SUCLG1 encodes the alpha subunit of succinyl-CoA synthetase, a TCA cycle enzyme catalyzing the only substrate-level phosphorylation step by coupling succinyl-CoA hydrolysis to ATP or GTP synthesis 1. The alpha subunit binds coenzyme A and phosphate substrates, while beta subunits determine nucleotide specificity and succinate binding 2. SUCLG1 also exhibits itaconyl- and malyl-CoA synthetase activities 2. Beyond canonical TCA function, SUCLG1 regulates mitochondrial biogenesis by restricting succinyl-CoA levels to suppress lysine succinylation of mitochondrial RNA polymerase (POLRMT), maintaining mtDNA transcription 3. Additionally, SUCLG1 controls histone succinylation levels, with SUCLG1 depletion causing histone hypersuccinylation that impairs BRD4-mediated oncogene expression in acute myeloid leukemia 4. SUCLG1 promotes aerobic respiration and mitochondrial quality control in tumor progression 5. Pathogenic SUCLG1 variants cause mitochondrial DNA depletion syndrome 9 (MDDS9), characterized by impaired mtDNA synthesis leading to encephalomyopathic presentations with hypotonia and neurological features 67. SUCLG1 mutations are associated with Leigh syndrome, a severe pediatric mitochondrial disease with variable prognosis 8. Post-translational β-hydroxybutyrylation of SUCLG1 enhances its enzymatic activity and ATP production, relevant to metabolic interventions in neurodegeneration 9.