SUCLA2 encodes the ADP-forming subunit beta of succinyl-CoA synthetase, a critical TCA cycle enzyme catalyzing substrate-level phosphorylation through coupling succinyl-CoA hydrolysis to ATP synthesis 1. The beta subunit provides nucleotide specificity and binds substrate succinate, while also functioning as an ATP-specific itaconyl- and malyl-CoA synthetase 2. Beyond canonical TCA function, SUCLA2 acts as a regulatory hub controlling cellular metabolism. SUCLA2-generated succinyl-CoA post-translationally modifies partner proteins via succinylation: it activates OXCT1 to promote ketolysis in hepatocellular carcinoma 3, modulates glutaminase activity to regulate oxidative stress responses in pancreatic cancer 4, and influences AMPK-mediated inflammation in obesity 5. Pathogenic SUCLA2 mutations cause mitochondrial DNA depletion syndrome 5, an autosomal recessive disorder characterized by severe mtDNA depletion due to impaired nucleotide metabolism 6. Disease manifestations include progressive encephalomyopathy, hearing impairment, and methylmalonic aciduria, with patient-derived cells exhibiting global protein hyper-succinylation 7. SUCLA2 mutations present variable phenotypes ranging from severe infantile-onset disease to slowly progressive neurological decline 8, with SIRT5-mediated desuccinylation showing therapeutic potential 7.