MCCC2 encodes the β-subunit of 3-methylcrotonyl-CoA carboxylase (MCC), a mitochondrial enzyme catalyzing the conversion of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA during leucine and isovaleric acid catabolism 1. This enzymatic step is essential for branched-chain amino acid metabolism in the mitochondrial matrix. Losses-of-function mutations in MCCC2 cause 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD), an autosomal recessive disorder with highly variable penetrance 1. While 57% of identified patients remain asymptomatic with normal development 2, approximately 5% present acute metabolic decompensations resembling classical organic acidurias 1. Beyond metabolic catabolism, emerging evidence reveals MCCC2's role in cancer progression and cellular metabolism. MCCC2 functions as a hypoxic metabolic regulator; mitochondrial VHL inhibits MCCC2 under hypoxia, allowing leucine accumulation to activate glutaminolysis and support tumor growth 3. In colorectal cancer, MCCC2 mediates interactions between mitochondria and telomeres, with elevated expression correlating with poorer prognosis 45. MCCC2 also promotes glioblastoma and gastric cancer progression through ERK/MAPK pathway activation and aerobic glycolysis enhancement 67. SIRT4-mediated MCCC2 deacetylation enhances acetyl-CoA production, supporting hepatocellular carcinoma stemness 8. These findings establish MCCC2 as a dual-function protein linking leucine catabolism to oncogenic metabolic reprogramming.