Mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase that catalyzes a cation-dependent cleavage of (S)-3-hydroxy-3-methylglutaryl-CoA into acetyl-CoA and acetoacetate, a key step in ketogenesis. Terminal step in leucine catabolism. Ketone bodies (beta-hydroxybutyrate, acetoacetate and acetone) are essential as an alternative source of energy to glucose, as lipid precursors and as regulators of metabolism. (3S)-hydroxy-3-methylglutaryl-CoA = acetoacetate + acetyl-CoA Stimulated by reducing agents such as dithiothreitol (DTT). Metabolic intermediate metabolism; (S)-3-hydroxy-3-methylglutaryl-CoA degradation; acetoacetate from (S)-3-hydroxy-3-methylglutaryl-CoA: step 1/1. Homodimer; disulfide-linked. Can also form homotetramers. Unprocessed form is peroxisomal. Highest expression in liver. Expressed in pancreas, kidney, intestine, testis, fibroblasts and lymphoblasts. Very low expression in brain and skeletal muscle. The relative expression of isoform 2 (at mRNA level) is highest in heart (30%), skeletal muscle (22%), and brain (14%). The disease is caused by variants affecting the gene represented in this entry. The transcript is not translated, but would result in a catalytically impaired product if it was. Very low expression. The transcript is not translated, but would result in a catalytically inactive product if it was. Belongs to the HMG-CoA lyase family.