3-hydroxyisobutyryl-CoA hydrolase, mitochondrial

HIBCH (3-hydroxyisobutyryl-CoA hydrolase, mitochondrial) is a 386-amino-acid enzyme that catalyzes the hydrolysis of 3-hydroxyisobutyryl-CoA and related acyl-CoA substrates (UniProt: Q6NVY1). The protein functions in valine catabolism and branched-chain amino acid metabolism within mitochondria. Beyond its normal metabolic role, mutations in HIBCH cause 3-hydroxyisobutyrl-CoA hydrolase deficiency (HIBCHD, MIM 250620), an autosomal recessive inborn error of metabolism characterized by severe psychomotor delay, neurodegeneration, elevated lactate, and basal ganglia lesions (UniProt: Q6NVY1).

In Alzheimer's disease, HIBCH shows disease-relevant dysregulation. Proteomic analysis of post-mortem AD brain tissue versus age-matched controls detected HIBCH as upregulated across two subcellular fractions (mean log2 fold-change: 0.30; Chaparral AD proteomics). The upregulation was observed in a TMT-labeled, data-dependent acquisition study spanning four subcellular compartments (P2, P3, S2, S3). This elevated expression in AD brain suggests a potential role in the metabolic or mitochondrial stress responses associated with Alzheimer's pathology, though the functional significance requires further investigation.