Acyl-CoA synthetase short-chain family member 3, mitochondrial

ACSS3 (acyl-CoA synthetase short-chain family member 3, mitochondrial) is a mitochondrial enzyme that catalyzes the conversion of short-chain fatty acids to acetyl-CoA, with propionate as the preferred substrate and lower-affinity activity toward acetate and butyrate (UniProt: Q9H6R3). This enzymatic function positions the protein within lipid metabolism and acetyl-CoA generation pathways, critical for mitochondrial energy production and biosynthetic processes.

ACSS3 has been detected in human post-mortem brain tissue and localized to mitochondrial subcellular fractions. No disease associations are listed in UniProt; however, the protein is tagged as relevant to Alzheimer's Disease in the Chaparral Knowledge Platform.

In Alzheimer's Disease brain tissue, ACSS3 is significantly upregulated compared to age-matched controls (mean log2FC = 0.59; Chaparral AD proteomics). This elevation across multiple subcellular fractions of human post-mortem AD brain suggests altered lipid and energy metabolism in the disease state, potentially reflecting compensatory or pathological shifts in mitochondrial acetyl-CoA production.