Malonate--CoA ligase ACSF3, mitochondrial

ACSF3 (malonate–CoA ligase) is a mitochondrial enzyme that catalyzes activation of malonate and methylmalonate into their CoA thioesters, supporting intramitochondrial fatty acid synthesis (UniProt: Q4G176). The protein may preferentially act on very-long-chain substrates. In humans, ACSF3 mutations cause combined malonic and methylmalonic aciduria (CMAMMA, MIM 614265), a metabolic disorder presenting with neurological manifestations including seizures, cognitive decline, and developmental delay.

ACSF3 is relevant to Alzheimer's disease, where it shows reduced abundance in post-mortem AD brain tissue compared to age-matched controls (Chaparral AD proteomics). The mean log2 fold-change was −0.44 across analyzed subcellular fractions, indicating down-regulation. This reduction may reflect impaired mitochondrial fatty acid metabolism in the AD brain, potentially contributing to metabolic dysfunction associated with neurodegeneration.