Work

The malonyl-CoA synthetase ACSF3 is required for metabolic editing downstream of biotin carboxylation

Year: 2026

Type: article

Abstract: Acsf3, a mitochondrial malonyl-CoA synthetase, is mutated in humans with inborn error Combined Malonic and Methylmalonic Aciduria. To clarify its role in mammalian metabolism, we generated Acsf3 knockout mice. We show that the loss of Acsf3 results in high concentrations of malonate and methylmalonate and exhibits expected defects in mitochondrial metabolism, but the KO mice are largely healthy, similar to the human inborn error. Acsf3 KO mice exhibit redundancy in malonyl-CoA synthetase activity, suggesting a genetic modifier of disease severity. Malonate and methylmalonate are metabolic poisons generated as a by-product of biotin-dependent carboxylation that require metabolic editing. Indeed, the liver-specific loss of the biotin ligase, Holocarboxylase Synthetase (hlcs), inhibits all biotin-dependent carboxylation and results in broad changes in liver mRNA, protein, posttranslational, and metabolic regulation. Loss of Hlcs suppresses the metabolic deficits in Acsf3KO liver due to the inhibition of malonate and methylmalonate generation. Mice with a double knockout of Acsf3 and Hlcs maintained mitochondrial lipoylation, demonstrating the highly redundant generation of mitochondrial malonyl-CoA. These data define the role of Acsf3 in metabolic editing of malonate and methylmalonate to maintain mitochondrial metabolism in the face of endogenously produced anti-metabolites.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2026.113648

Authors: Joseph Choi, Jasmine Encarnacion, Daria Kurganova, Susanna Scafidi, Michael J. Wolfgang

Institutions: Johns Hopkins University, Johns Hopkins Medicine

Language: English

Topic: Metabolism and Genetic Disorders

Subfield: Clinical Biochemistry

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,430