ACSF3

Acyl-CoA synthetase family member 3 (ACSF3) is a mitochondrial enzyme that in humans is encoded by the ACSF3 gene.^[5] The enzyme belongs to the acyl-CoA synthetase family.^[6]

ACSF3
Identifiers
Aliases	ACSF3, acyl-CoA synthetase family member 3
External IDs	OMIM: 614245; MGI: 2182591; HomoloGene: 14958; GeneCards: ACSF3; OMA:ACSF3 - orthologs
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16q24.3 Start 89,088,375 bp[1] End 89,164,121 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8|8 E1 Start 122,775,486 bp[2] End 122,817,880 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in mucosa of transverse colon granulocyte right adrenal gland sural nerve bone marrow cells right adrenal cortex left adrenal gland left adrenal cortex right lobe of liver appendix Top expressed in Ileal epithelium interventricular septum cardiac muscle tissue of left ventricle right kidney lactiferous gland corneal stroma brown adipose tissue otic vesicle proximal tubule left lobe of liver More reference expression data BioGPS n/a
Gene ontology Molecular function nucleotide binding malonyl-CoA synthetase activity ligase activity ATP binding catalytic activity acid-thiol ligase activity very long-chain fatty acid-CoA ligase activity Cellular component mitochondrial matrix mitochondrion Biological process malonate catabolic process metabolism fatty acid biosynthetic process long-chain fatty-acyl-CoA biosynthetic process fatty acid metabolic process lipid metabolism Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 197322 257633 Ensembl ENSG00000176715 ENSMUSG00000015016 UniProt Q4G176 Q3URE1 RefSeq (mRNA) NM_001127214 NM_001243279 NM_001284316 NM_174917 NM_144932 RefSeq (protein) NP_001120686 NP_001230208 NP_001271245 NP_777577 NP_659181 Location (UCSC) Chr 16: 89.09 – 89.16 Mb Chr 8: 122.78 – 122.82 Mb PubMed search [3] [4]
Wikidata
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Structure

The ACSF3 gene is located on the 16th chromosome, with its specific location being 16q24.3. The gene contains 17 exons.^[5] ACSF3 encodes a 64.1 kDa protein that is composed of 576 amino acids; 20 peptides have been observed through mass spectrometry data.^[7][8]

Potential post-translational modifications on ACSF3:

• Acetylation at lysine 565 (K565)^[9]

Function

This gene encodes a member of the acyl-CoA synthetase family of enzymes that activate fatty acids by catalyzing the formation of a thioester linkage between fatty acids and coenzyme A. The encoded protein is localized to mitochondria, has high specificity for malonate and methylmalonate and possesses malonyl-CoA synthetase activity:^[5][10]

ATP + malonate + CoA ${\displaystyle \rightleftharpoons }$ AMP + diphosphate + malonyl-CoA

ACSF3 most efficiently converts malonate to malonyl-CoA, but methylmalonate is also effectively activated at approximately 70% of that activity.^[11]

Degradation of malonic acid and methylmalonic acid

The role of ACSF3 in the propionate metabolism pathway.

By converting malonate into malonyl-CoA, ACSF3 plays a critical role in clearing intramitochondrial malonate, a potent inhibitor of mitochondrial respiration.^[12][13] Malonate competitively inhibits succinate dehydrogenase (SDH), an enzyme that functions both in the citric acid cycle and as Complex II of the electron transport chain.^[12][13] Methylmalonate, by contrast, impairs SDH activity indirectly by interfering with mitochondrial succinate import rather than by direct enzymatic inhibition.^[14] The clearance of both acids is essential not only to prevent mitochondrial dysfunction, but also to avoid metabolic acidosis.^[15][16] According to an Acsf3 knockout mouse model, threonine catabolism was identified as the major contributor to the accumulation of methylmalonic acid.^[15]

Synthesis of mitochondrial malonyl-CoA

Mitochondrial fatty acid synthesis (mtFAS)

The role of ACSF3 in the mitochondrial fatty acid synthesis pathway.

Malonyl-CoA, produced on the one hand via ACSF3 and on the other from acetyl-CoA via the mitochondrial isoform of acetyl-CoA carboxylase 1 (mtACC1), provides the extender units required for mitochondrial fatty acid synthesis (mtFAS).^[17] The resulting acyl-ACP species serve different functions depending on their chain length: for example, octanoyl-ACP (C8) is required for the biosynthesis of lipoic acid, a cofactor of key mitochondrial enzyme complexes such as the pyruvate dehydrogenase complex (PDC), the 2-oxoglutarate dehydrogenase complex (OGDC), the 2-oxoadipate dehydrogenase complex (OADHC), the branched-chain α-keto acid dehydrogenase complex (BCKDHC), and the glycine cleavage system (GCS).^[18] Longer-chain species (C10-16) allosterically activate the network of LYRM proteins.^[19][20] In humans, this network comprises at least 12 proteins and regulates mitochondrial translation, iron–sulfur cluster biogenesis, and the assembly of electron transport chain complexes.^[21][20]

Protein malonylation

In addition to its role in mtFAS, malonyl-CoA is also essential for lysine malonylation of mitochondrial proteins, a post-translational modification that contributes to metabolic efficiency in mammalian cells.^[12] ACSF3 regulates the rhythmic malonylation of mitochondrial proteins in a feeding-dependent manner, modulating hepatic metabolic pathways such as glycogen mobilization, lipid synthesis, and triglyceride accumulation.^[22] However, lysine malonylation levels appear to be affected by ACSF3 suppression in a cell type-specific manner.^[15]

Synthesis of acetyl-CoA

Furthermore, malonyl-CoA can also be converted to acetyl-CoA by malonyl-CoA decarboxylase (MLYCD), which then feeds into the citric acid cycle.^[22]

Clinical significance

Combined malonic and methylmalonic aciduria (CMAMMA)

Mutations in ACSF3 gene have been shown to cause the metabolic disorder combined malonic and methylmalonic aciduria (CMAMMA).^[16] CMAMMA is a condition characterized by high levels of malonic acid and methylmalonic acid, because deficiencies in this gene cause these metabolites to not be broken down. The disease is typically diagnosed by either genetic testing or higher levels of methylmalonic acid than malonic acid, although both are elevated. By calculating the malonic acid to methylmalonic acid ratio in blood plasma, CMAMMA can be distinguished from classic methylmalonic acidemia.^[23] The disorder typically presents symptoms early in childhood, first starting with high levels of acid in the blood (ketoacidosis). The disorder can also present as involuntary muscle tensing (dystonia), weak muscle tone (hypotonia), developmental delay, an inability to grow and gain weight at the expected rate (failure to thrive), low blood sugar (hypoglycemia), and coma. Some affected children can even have microcephaly. Other people with CMAMMA do not develop signs and symptoms until adulthood. These individuals usually have neurological problems, such as seizures, loss of memory, a decline in thinking ability, or psychiatric diseases.^[5]

Chronic obstructive pulmonary disease (COPD)

An epigenetic study found differential DNA methylation of the ACSF3 gene in fetal lung tissue exposed to maternal smoking, suggesting a potential role in the developmental origins of chronic obstructive pulmonary disease (COPD).^[24] Furthermore, integrative analyses of lung tissue DNA methylation and gene expression have identified ACSF3 as a key regulator of COPD.^[24]

Metabolic dysfunction-associated steatotic liver disease (MASLD)

ACSF3 is involved in the pathophysiology of metabolic dysfunction–associated steatotic liver disease (MASLD, formerly NAFLD).^[9] Its expression is increased in mouse models of a high-fat diet as well as in the diseases obesity and alcoholic liver disease, both of which are associated with impaired mitochondrial fatty acid metabolism and increased lipid peroxidation.^[9] Deacetylation of ACSF3 by the mitochondrial deacetylase sirtuin 3 (SIRT3) leads to decreased stability and promotes degradation of ACSF3, which, under high-fat diet conditions, improves hepatic lipid homeostasis and reduces steatosis in mouse models.^[9] The phenolic compound protocatechuic acid (PCA) has been shown to activate SIRT3, highlighting the SIRT3–ACSF3 axis as a potential therapeutic target for MASLD.^[9][25]

Evolutionary role

An ancient human-specific regulatory variant, rs34590044-A, enhances expression the ACSF3 gene, promoting greater height and basal metabolic rate (BMR).^[15] Compared to non-human great apes, anatomically modern humans show both higher ACSF3 expression and elevated BMR, suggesting an evolutionary shift.^[15] This variant likely facilitated adaptation to meat-rich diets, particularly via improved threonine metabolism.^[15] Mouse and cell studies show that ACSF3 supports mitochondrial function and bone growth, while its disruption impairs both.^[15] The findings link ACSF3 to the coevolution of stature, metabolism, and dietary changes in human evolution.^[15]

See also

• MECR