{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ACSF3 encodes a mitochondrial enzyme that functions as a malonyl‐CoA synthetase, catalyzing the ATP‐dependent conversion of malonate into malonyl‐CoA within the mitochondrial matrix."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " This reaction is critical both for the detoxification of malonate—a competitive inhibitor of succinate dehydrogenase—and for providing an intramitochondrial pool of malonyl‐CoA that can serve as a substrate for protein lysine malonylation and possibly for mitochondrial fatty acid biosynthesis. In humans, pathogenic mutations in ACSF3 have been identified as the cause of combined malonic and methylmalonic aciduria (CMAMMA), a disorder characterized by elevated levels of malonic and methylmalonic acids that, in many cases, follows a clinically benign course."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": " Furthermore, genetic association studies have linked single nucleotide variants in ACSF3 with alterations in circulating methylmalonic acid levels, and expression changes in the gene have been observed in the context of liver disorders and altered lipid metabolism, supporting an expanding role for ACSF3 in overall metabolic flexibility and regulation of fatty acid homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In addition, studies in mitochondrial fatty acid synthesis indicate that ACSF3 contributes to the production of malonyl‐CoA in a manner that may be partially redundant with other pathways required for the synthesis of essential cofactors such as lipoic acid."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these findings establish ACSF3 as a key regulator of intramitochondrial malonyl‐CoA metabolism, with important implications for mitochondrial protein modification, energy homeostasis, and the pathogenesis of metabolic disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jennifer L Sloan, Jennifer J Johnston, Irini Manoli, et al. 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