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This organic acid arises from thioester cleavage of 3\u2010methylglutaconyl CoA (3MG CoA), an intermediate in leucine catabolism. In individuals harboring mutations in 3MG CoA hydratase (i.e., primary 3MGA\u2010uria), dietary leucine is the source of 3MGA. In secondary 3MGA\u2010uria, however, no leucine metabolism defects have been reported. While others have suggested 3MGA arises from aberrant isoprenoid shunting from cytosol to mitochondria, an alternative route posits that 3MG CoA arises in three steps from mitochondrial acetyl CoA. Support for this biosynthetic route in IEMs is seen by its regulated occurrence in microorganisms. The fungus,<jats:italic>Ustilago maydis<\/jats:italic>, the myxobacterium,<jats:italic>Myxococcus xanthus<\/jats:italic>and the marine cyanobacterium,<jats:italic>Lyngbya majuscule,<\/jats:italic>generate 3MG CoA (or acyl carrier protein derivative) in the biosynthesis of iron chelating siderophores, iso\u2010odd chain fatty acids and polyketide\/nonribosomal peptide products, respectively. The existence of this biosynthetic machinery in these organisms supports a model wherein, under conditions of mitochondrial dysfunction, accumulation of acetyl CoA in the inner mitochondrial space as a result of inefficient fuel utilization drives<jats:italic>de novo<\/jats:italic>synthesis of 3MG CoA. Since humans lack the downstream biosynthetic capability of the organisms mentioned above, as 3MG CoA levels rise, thioester hydrolysis yields 3MGA, which is excreted in urine as unspent fuel. Understanding the metabolic origins of 3MGA may increase its utility as a biomarker.<\/jats:p>","DOI":"10.1007\/s10545-016-9933-1","type":"journal-article","created":{"date-parts":[[2016,4,18]],"date-time":"2016-04-18T07:01:47Z","timestamp":1460962907000},"page":"749-756","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["On the origin of 3\u2010methylglutaconic acid in disorders of mitochondrial energy metabolism"],"prefix":"10.1002","volume":"39","author":[{"given":"Nikita","family":"Ikon","sequence":"first","affiliation":[{"name":"Children's Hospital Oakland Research Institute 5700 Martin Luther King Jr. Way Oakland CA 94609 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert O.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Children's Hospital Oakland Research Institute 5700 Martin Luther King Jr. Way Oakland CA 94609 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