title: Developmental Defects of Caenorhabditis elegans Lacking Branched-chain α-Ketoacid Dehydrogenase Are Mainly Caused by Monomethyl Branched-chain Fatty Acid Deficiency.
abstract: Branched-chain α-ketoacid dehydrogenase (BCKDH) catalyzes the critical step in the branched-chain amino acid (BCAA) catabolic pathway and has been the focus of extensive studies. Mutations in the complex disrupt many fundamental metabolic pathways and cause multiple human diseases including maple syrup urine disease (MSUD), autism, and other related neurological disorders. BCKDH may also be required for the synthesis of monomethyl branched-chain fatty acids (mmBCFAs) from BCAAs. The pathology of MSUD has been attributed mainly to BCAA accumulation, but the role of mmBCFA has not been evaluated. Here we show that disrupting BCKDH in Caenorhabditis elegans causes mmBCFA deficiency, in addition to BCAA accumulation. Worms with deficiency in BCKDH function manifest larval arrest and embryonic lethal phenotypes, and mmBCFA supplementation suppressed both without correcting BCAA levels. The majority of developmental defects caused by BCKDH deficiency may thus be attributed to lacking mmBCFAs in worms. Tissue-specific analysis shows that restoration of BCKDH function in multiple tissues can rescue the defects, but is especially effective in neurons. Taken together, we conclude that mmBCFA deficiency is largely responsible for the developmental defects in the worm and conceivably might also be a critical contributor to the pathology of human MSUD.
authors.affiliation: From the Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado 80309-0347.
authors.forename: Fan
authors.initials: F
authors.lastname: Jia
authors.affiliation: From the Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado 80309-0347.
authors.forename: Mingxue
authors.initials: M
authors.lastname: Cui
authors.affiliation: From the Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado 80309-0347.
authors.forename: Minh T
authors.initials: MT
authors.lastname: Than
authors.affiliation: From the Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado 80309-0347 mhan@colorado.edu.
authors.forename: Min
authors.initials: M
authors.lastname: Han
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008375:Maple Syrup Urine Disease / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000201:enzymology*
chemical_list: D029742:Caenorhabditis elegans Proteins; D005227:Fatty Acids; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
keywords: Caenorhabditis elegans (C. elegans); amino acid; branched-chain amino acid (BCAA); branched-chain fatty acid; dbt-1; dihydrolipoamide branched-chain transacylase (DBT); fatty acid metabolism; inborn error of metabolism; maple syrup urine disease (MSUD); neurological disease