title: Mechanisms underlying metabolic and neural defects in zebrafish and human multiple acyl-CoA dehydrogenase deficiency (MADD).
abstract: In humans, mutations in electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH) lead to MADD/glutaric aciduria type II, an autosomal recessively inherited disorder characterized by a broad spectrum of devastating neurological, systemic and metabolic symptoms. We show that a zebrafish mutant in ETFDH, xavier, and fibroblast cells from MADD patients demonstrate similar mitochondrial and metabolic abnormalities, including reduced oxidative phosphorylation, increased aerobic glycolysis, and upregulation of the PPARG-ERK pathway. This metabolic dysfunction is associated with aberrant neural proliferation in xav, in addition to other neural phenotypes and paralysis. Strikingly, a PPARG antagonist attenuates aberrant neural proliferation and alleviates paralysis in xav, while PPARG agonists increase neural proliferation in wild type embryos. These results show that mitochondrial dysfunction, leading to an increase in aerobic glycolysis, affects neurogenesis through the PPARG-ERK pathway, a potential target for therapeutic intervention.
authors.affiliation: Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Yuanquan
authors.initials: Y
authors.lastname: Song
authors.forename: Mary A
authors.initials: MA
authors.lastname: Selak
authors.forename: Corey T
authors.initials: CT
authors.lastname: Watson
authors.forename: Christopher
authors.initials: C
authors.lastname: Coutts
authors.forename: Paul C
authors.initials: PC
authors.lastname: Scherer
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Panzer
authors.forename: Sarah
authors.initials: S
authors.lastname: Gibbs
authors.forename: Marion O
authors.initials: MO
authors.lastname: Scott
authors.forename: Gregory
authors.initials: G
authors.lastname: Willer
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gregg
authors.forename: Declan W
authors.initials: DW
authors.lastname: Ali
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bennett
authors.forename: Rita J
authors.initials: RJ
authors.lastname: Balice-Gordon
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000378:metabolism; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D003001:Cloning, Molecular; D044927:Electron-Transferring Flavoproteins / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007506:Iron-Sulfur Proteins / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D054069:Multiple Acyl Coenzyme A Dehydrogenase Deficiency / Q000378:metabolism* / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009420:Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D010641:Phenotype; D015027:Zebrafish / Q000378:metabolism*
chemical_list: D002264:Carboxylic Acids; D044927:Electron-Transferring Flavoproteins; D007506:Iron-Sulfur Proteins; D016376:Oligonucleotides, Antisense; D047492:Peroxisome Proliferator-Activated Receptors; C116917:acylcarnitine; D000587:Oxidoreductases Acting on CH-NH Group Donors; C023120:electron-transferring-flavoprotein dehydrogenase; D048049:Extracellular Signal-Regulated MAP Kinases; D002331:Carnitine