PUBLICATION

Mechanisms Underlying Metabolic and Neural Defects in Zebrafish and Human Multiple Acyl-CoA Dehydrogenase Deficiency (MADD)

Authors
Song, Y., Selak, M.A., Watson, C.T., Coutts, C., Scherer, P.C., Panzer, J.A., Gibbs, S., Scott, M.O., Willer, G., Gregg, R.G., Ali, D.W., Bennett, M.J., and Balice-Gordon, R.J.
ID
ZDB-PUB-091221-31
Date
2009
Source
PLoS One   4(12): e8329 (Journal)
Registered Authors
Balice-Gordon, Rita J., Gregg, Ronald G., Watson, Corey, Willer, Greg
Keywords
Embryos, Mitochondria, Fibroblasts, Glycolysis, Fatty acids, Gene expression, Immunostaining, Spinal cord
MeSH Terms
  • Carnitine/analogs & derivatives
  • Carnitine/blood
  • Peroxisome Proliferator-Activated Receptors/metabolism
  • Fibroblasts/drug effects
  • Fibroblasts/pathology
  • Nervous System/drug effects
  • Nervous System/metabolism*
  • Nervous System/pathology*
  • Zebrafish/metabolism*
  • Humans
  • Oxidoreductases Acting on CH-NH Group Donors/genetics
  • Cloning, Molecular
  • Glycolysis/drug effects
  • Cell Proliferation/drug effects
  • Oligonucleotides, Antisense/pharmacology
  • Phenotype
  • Carboxylic Acids/metabolism
  • Extracellular Signal-Regulated MAP Kinases/metabolism
  • Animals
  • Iron-Sulfur Proteins/genetics
  • Neurons/drug effects
  • Neurons/enzymology
  • Neurons/pathology
  • Electron-Transferring Flavoproteins/genetics
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency/metabolism*
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency/pathology*
  • Enzyme Activation/drug effects
  • Infant, Newborn
  • Mitochondria/drug effects
  • Mitochondria/pathology
  • Infant
  • Mutation/genetics
PubMed
20020044 Full text @ PLoS One
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.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping