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: Yuanquan Song, Mary A Selak, Corey T Watson, Christopher Coutts, Paul C Scherer, Jessica A Panzer, Sarah Gibbs, Marion O Scott, Gregory Willer, Ronald G Gregg, Declan W Ali, Michael J Bennett, Rita J Balice-Gordon
• Journal: PloS one (PLoS One) Vol. 4 Issue 12 Pg. e8329 (Dec 17 2009) ISSN: 1932-6203 [Electronic] United States
• PMID: 20020044 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Carboxylic Acids
• Electron-Transferring Flavoproteins
• Iron-Sulfur Proteins
• Oligonucleotides, Antisense
• Peroxisome Proliferator-Activated Receptors
• acylcarnitine
• Oxidoreductases Acting on CH-NH Group Donors
• electron-transferring-flavoprotein dehydrogenase
• Extracellular Signal-Regulated MAP Kinases
• Carnitine

Topics

• Animals
• Carboxylic Acids (metabolism)
• Carnitine (analogs & derivatives, blood)
• Cell Proliferation (drug effects)
• Cloning, Molecular
• Electron-Transferring Flavoproteins (genetics)
• Enzyme Activation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fibroblasts (drug effects, pathology)
• Glycolysis (drug effects)
• Humans
• Infant
• Infant, Newborn
• Iron-Sulfur Proteins (genetics)
• Mitochondria (drug effects, pathology)
• Multiple Acyl Coenzyme A Dehydrogenase Deficiency (metabolism, pathology)
• Mutation (genetics)
• Nervous System (drug effects, metabolism, pathology)
• Neurons (drug effects, enzymology, pathology)
• Oligonucleotides, Antisense (pharmacology)
• Oxidoreductases Acting on CH-NH Group Donors (genetics)
• Peroxisome Proliferator-Activated Receptors (metabolism)
• Phenotype
• Zebrafish (metabolism)