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

Date Published: December 17, 2009

Publisher: Public Library of Science

Author(s): 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, Bruce Riley.

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.

Partial Text: Mitochondria, the cellular power plants in most eukaryotic organisms, play pivotal roles in cell signaling, differentiation, and the control of cell cycle, growth and death. Particularly in the nervous system, mitochondrial function is essential in meeting the high energy demand in neurons and glia[1], [2]. During nervous system development, mitochondria regulate neural proliferation and differentiation by supporting the different bioenergetic requirements of highly proliferative neural stem cells compared to postmitotic neurons[3]. Mitochondrial dysfunction has been implicated in various aspects of neuronal and glial dysfunction, aging, as well as in the pathogenesis of neurodegenerative diseases[1], [2], [4]. However, how mitochondria cause and compensate for physiological and pathological challenges, and how this in turn affects neurogenesis, neural development, and nervous system function, remain poorly understood.

We report that the xav mutation causes a loss of ETFDH function and defective electron transfer, and that both xav and fibroblasts from a phenotypically severe MADD patient have similar metabolic defects and mitochondrial dysfunction, including altered energy metabolism, dysregulated ROS production and altered expression of genes critical for mitochondrial function. xav mutants and MADD fibroblasts exhibit increased aerobic glycolysis, similar to the Warburg effect observed in cancer cells, leading to excessive neural proliferation in xav, mediated by upregulation of the PPARG-ERK pathway. xav mutants also display motility defects culminating in paralysis, abnormal glial patterning, reduced motor axon branching and neuromuscular synapse number, but muscle fiber and neuromuscular synapse function appear normal. While there is increased apoptosis throughout the nervous system, many of these phenotypes are independent of cell death, as they are not rescued when cell death is blocked. Strikingly, a PPARG antagonist attenuates aberrant neural proliferation and alleviates paralysis in xav, while PPARG agonists increase neural proliferation in wild type embryos. This work provides further insights into the relationship between metabolism and neural development, specifically that mitochondrial dysfunction leads to an increase in aerobic glycolysis which affects neurogenesis, at least in part through the PPARG-ERK pathway.



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