Fessel 2013 Abstract IOC75
|Fessel JP (2013) Structural, functional, and signaling abnormalities in mitochondria and multiple organ systems in a novel zebrafish model of multiple Acyl-CoA dehydrogenase deficiency (MADD). Mitochondr Physiol Network 18.03.|
Link: IOC75 Open Access
Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of mitochondrial fatty acid oxidation with variable clinical presentations, ranging from the lethal neonatal form with congenital developmental abnormalities (type I) to neonatal hypoglycemia and hypoketosis without developmental defects (type II) to a later onset form with myopathy (type 3). MADD is due to mutations in the electron transfer flavoprotein (ETF) system that moves electrons from fatty acid beta oxidation into the electron transport chain, with specific mutations in humans identified in ETFA, ETFB, and ETF dehydrogenase [1, 2]. A mechanistic understanding of MADD has been hampered by a paucity of animal models . In a forward mutagenesis screen in zebrafish, we identified a novel mutant termed dark xavier (dxavu463), shown by sequencing to be a mutation in the etfa gene, that exhibits structural developmental abnormalities in brain, liver, and kidney. Ultrastructural analyses showed massively swollen mitochondria with effacement of cristae. Consistent with this, oxygen consumption measurements of intact wild-type and dxavu463 zebrafish showed a significant reduction in basal oxygen consumption in the mutants compared to wild-type siblings. Mutants were shown to have substantial alterations in lipid metabolism and pathological lipid deposition in multiple tissues. In the dxavu463 mutants, mammalian target of rapamycin complex 1 (mTORC1) signaling was shown to be increased, and the disease phenotype could be partially ameliorated with rapamycin treatment. Interestingly, we found that maternal overfeeding would substantially exacerbate the severity of the MADD-like phenotype in offspring. Taken together, these findings point to novel avenues of inquiry for further mechanistic investigations as well as potential new therapeutic approaches for this devastating disease.
- Amendt BA, Rhead WJ. The multiple acyl-coenzyme A dehydrogenation disorders, glutaric aciduria type II and ethylmalonic-adipic aciduria. Mitochondrial fatty acid oxidation, acyl-coenzyme A dehydrogenase, and electron transfer flavoprotein activities in fibroblasts. J Clin Invest 1986;78:205-13.
- Wilson GN, de Chadarevian JP, Kaplan P, Loehr JP, Frerman FE, Goodman SI. Glutaric aciduria type II: review of the phenotype and report of an unusual glomerulopathy. Am J Med Genet 1989;32:395-401.
- Song Y, Selak MA, Watson CT, Coutts C, Scherer PC, Panzer JA, Gibbs S, Scott MO, Willer G, Gregg RG, Ali DW, Bennett MJ, Balice-Gordon RJ. Mechanisms underlying metabolic and neural defects in zebrafish and human multiple acyl-CoA dehydrogenase deficiency (MADD). PLoS One 2009;4:e8329.
• O2k-Network Lab: US TN Nashville Fessel JP
Labels: MiParea: Pharmacology;toxicology
Seok-Hyung Kim1, Sarah A. Scott2, Michael J. Bennett3, Robert P. Carson1, Joshua Fessel4,*, H. Alex Brown2, and Kevin C. Ess1
- Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN 37232 USA
- Department of Pharmacology, The Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 USA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia, PA 19104 USA
- Department of Medicine, Division of Allergy Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232 USA