Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10833081 | Molecular Genetics and Metabolism | 2014 | 10 Pages |
Abstract
Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is an autosomal recessive inborn error of metabolism that leads to the impaired mitochondrial fatty acid β-oxidation of short chain fatty acids. It is heterogeneous in clinical presentation including asymptomatic in most patients identified by newborn screening. Multiple mutations have been identified in patients; however, neither clear genotype-phenotype relationships nor a good correlation between genotype and current biochemical markers for diagnosis has been identified. The definition and pathophysiology of this deficiency remain unclear. To better understand this disorder at a global level, quantitative alterations in the mitochondrial proteome in SCAD deficient mice were examined using a combined proteomics approach: two-dimensional gel difference electrophoresis (2DIGE) followed by protein identification with MALDI-TOF/TOF and iTRAQ labeling followed by nano-LC/MALDI-TOF/TOF. We found broad mitochondrial dysfunction in SCAD deficiency. Changes in the levels of multiple energy metabolism related proteins were identified indicating that a more complex mechanism for development of symptoms may exist. Affected pathways converge on disorders with neurologic symptoms, suggesting that even asymptomatic individuals with SCAD deficiency may be at risk to develop more severe disease. Our results also identified a pattern associated with hepatotoxicity implicated in mitochondrial dysfunction, fatty acid metabolism, decrease of depolarization of mitochondria and mitochondrial membranes, and swelling of mitochondria, demonstrating that SCAD deficiency relates more directly to mitochondrial dysfunction and alteration of fatty acid metabolism. We propose several candidate molecules that may serve as markers for recognition of clinical risk associated with this disorder.
Keywords
Deficient miceEMATCAOXPHOSshort chain acyl-CoA dehydrogenase deficiencyOTCSCADDITRAQMitochondrial ProteomicsMALDI-TOF/TOFshort-chain acyl-CoA dehydrogenasetricarboxylic acidSDS-PAGEFatty acid oxidationFatty acid beta-oxidationisobaric tags for relative and absolute quantificationNetwork analysisOrnithine transcarbamylaseelectron transport chainMass spectrometryFAOOxidative phosphorylationetc.Scadliquid chromatography
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Authors
Wei Wang, Al-Walid Mohsen, Guy Uechi, Emanuel Schreiber, Manimalha Balasubramani, Billy Day, M. Michael Barmada, Jerry Vockley,