title: Complex changes in the liver mitochondrial proteome of short chain acyl-CoA dehydrogenase deficient mice.
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.
authors.affiliation: Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, China; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA. Electronic address: wangwei@shchildren.com.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, USA.
authors.forename: Al-Walid
authors.initials: AW
authors.lastname: Mohsen
authors.affiliation: Genomics and Proteomics Core laboratories, University of Pittsburgh, Pittsburgh, USA.
authors.forename: Guy
authors.initials: G
authors.lastname: Uechi
authors.affiliation: Genomics and Proteomics Core laboratories, University of Pittsburgh, Pittsburgh, USA.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Schreiber
authors.affiliation: Genomics and Proteomics Core laboratories, University of Pittsburgh, Pittsburgh, USA.
authors.forename: Manimalha
authors.initials: M
authors.lastname: Balasubramani
authors.affiliation: Genomics and Proteomics Core laboratories, University of Pittsburgh, Pittsburgh, USA.
authors.forename: Billy
authors.initials: B
authors.lastname: Day
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA.
authors.forename: M
authors.initials: M
authors.lastname: Michael Barmada
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA; Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, USA; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Vockley
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000737:chemistry / Q000172:deficiency*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D008052:Lipid Metabolism, Inborn Errors / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000737:chemistry* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000032:analysis*; D010084:Oxidation-Reduction; D020543:Proteome / Q000032:analysis*
chemical_list: D015415:Biomarkers; D005227:Fatty Acids; D024101:Mitochondrial Proteins; D020543:Proteome; D042964:Acyl-CoA Dehydrogenase
keywords: Deficient mice; Fatty acid beta-oxidation; Mitochondrial proteomics; Network analysis; Pathways analysis; Short chain acyl-CoA dehydrogenase deficiency