title: Toxic response caused by a misfolding variant of the mitochondrial protein short-chain acyl-CoA dehydrogenase.
abstract: BACKGROUND
  Variations in the gene ACADS, encoding the mitochondrial protein short-chain acyl CoA-dehydrogenase (SCAD), have been observed in individuals with clinical symptoms. The phenotype of SCAD deficiency (SCADD) is very heterogeneous, ranging from asymptomatic to severe, without a clear genotype-phenotype correlation, which suggests a multifactorial disorder. The pathophysiological relevance of the genetic variations in the SCAD gene is therefore disputed, and has not yet been elucidated, which is an important step in the investigation of SCADD etiology.
  
  
  OBJECTIVE
  To determine whether the disease-associated misfolding variant of SCAD protein, p.Arg107Cys, disturbs mitochondrial function.
  
  
  METHODS
  We have developed a cell model system, stably expressing either the SCAD wild-type protein or the misfolding SCAD variant protein, p.Arg107Cys (c.319 C > T). The model system was used for investigation of SCAD with respect to expression, degree of misfolding, and enzymatic SCAD activity. Furthermore, cell proliferation and expression of selected stress response genes were investigated as well as proteomic analysis of mitochondria-enriched extracts in order to study the consequences of p.Arg107Cys protein expression using a global approach.
  
  
  CONCLUSIONS
  We found that expression of the p.Arg107Cys variant SCAD protein gives rise to inactive misfolded protein species, eliciting a mild toxic response manifested though a decreased proliferation rate and oxidative stress, as shown by an increased demand for the mitochondrial antioxidant SOD2. In addition, we found markers of apoptotic activity in the p.Arg107Cys expressing cells, which points to a possible pathophysiological role of this variant protein.
authors.affiliation: Research Unit for Molecular Medicine, Aarhus University Hospital, Skejby, Denmark. stinne@ki.au.dk
authors.forename: Stinne P
authors.initials: SP
authors.lastname: Schmidt
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Corydon
authors.forename: Christina B
authors.initials: CB
authors.lastname: Pedersen
authors.forename: Søren
authors.initials: S
authors.lastname: Vang
authors.forename: Johan
authors.initials: J
authors.lastname: Palmfeldt
authors.forename: Vibeke
authors.initials: V
authors.lastname: Stenbroen
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Jos P N
authors.initials: JP
authors.lastname: Ruiter
authors.forename: Niels
authors.initials: N
authors.lastname: Gregersen
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D044926:Butyryl-CoA Dehydrogenase / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D049109:Cell Proliferation; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D051379:Mice; D028361:Mitochondrial Diseases / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry*; D018384:Oxidative Stress; D010641:Phenotype; D011489:Protein Denaturation; D017510:Protein Folding; D040901:Proteomics / Q000379:methods
chemical_list: D000975:Antioxidants; D024101:Mitochondrial Proteins; D044926:Butyryl-CoA Dehydrogenase