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Published in: Journal of Inherited Metabolic Disease 2/2011

Open Access 01-04-2011 | Original Article

Toxic response caused by a misfolding variant of the mitochondrial protein short-chain acyl-CoA dehydrogenase

Authors: Stinne P. Schmidt, Thomas J. Corydon, Christina B. Pedersen, Søren Vang, Johan Palmfeldt, Vibeke Stenbroen, Ronald J. A. Wanders, Jos P. N. Ruiter, Niels Gregersen

Published in: Journal of Inherited Metabolic Disease | Issue 2/2011

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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.

Aim

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.
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Metadata
Title
Toxic response caused by a misfolding variant of the mitochondrial protein short-chain acyl-CoA dehydrogenase
Authors
Stinne P. Schmidt
Thomas J. Corydon
Christina B. Pedersen
Søren Vang
Johan Palmfeldt
Vibeke Stenbroen
Ronald J. A. Wanders
Jos P. N. Ruiter
Niels Gregersen
Publication date
01-04-2011
Publisher
Springer Netherlands
Published in
Journal of Inherited Metabolic Disease / Issue 2/2011
Print ISSN: 0141-8955
Electronic ISSN: 1573-2665
DOI
https://doi.org/10.1007/s10545-010-9255-7

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