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

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 genot...

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Autores principales: Schmidt, Stinne P., Corydon, Thomas J., Pedersen, Christina B., Vang, Søren, Palmfeldt, Johan, Stenbroen, Vibeke, Wanders, Ronald J. A., Ruiter, Jos P. N., Gregersen, Niels
Formato: Texto
Lenguaje:English
Publicado: Springer Netherlands 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063561/
https://www.ncbi.nlm.nih.gov/pubmed/21170680
http://dx.doi.org/10.1007/s10545-010-9255-7
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author Schmidt, Stinne P.
Corydon, Thomas J.
Pedersen, Christina B.
Vang, Søren
Palmfeldt, Johan
Stenbroen, Vibeke
Wanders, Ronald J. A.
Ruiter, Jos P. N.
Gregersen, Niels
author_facet Schmidt, Stinne P.
Corydon, Thomas J.
Pedersen, Christina B.
Vang, Søren
Palmfeldt, Johan
Stenbroen, Vibeke
Wanders, Ronald J. A.
Ruiter, Jos P. N.
Gregersen, Niels
author_sort Schmidt, Stinne P.
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10545-010-9255-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-30635612011-04-05 Toxic response caused by a misfolding variant of the mitochondrial protein short-chain acyl-CoA dehydrogenase Schmidt, Stinne P. Corydon, Thomas J. Pedersen, Christina B. Vang, Søren Palmfeldt, Johan Stenbroen, Vibeke Wanders, Ronald J. A. Ruiter, Jos P. N. Gregersen, Niels J Inherit Metab Dis Original Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10545-010-9255-7) contains supplementary material, which is available to authorized users. Springer Netherlands 2010-12-18 2011 /pmc/articles/PMC3063561/ /pubmed/21170680 http://dx.doi.org/10.1007/s10545-010-9255-7 Text en © The Author(s) 2010 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Original Article
Schmidt, Stinne P.
Corydon, Thomas J.
Pedersen, Christina B.
Vang, Søren
Palmfeldt, Johan
Stenbroen, Vibeke
Wanders, Ronald J. A.
Ruiter, Jos P. N.
Gregersen, Niels
Toxic response caused by a misfolding variant of the mitochondrial protein short-chain acyl-CoA dehydrogenase
title Toxic response caused by a misfolding variant of the mitochondrial protein short-chain acyl-CoA dehydrogenase
title_full Toxic response caused by a misfolding variant of the mitochondrial protein short-chain acyl-CoA dehydrogenase
title_fullStr Toxic response caused by a misfolding variant of the mitochondrial protein short-chain acyl-CoA dehydrogenase
title_full_unstemmed Toxic response caused by a misfolding variant of the mitochondrial protein short-chain acyl-CoA dehydrogenase
title_short Toxic response caused by a misfolding variant of the mitochondrial protein short-chain acyl-CoA dehydrogenase
title_sort toxic response caused by a misfolding variant of the mitochondrial protein short-chain acyl-coa dehydrogenase
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063561/
https://www.ncbi.nlm.nih.gov/pubmed/21170680
http://dx.doi.org/10.1007/s10545-010-9255-7
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