Document Detail

Antioxidant dysfunction: potential risk for neurotoxicity in ethylmalonic aciduria.
MedLine Citation:
PMID:  20443061     Owner:  NLM     Status:  MEDLINE    
Mitochondrial dysfunction and oxidative stress are central to the molecular basis of several human diseases associated with neuromuscular disabilities. We hypothesize that mitochondrial dysfunction also contributes to the neuromuscular symptoms observed in patients with ethylmalonic aciduria and homozygosity for ACADS c.625G>A-a common variant of the short-chain acyl-coenzyme A (CoA) dehydrogenase (SCAD) enzyme in the mitochondrial fatty acid oxidation pathway. This study sought to identify the specific factors that initiate cell dysfunction in these patients. We investigated fibroblast cultures from 10 patients with neuromuscular disabilities, elevated levels of ethylmalonic acid (EMA) (>50 mmol/mol creatinine), and ACADS c.625G>A homozygosity. Functional analyses, i.e., ACADS gene and protein expression as well as SCAD enzyme activity measurements, were performed together with a global nano liquid chromatography tandem mass spectroscopy (nano-LC-MS/MS)-based screening of the mitochondrial proteome in patient fibroblasts. Moreover, cell viability of patient fibroblasts exposed to menadione-induced oxidative stress was evaluated. Loss of SCAD function was detected in the patient group, most likely due to decreased ACADS gene expression and/or elimination of misfolded SCAD protein. Analysis of the mitochondrial proteome in patient fibroblasts identified a number of differentially expressed protein candidates, including reduced expression of the antioxidant superoxide dismutase 2 (SOD2). Additionally, patient fibroblasts demonstrated significantly higher sensitivity to oxidative stress than control fibroblasts. We propose that reduced mitochondrial antioxidant capacity is a potential risk factor for ACADS c.625G>A-associated ethylmalonic aciduria and that mitochondrial dysfunction contributes to the neurotoxicity observed in patients.
Christina B Pedersen; Zarazuela Zolkipli; Søren Vang; Johan Palmfeldt; Margrethe Kjeldsen; Vibeke Stenbroen; Stinne P Schmidt; Ronald J A Wanders; Jos P N Ruiter; Flemming Wibrand; Ingrid Tein; Niels Gregersen
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-05
Journal Detail:
Title:  Journal of inherited metabolic disease     Volume:  33     ISSN:  1573-2665     ISO Abbreviation:  J. Inherit. Metab. Dis.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-05-27     Completed Date:  2010-09-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7910918     Medline TA:  J Inherit Metab Dis     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  211-22     Citation Subset:  IM    
Research Unit for Molecular Medicine, Aarhus University Hospital, Skejby, Brendstrupgaardsvej 100, Aarhus N, Denmark.
Data Bank Information
Bank Name/Acc. No.:
OMIM/201470;  602473
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MeSH Terms
Antioxidants / metabolism*
Butyryl-CoA Dehydrogenase / genetics
Cell Survival
Child, Preschool
Chromatography, Liquid / methods
Fibroblasts / metabolism
Malonates / urine*
Mass Spectrometry / methods
Metabolism, Inborn Errors / diagnosis*,  genetics
Mitochondria / metabolism
Models, Genetic
Oxidative Stress
Proteomics / methods
Risk Factors
Reg. No./Substance:
0/Antioxidants; 0/Malonates; 601-75-2/ethylmalonic acid; EC Dehydrogenase

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