ArticlePloS one2011
Vulnerability to oxidative stress in vitro in pathophysiology of mitochondrial short-chain acyl-CoA dehydrogenase deficiency: response to antioxidants.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Evidence that Oxidative Disbalance and Mitochondrial Dysfunction are Involved in the Pathophysiology of Fatty Acid Oxidation Disorders.Cellular and molecular neurobiology · 2022Review
- Oxidized LDL-dependent pathway as new pathogenic trigger in arrhythmogenic cardiomyopathy.EMBO molecular medicine · 2021Article
- Variants in the ethylmalonyl-CoA decarboxylase (ECHDC1) gene: a novel player in ethylmalonic aciduria?Journal of inherited metabolic disease · 2021Article
- Increased antioxidant response in medium-chain acyl-CoA dehydrogenase deficiency: does lipoic acid have a protective role?Pediatric research · 2020Article
- Cellular Stress in the Pathogenesis of Muscular Disorders-From Cause to Consequence.International journal of molecular sciences · 2020Review
- Review
- Short-chain acyl-CoA dehydrogenase deficiency: from gene to cell pathology and possible disease mechanisms.Journal of inherited metabolic disease · 2017Review
- Higher Vulnerability of Menadione-Exposed Cortical Astrocytes of Glutaryl-CoA Dehydrogenase Deficient Mice to Oxidative Stress, Mitochondrial Dysfunction, and Cell Death: Implications for the Neurodegeneration in Glutaric Aciduria Type I.Molecular neurobiology · 2017Article
- Ornithine and Homocitrulline Impair Mitochondrial Function, Decrease Antioxidant Defenses and Induce Cell Death in Menadione-Stressed Rat Cortical Astrocytes: Potential Mechanisms of Neurological Dysfunction in HHH Syndrome.Neurochemical research · 2016Article
- Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism.Journal of inherited metabolic disease · 2015Review
- Article
- Article
- HEPNet: A Knowledge Base Model of Human Energy Pool Network for Predicting the Energy Availability Status of an Individual.PloS one · 2015Article
- Ethylmalonic acid induces permeability transition in isolated brain mitochondria.Neurotoxicity research · 2014Article
- Complex changes in the liver mitochondrial proteome of short chain acyl-CoA dehydrogenase deficient mice.Molecular genetics and metabolism · 2014Article
- The domain-specific and temperature-dependent protein misfolding phenotype of variant medium-chain acyl-CoA dehydrogenase.PloS one · 2014Article
- Mitochondrial proteomics--a tool for the study of metabolic disorders.Journal of inherited metabolic disease · 2012Review
- The story of equine atypical myopathy: a review from the beginning to a possible end.ISRN veterinary science · 2012Article
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Authors and funding
5 authors.
Funding
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Abstract
objectiveTo elucidate the pathophysiology of SCAD deficient patients who have a unique neurological phenotype, among fatty acid oxidation disorders, with early developmental delay, CNS malformations, intractable seizures, myopathy and clinical signs suggesting oxidative stress.
methodsWe studied skin fibroblast cultures from patients homozygous for ACADS common variant c.625G>A (n = 10), compound heterozygous for c.625G>A/c.319C>T (n = 3) or homozygous for pathogenic c.319C>T (n = 2) and c.1138C>T (n = 2) mutations compared to fibroblasts from patients with carnitine palmitoyltransferase 2 (CPT2) (n = 5), mitochondrial trifunctional protein (MTP)/long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) (n = 7), and medium-chain acyl-CoA dehydrogenase (MCAD) deficiencies (n = 4) and normal controls (n = 9). All were exposed to 50 µM menadione at 37°C. Additional conditions included exposure to 39°C and/or hypoglycemia. Time to 100% cell death was confirmed with trypan blue dye exclusion. Experiments were repeated with antioxidants (Vitamins C and E or N-acetylcysteine), Bezafibrate or glucose and temperature rescue.
resultsThe most significant risk factor for vulnerability to menadione-induced oxidative stress was the presence of a FAO defect. SCADD fibroblasts were the most vulnerable compared to other FAO disorders and controls, and were similarly affected, independent of genotype. Cell death was exacerbated by hyperthermia and/or hypoglycemia. Hyperthermia was a more significant independent risk factor than hypoglycemia. Rescue significantly prolonged survival. Incubation with antioxidants and Bezafibrate significantly increased viability of SCADD fibroblasts.
interpretationVulnerability to oxidative stress likely contributes to neurotoxicity of SCADD regardless of ACADS genotype and is significantly exacerbated by hyperthermia. We recommend rigorous temperature control in SCADD patients during acute illness. Antioxidants and Bezafibrate may also prove instrumental in their management.
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