Induction of oxidative stress by the metabolites accumulating in 3-methylglutaconic aciduria in cerebral cortex of young rats

Leipnitz, Guilhian; Seminotti, Bianca; Amaral, Alexandre Umpierrez; Bortoli, Giorgia de; Solano, Alexandre Francisco; Schuck, Patrícia Fernanda; Wyse, Ângela T. S.; Wannmacher, Clóvis Milton Duval; Latini, Alexandra; Wajner, Moaçir

doi:10.1016/j.lfs.2007.12.024

Cited by 36 publications

(20 citation statements)

References 45 publications

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“…Transcripts of mitochondrial respiratory chain complexes I, II and IV were significantly differentially expressed (Table 4) affecting the OXPHOS system (NDUFS2, SDHD, MT-CO1/COX1, COX6 and COX17). This result correlates with the finding that the metabolites, MCG and MCA, inhibited mitochondrial respiratory chain complexes II and III in vitro in rat brain homogenates [55] and could induced lipid and protein oxidative damage [55,57,64].…”

Section: Discussionsupporting

confidence: 89%

“…Similar to the transcriptome of symptomatic, clinically severe MCC deficiency and neurological studies on the cerebral cortex of young rats [55][56][57][60][61][62][63][64][65], this marginal MCC deficiency skin fibroblast transcriptome also had a genetic footprint suggestive of partial mitochondrial dysfunction, oxidative stress and disruption of energy homeostasis. Transcripts of mitochondrial respiratory chain complexes I, II and IV were significantly differentially expressed (Table 4) affecting the OXPHOS system (NDUFS2, SDHD, MT-CO1/COX1, COX6 and COX17).…”

Section: Discussionmentioning

confidence: 61%

“…Imbalances in eicosanoid metabolism signalling have been detected in individuals with a weak tolerance to environmental factors and susceptibility to environmental stressors that often result in asthma [94][95][96][97], allergy, eczema [98][99][100], arthritis [81] as well as the development of cancer [73] and might also play a role in the development of non-specific symptoms of marginal MCC deficiency. Therefore, life-long monitoring of ROS levels of individuals with MCC deficiency along with the administration of anti-oxidants to prevent and manage deleterious secondary signalling responses may be beneficial as previously proposed (Figure 3) [55,56,60,64,65,101].…”

Section: Discussionmentioning

confidence: 96%

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Biochemical Characterisation and Whole Genome Expression Profiling of Cultured Skin Fibroblasts from Two South African Adults with Urinary 3-Hydroxyisovaleric Acid and 3-Methylcrotonylglycine

Berg¹,

Erasmus²,

Suormala³

et al. 2016

J Rare Disord Diagn Ther

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We report on the first case of marginal 3-methylcrotonyl-CoA carboxylase (MCC) deficiency in South Africa. Urinary 3-hydroxyisovaleric acid and 3-methylcrotonylglycine were detected in four males of a non-consanguineous family. Only the index patient (NWU001) had non-specific symptoms, the others were asymptomatic. The inherited metabolite profile and partially reduced MCC activity were indicative of marginal MCC deficiency. In vivo L-leucine loading confirmed a reduced flux through the leucine degradation pathway. No known deleterious mutations were detected in the open reading frames of MCCC1 and MCCC2. NWU001 was heterozygous for a SNP in MCCC1 (rs2270968; c.1391A>C, p.H464P). NWU002 was heterozygous for a MCCC2 splice variant which skips exon 7 and causes an in frame deletion of 38 amino acids that is identical to a predicted shorter MCCC2 isoform-2 (Q9HCC0-2). Whole genome expression profiles from cultured skin fibroblasts of NWU001 and NWU002 and two healthy adults using Affymetrix ® HuExST1.0 arrays detected 14237 significantly differentially expressed transcript IDs of which only 1277 have known annotation and gene association. The underlying molecular interactions, secondary signalling responses and functional relationships of these 1277 transcripts were inspected following a knowledge-based functional analyses approach using Ingenuity Pathway Analysis software. The transcriptome had a footprint of oxidative stress, disruption of energy homeostasis, inflammation, impaired cellular maintenance and repair mechanisms. Of note was the significant up regulation of the fatty acid amide hydrolase variant 2 (FAAH2) HuChrX transcript in the anandamide degradation canonical pathway. The observations that the two MCC transcripts were not significantly differentially expressed and that more than 90% of the significantly differently expressed transcripts are still poorly annotated further support the notion that secondary factors other than the MCC loci impact on the MCC deficiency phenome.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 96%

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Biochemical Characterisation and Whole Genome Expression Profiling of Cultured Skin Fibroblasts from Two South African Adults with Urinary 3-Hydroxyisovaleric Acid and 3-Methylcrotonylglycine

Berg¹,

Erasmus²,

Suormala³

et al. 2016

J Rare Disord Diagn Ther

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“…In the last few years, various in vivo and in vitro findings have suggested the involvement of oxidative stress in the etiology of the neurological damage observed in some organic acidurias (Wajner et al 2004;Latini et al 2002;de Oliveira Marques et al 2003;Fontella et al 2000;Richard et al 2007;Ribas et al 2010;Solano et al 2008;Leipnitz et al 2008). Oxidative stress was also demonstrated in disorders of amino acid metabolism, such as maple syrup urine disease (MSUD), tyrosinemia type I, and homocystinuria (Barschak et al , 2007(Barschak et al , and 2008Bridi et al 2005;Bird et al 1995;Streck et al 2001 andWyse et al 2002).…”

Section: Oxidative Stress and Neurodegenerationmentioning

confidence: 99%

Oxidative Stress in Phenylketonuria: What is the Evidence?

et al. 2011

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Phenylketonuria (PKU) is an inborn error of amino acid metabolism caused by severe deficiency of phenylalanine hydroxylase activity, leading to the accumulation of phenylalanine and its metabolites in blood and tissues of affected patients. Phenylketonuric patients present as the major clinical feature mental retardation, whose pathomechanisms are poorly understood. In recent years, mounting evidence has emerged indicating that oxidative stress is possibly involved in the pathology of PKU. This article addresses some of the recent developments obtained from animal studies and from phenylketonuric patients indicating that oxidative stress may represent an important element in the pathophysiology of PKU. Several studies have shown that enzymatic and non-enzymatic antioxidant defenses are decreased in plasma and erythrocytes of PKU patients, which may be due to an increased free radical generation or secondary to the deprivation of micronutrients which are essential for these defenses. Indeed, markers of lipid, protein, and DNA oxidative damage have been reported in PKU patients, implying that reactive species production is increased in this disorder. A considerable set of data from in vitro and in vivo animal studies have shown that phenylalanine and/or its metabolites elicit reactive species in brain rodent. These findings point to a disruption of pro-oxidant/antioxidant balance in PKU. Considering that the brain is particularly vulnerable to oxidative attack, it is presumed that the administration of appropriate antioxidants as adjuvant agents, in addition to the usual treatment based on restricted diets or supplementation of tetrahydrobiopterin, may represent another step in the prevention of the neurological damage in PKU.

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“…The “accumulation of toxic metabolites may give rise to slow-onset excitotoxicity with cellular dysfunction and eventually cell death” [1]. It has been previously demonstrated that 3-MGA exhibits a toxic effect on the cerebral cortex in rats [14]. There is also evidence that 3-MGA and 3-HIVA accumulation is both neurotoxic and hepatotoxic and can cause brain damage [15, 16].…”

Section: Discussionmentioning

confidence: 99%

3-Methylglutaconyl-Coenzyme-A Hydratase Deficiency and the Development of Dilated Cardiomyopathy

et al. 2014

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A 25-year-old Canadian male with a history of 3-methylglutaconyl-coenzyme-A hydratase deficiency, also known as 3-methylglutaconic aciduria type I, a very rare inborn error of metabolism, presented with respiratory distress, nausea, vomiting and signs of multisystem organ failure due to a suspected underlying infectious process. An electrocardiogram revealed bilateral atrial enlargement and an elevated brain natriuretic peptide on the initial laboratory studies, which prompted a more thorough cardiac workup. The transthoracic echocardiogram revealed a dilated cardiomyopathy with severe systolic dysfunction. The deficient enzyme present in this patient is involved in the pathway of leucine catabolism and is particularly important in various tissues for energy production and sterol synthesis. The dilated cardiomyopathy in this patient possibly had a variety of potential mechanisms including: a mitochondrial myopathy due to the deficiency of this enzyme leading to a defect in energy production inside cardiac myocytes; or a direct toxicity from 3-methylglutaconic acid (3-MGA) and its toxic metabolites; or a cardiac dysfunction due to a variety of other potential mechanisms. In conclusion, this patient’s clinical presentation suggested that 3-methylglutaconyl-CoA hydratase deficiency could cause a severe dilated cardiomyopathy and heart failure.

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Induction of oxidative stress by the metabolites accumulating in 3-methylglutaconic aciduria in cerebral cortex of young rats

Cited by 36 publications

References 45 publications

Biochemical Characterisation and Whole Genome Expression Profiling of Cultured Skin Fibroblasts from Two South African Adults with Urinary 3-Hydroxyisovaleric Acid and 3-Methylcrotonylglycine

Biochemical Characterisation and Whole Genome Expression Profiling of Cultured Skin Fibroblasts from Two South African Adults with Urinary 3-Hydroxyisovaleric Acid and 3-Methylcrotonylglycine

Oxidative Stress in Phenylketonuria: What is the Evidence?

3-Methylglutaconyl-Coenzyme-A Hydratase Deficiency and the Development of Dilated Cardiomyopathy

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