3-Methylcrotonylglycine Disrupts Mitochondrial Energy Homeostasis and Inhibits Synaptic Na+,K+-ATPase Activity in Brain of Young Rats

Moura, Alana Pimentel; Ribeiro, César Augusto João; Zanatta, Ângela; Busanello, Estela Natacha Brandt; Tonin, Anelise Miotti; Wajner, Moaçir

doi:10.1007/s10571-011-9761-7

Cited by 15 publications

(11 citation statements)

References 52 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: 60%

“…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%

“…Since oxidative stress and unregulated reactive oxygen species (ROS) were reported to contribute to MCC deficiency related neurological symptoms [55][56][57], the knowledge-based ROS interactome of marginal MCC deficiency was compiled and inspected. Secondary signalling responses and the associated impact on target transcripts of the interactome were identified with IPA software (Figure 3).…”

Section: Functional Analyses and Targeted Inspection Of Pathways And mentioning

confidence: 99%

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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: 60%

Section: Discussionmentioning

confidence: 96%

Section: Functional Analyses and Targeted Inspection Of Pathways And mentioning

confidence: 99%

See 2 more Smart Citations

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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“…S2). Accumulation of excess MCA and MCG, which interferes with mitochondrial respiration in the brain (25), results in a disease characterized by several symptoms, such as failure to thrive, vomiting, metabolic acidosis, delayed mental development, and death (26). The genes encoding for the enzymes indoleamine 2,3-dioxygenase and kynureninase, which are part of the tryptophan degradation pathway and are associated with the congenital human disease hyperkynureninuria, correspond to another fungal DNGP.…”

Section: Resultsmentioning

confidence: 99%

Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds

McGary

Slot

Rokas

2013

Proc. Natl. Acad. Sci. U.S.A.

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Genomic analyses have proliferated without being tied to tangible phenotypes. For example, although coordination of both gene expression and genetic linkage have been offered as genetic mechanisms for the frequently observed clustering of genes participating in fungal metabolic pathways, elucidation of the phenotype(s) favored by selection, resulting in cluster formation and maintenance, has not been forthcoming. We noted that the cause of certain well-studied human metabolic disorders is the accumulation of toxic intermediate compounds (ICs), which occurs when the product of an enzyme is not used as a substrate by a downstream neighbor in the metabolic network. This raises the hypothesis that the phenotype favored by selection to drive gene clustering is the mitigation of IC toxicity. To test this, we examined 100 diverse fungal genomes for the simplest type of cluster, gene pairs that are both metabolic neighbors and chromosomal neighbors immediately adjacent to each other, which we refer to as "double neighbor gene pairs" (DNGPs). Examination of the toxicity of their corresponding ICs shows that, compared with chromosomally nonadjacent metabolic neighbors, DNGPs are enriched for ICs that have acutely toxic LD 50 doses or reactive functional groups. Furthermore, DNGPs are significantly more likely to be divergently oriented on the chromosome; remarkably, ∼40% of these DNGPs have ICs known to be toxic. We submit that the structure of synteny in metabolic pathways of fungi is a signature of selection for protection against the accumulation of toxic metabolic intermediates.gene cluster | gene orientation | inborn error of metabolism | secondary metabolism | specialized metabolism T here is a critical distinction between selection for a trait, which occurs at the phenotypic level, and selection of the underlying molecular genetic mechanisms that generate the trait (1). For example, some butterfly species avoid predation by mimicking the wing-pattern morphs of other butterflies that are toxic to birds (2, 3). In this case, predation avoidance selects for specific wing-pattern morphs, resulting in the selection of specific allelic combinations of genes in a supergene locus (4).The rise of molecular biology and subsequent abundance of genomic data have shifted the focus from phenotypes to genotypes, blurring the distinction between selection for and selection of. For example, many studies indicate that selection has sculpted the order and orientation of genes in eukaryotic genomes (5-13); although these analyses convincingly argue that specific genetic mechanisms are important in fine-tuning the structure of synteny on chromosomes, they implicitly assume that it is the genetic mechanisms themselves, rather than organismal phenotypes, that selection targets.One of the most conspicuous characteristics of fungal genomes is that the genes participating in a metabolic pathway are often physically linked, or clustered. Although both coordination of gene expression (5,6,(11)(12)(13)(14)(15)(16) and genetic linkage (7, 17) h...

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Neurochemical Evidence that the Metabolites Accumulating in 3-Methylcrotonyl-CoA Carboxylase Deficiency Induce Oxidative Damage in Cerebral Cortex of Young Rats

et al. 2012

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Isolated 3-methylcrotonyl-CoA carboxylase deficiency (3MCCD) is an autosomal recessive disorder of leucine metabolism biochemically characterized by accumulation of 3-methylcrotonylglycine (3MCG), 3-methylcrotonic acid (3MCA) and 3-hydroxyisovaleric acid. A considerable number of affected individuals present neurological symptoms with or without precedent crises of metabolic decompensation and brain abnormalities whose pathogenesis is poorly known. We investigated the in vitro effects of 3MCG and 3MCA on important parameters of oxidative stress in cerebral cortex of young rats. 3MCG and 3MCA significantly increased TBA-RS and carbonyl formation, indicating that these compounds provoke lipid and protein oxidation, respectively. In contrast, nitric oxide production was not affected by 3MCG and 3MCA. Furthermore, 3MCG- and 3MCA-induced elevation of TBA-RS values was fully prevented by melatonin, trolox and reduced glutathione, but not by the nitric oxide inhibitor N(ω)-nitro-L-arginine methyl ester or the combination of catalase plus superoxide dismutase, indicating that reactive oxygen species were involved in the oxidative damage caused by these compounds. We also found that the activity of the antioxidant enzymes glutathione peroxidase, catalase, superoxide dismutase and glutathione reductase were not altered in vitro by 3MCG and 3MCA. It is therefore presumed that alterations of the cellular redox homeostasis caused by the major metabolites accumulating in 3MCCD may potentially be involved in the pathophysiology of the neurological dysfunction and structural brain alterations found in patients affected by this disorder.

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3-Methylcrotonylglycine Disrupts Mitochondrial Energy Homeostasis and Inhibits Synaptic Na+,K+-ATPase Activity in Brain of Young Rats

Cited by 15 publications

References 52 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

Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds

Neurochemical Evidence that the Metabolites Accumulating in 3-Methylcrotonyl-CoA Carboxylase Deficiency Induce Oxidative Damage in Cerebral Cortex of Young Rats

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