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

Abstract

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.

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

“…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].…”

“…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).…”

“…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).…”

Outcomes of cases with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency - Report from the Inborn Errors of Metabolism Information System

“…Historically, 3-MCC deficiency was reported to be associated with developmental delays, hypoglycemia, acidosis, failure to thrive and other poor outcomes [3,8–10,13,19,20,24]. Rat models have noted the metabolites of 3-MCC deficiency are associated with oxidative damage in the brain [29]. With NBS, the incidence of this disorder is much higher than previously expected with the majority of cases having largely normal medical and developmental outcome.…”

Metabonomic Study of the Effects of Acanthopanax senticosus on Peripheral System of Rats

“…In addition, the levels of two potentially toxic metabolites, 3-methylcrotonylglycine and glycocholic acid, were reduced by AS. The accumulation of 3-methylcrotonylglycine can induce oxidative damage by provoking lipid and protein oxidation [26]. Glycocholic acid is a sensitive indicator of hepatobiliary disease, whose upregulation is related to hepatocellular necrosis, edema of the portal tracts, and disruption of the limiting plate and parenchymal fibrosis [27].…”