3-Methylglutaric acid in energy metabolism

Jones, Dylan E.; Perez, Leanne; Ryan, Robert O.

doi:10.1016/j.cca.2019.11.006

Cited by 30 publications

(31 citation statements)

References 42 publications

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“…These results are concordant with previous observations made in NIH3T3 murine cells, which showed that HACE1 was barely expressed in the mitochondria but cofractionate with cytosolic and endoplasmatic reticulum markers [30]. Since 3-MGA-uria is frequently associated to alterations of the mitochondrial morphology and the assembly of the OXPHOS system [19,32], we performed a detailed analysis of the mitochondrial function in HACE1 mutated cells. The results showed alterations in the mitochondrial morphology and a partial disassembly of the OXPHOS system.…”

Section: Discussionsupporting

confidence: 91%

“…The clinical data of the previously described individuals do not differ from the phenotype of the patient reported here, but 3-MGA-uria has not been reported in any of the previous cases. Although the true origin of 3-MGA excretion is not well known, the presence of this metabolite in urine is considered a good biomarker of mitochondrial dysfunction; in particular, it has been associated to mutations in genes encoding for proteins related to the mitochondrial membrane [19,32]. Even though the patient phenotype could resemble a mitochondrial disorder, a subcellular fractionation analysis performed in control fibroblasts demonstrated that HACE1 mainly localizes in the cytosolic fraction.…”

Section: Discussionmentioning

confidence: 99%

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Physiopathological Bases of the Disease Caused by HACE1 Mutations: Alterations in Autophagy, Mitophagy and Oxidative Stress Response

Ugarteburu

Sánchez-Vilés

Ramos

et al. 2020

JCM

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Recessive HACE1 mutations are associated with a severe neurodevelopmental disorder (OMIM: 616756). However, the physiopathologycal bases of the disease are yet to be completely clarified. Whole-exome sequencing identified homozygous HACE1 mutations (c.240C>A, p.Cys80Ter) in a patient with brain atrophy, psychomotor retardation and 3-methylglutaconic aciduria, a biomarker of mitochondrial dysfunction. To elucidate the pathomechanisms underlying HACE1 deficiency, a comprehensive molecular analysis was performed in patient fibroblasts. Western Blot demonstrated the deleterious effect of the mutation, as the complete absence of HACE1 protein was observed. Immunofluorescence studies showed an increased number of LC3 puncta together with the normal initiation of the autophagic cascade, indicating a reduction in the autophagic flux. Oxidative stress response was also impaired in HACE1 fibroblasts, as shown by the reduced NQO1 and Hmox1 mRNA levels observed in H2O2-treated cells. High levels of lipid peroxidation, consistent with accumulated oxidative damage, were also detected. Although the patient phenotype could resemble a mitochondrial defect, the analysis of the mitochondrial function showed no major abnormalities. However, an important increase in mitochondrial oxidative stress markers and a strong reduction in the mitophagic flux were observed, suggesting that the recycling of damaged mitochondria might be targeted in HACE1 cells. In summary, we demonstrate for the first time that the impairment of autophagy, mitophagy and oxidative damage response might be involved in the pathogenesis of HACE1 deficiency.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Physiopathological Bases of the Disease Caused by HACE1 Mutations: Alterations in Autophagy, Mitophagy and Oxidative Stress Response

Ugarteburu

Sánchez-Vilés

Ramos

et al. 2020

JCM

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“…In primary 3MGC aciduria, mutations in genes encoding either of two leucine metabolic pathway enzymes results in a buildup of upstream intermediates and excretion of 3MGC acid. Specifically, deficiencies in 3MGC CoA hydratase ( AUH ) or 3‐hydroxy‐3‐methylglutaryl (HMG) CoA lyase ( HMGCL ) are associated with 3MGC aciduria 2 . In leucine metabolism, AUH catalyzes hydration of trans ‐3MGC CoA to ( S )‐HMG CoA while HMG CoA lyase cleaves ( S )‐HMG CoA to acetoacetate plus acetyl CoA.…”

Section: Introductionmentioning

confidence: 99%

“…By interfering with the efficiency of aerobic respiration, electron transport chain (ETC) activity, and oxidative phosphorylation, are compromised. Under these circumstances, in cardiac and skeletal muscle mitochondria, NADH levels rise, the TCA cycle is inhibited and, in three steps, acetyl CoA is diverted to 3MGC CoA 2 . The enzymes involved include methylacetoacetyl‐CoA thiolase, HMG CoA synthase 2 and AUH, which functions in the reverse direction, dehydrating ( S )‐HMG CoA to trans ‐3MGC CoA.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, deficiencies in 3MGC CoA hydratase (AUH) or 3-hydroxy-3-methylglutaryl (HMG) CoA lyase (HMGCL) are associated with 3MGC aciduria. 2 In leucine metabolism, AUH catalyzes hydration of trans-3MGC CoA to (S)-HMG CoA while HMG CoA lyase cleaves (S)-HMG CoA to acetoacetate plus acetyl CoA. When either of these enzymes is deficient, leucine administration results in increased urinary excretion of 3MGC acid.…”

Section: Introductionmentioning

confidence: 99%

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Isomerization of trans‐3‐methylglutaconic acid

et al. 2020

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3‐Methylglutaconic (3MGC) aciduria is a common phenotypic feature of a growing number of inborn errors of metabolism. “Primary” 3MGC aciduria is caused by deficiencies in leucine pathway enzymes while “secondary” 3MGC aciduria results from inborn errors of metabolism that impact mitochondrial energy production. The metabolic precursor of 3MGC acid is trans‐3MGC CoA, an intermediate in the leucine catabolism pathway. Gas chromatography‐mass spectrometry (GC‐MS) analysis of commercially available trans‐3MGC acid yielded a mixture of cis and trans isomers while 1H‐NMR spectroscopy of trans‐3MGC acid at 25°C provided no evidence for the cis isomer. When trans‐3MGC acid was incubated under conditions used for sample derivatization prior to GC‐MS (but with no trimethylsilane added), 1H‐NMR spectroscopy provided evidence of trans to cis isomerization. Incubation of trans‐3MGC acid at 37°C resulted in time‐dependent isomerization to cis‐3MGC acid. Cis‐3MGC acid behaved in a similar manner except that, under identical incubation conditions, less isomerization occurred. In agreement with these experimental results, molecular modeling studies provided evidence that the energy minimized structure of cis‐3MGC acid is 4 kJ/mol more stable than that for trans‐3MGC acid. Once generated in vivo, trans‐3MGC acid is proposed to isomerize via a mechanism involving π electron delocalization with formation of a resonance structure that permits bond rotation. The data presented are consistent with the occurrence of both diastereomers in urine samples of subjects with 3MGC aciduria.

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