A Plasma Metabolomic Signature Involving Purine Metabolism in Human Optic Atrophy 1 (<i>OPA1</i>)-Related Disorders

Bocca, Cinzia; Nzoughet, Judith Kouassi; Leruez, Stéphanie; Amati‐Bonneau, Patrizia; Ferré, Marc; Kane, Mariame-Selma; Veyrat-Durebex, Charlotte; Barca, Juan Manuel Chao de la; Chevrollier, Arnaud; Homedan, Chadi; Verny, Christophe; Miléa, Dan; Procaccio, Vincent; Simard, Gilles; Bonneau, Dominique; Lenaers, Guy; Reynier, Pascal

doi:10.1167/iovs.17-23027

Cited by 23 publications

(20 citation statements)

References 37 publications

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“…Hypoxanthine and xanthine concentrations are also reduced in POAG signature. Interestingly, we found similar decreased concentrations of hypoxanthine and xanthine in the plasma of patients with Dominant Optic Atrophy related to OPA1 mutations [9]. These findings argue in favor of a mitochondrial impairment that contribute to glaucoma pathogenesis, taking into account the role played by mitochondria in nucleotide metabolism and the similitude with primary mitochondrial diseases leading to optic neuropathy.…”

Section: Discussionsupporting

confidence: 71%

“…Metabolites 2019, 9,49 8 of 15 cystathionine, and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline. The biomarkers reported in this research were allocated to the identification level 1, according to the current metabolomics standards initiative (MSI) reporting standards [10].…”

Section: Resultsmentioning

confidence: 99%

“…Herein, we report a new signature of POAG plasma using a non-targeted liquid chromatography coupled to a high resolution mass spectrometry (LC-HRMS) workflow, associated to a data mining strategy, which has recently proved its efficacy in the discovery of clinical biomarkers [8,9].…”

Section: Introductionmentioning

confidence: 99%

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A Data Mining Metabolomics Exploration of Glaucoma

et al. 2020

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Glaucoma is an age related disease characterized by the progressive loss of retinal ganglion cells, which are the neurons that transduce the visual information from the retina to the brain. It is the leading cause of irreversible blindness worldwide. To gain further insights into primary open-angle glaucoma (POAG) pathophysiology, we performed a non-targeted metabolomics analysis on the plasma from POAG patients (n = 34) and age- and sex-matched controls (n = 30). We investigated the differential signature of POAG plasma compared to controls, using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS). A data mining strategy, combining a filtering method with threshold criterion, a wrapper method with iterative selection, and an embedded method with penalization constraint, was used. These strategies are most often used separately in metabolomics studies, with each of them having their own limitations. We opted for a synergistic approach as a mean to unravel the most relevant metabolomics signature. We identified a set of nine metabolites, namely: nicotinamide, hypoxanthine, xanthine, and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline with decreased concentrations and N-acetyl-L-Leucine, arginine, RAC-glycerol 1-myristate, 1-oleoyl-RAC-glycerol, cystathionine with increased concentrations in POAG; the modification of nicotinamide, N-acetyl-L-Leucine, and arginine concentrations being the most discriminant. Our findings open up therapeutic perspectives for the diagnosis and treatment of POAG.

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Section: Discussionsupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

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A Data Mining Metabolomics Exploration of Glaucoma

et al. 2020

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“…Interestingly, our study of plasma samples from individuals affected by dominant optic atrophy due to OPA1 mutations, another form of an age- dependent progressive optic neuropathy due to mitochondrial impairment, also revealed a 50% reduction of nicotinamide. 21 The main function of NAD as a redox cofactor consists in providing electrons from oxidized nutrients to the mitochondrial respiratory chain complex I, thus sustaining adenosine triphosphate (ATP) production. In parallel, NAD-consuming enzymes, such as those involved in DNA repair, for example, poly (ADP-ribose) polymerase (PARP), may consume NAD stocks excessively during aging, in particular to prevent the accumulation of DNA mutations.…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide Deficiency in Primary Open-Angle Glaucoma

Nzoughet

Barca

Guehlouz

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To investigate the plasma concentration of nicotinamide in primary open-angle glaucoma (POAG). METHODS. Plasma of 34 POAG individuals was compared to that of 30 age-and sex-matched controls using a semiquantitative method based on liquid chromatography coupled to highresolution mass spectrometry. Subsequently, an independent quantitative method, based on liquid chromatography coupled to mass spectrometry, was used to assess nicotinamide concentration in the plasma from the same initial cohort and from a replicative cohort of 20 POAG individuals and 15 controls. RESULTS. Using the semiquantitative method, the plasma nicotinamide concentration was significantly lower in the initial cohort of POAG individuals compared to controls and further confirmed in the same cohort, using the targeted quantitative method, with mean concentrations of 0.14 lM (median: 0.12 lM; range, 0.06-0.28 lM) in the POAG group (À30%; P ¼ 0.022) and 0.19 lM (median: 0.18 lM; range, 0.08-0.47 lM) in the control group. The quantitative dosage also disclosed a significantly lower plasma nicotinamide concentration (À33%; P ¼ 0.011) in the replicative cohort with mean concentrations of 0.14 lM (median: 0.14 lM; range, 0.09-0.25 lM) in the POAG group, and 0.19 lM (median: 0.21 lM; range, 0.09-0.26 lM) in the control group. CONCLUSIONS. Glaucoma is associated with lower plasmatic nicotinamide levels, compared to controls, suggesting that nicotinamide supplementation might become a future therapeutic strategy. Further studies are needed, in larger cohorts, to confirm these preliminary findings.

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“…We used the recently developed non-targeted metabolomics pipeline for the identification of metabolites 23 to investigate the plasma of patients with various OPA1-related phenotypes and pathogenic variants (n = 25) in comparison to healthy controls (n = 20) 24 . A robust predictive model characterizing OPA1 individuals was obtained, revealing alterations of the purine metabolism with an increase of inosine and a decrease of xanthine and hypoxanthine, related to the GTP/ATP (Guanosine Triphosphate/Adenosine Triphosphate) metabolism, as well as other metabolic alterations with a reduce concentration of urocanate, choline, glycerate, 1-oleoyl-rac-glycerol, rac-glycerol-1-myristate, aspartate and glutamate, and a rise in phosphocholine and in cysteine.…”

Section: Introductionmentioning

confidence: 99%

The Metabolomic Bioenergetic Signature of Opa1-Disrupted Mouse Embryonic Fibroblasts Highlights Aspartate Deficiency

Bocca

Kane

Veyrat-Durebex

et al. 2018

Sci Rep

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OPA1 (Optic Atrophy 1) is a multi-isoform dynamin GTPase involved in the regulation of mitochondrial fusion and organization of the cristae structure of the mitochondrial inner membrane. Pathogenic OPA1 variants lead to a large spectrum of disorders associated with visual impairment due to optic nerve neuropathy. The aim of this study was to investigate the metabolomic consequences of complete OPA1 disruption in Opa1−/− mouse embryonic fibroblasts (MEFs) compared to their Opa1+/+ counterparts. Our non-targeted metabolomics approach revealed significant modifications of the concentration of several mitochondrial substrates, i.e. a decrease of aspartate, glutamate and α-ketoglutaric acid, and an increase of asparagine, glutamine and adenosine-5′-monophosphate, all related to aspartate metabolism. The signature further highlighted the altered metabolism of nucleotides and NAD together with deficient mitochondrial bioenergetics, reflected by the decrease of creatine/creatine phosphate and pantothenic acid, and the increase in pyruvate and glutathione. Interestingly, we recently reported significant variations of five of these molecules, including aspartate and glutamate, in the plasma of individuals carrying pathogenic OPA1 variants. Our findings show that the disruption of OPA1 leads to a remodelling of bioenergetic pathways with the central role being played by aspartate and related metabolites.

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A Plasma Metabolomic Signature Involving Purine Metabolism in Human Optic Atrophy 1 (OPA1)-Related Disorders

Abstract: This first metabolic signature reported in the plasma of patient carrying OPA1 pathogenic variants highlights the unexpected involvement of purine metabolism in the pathophysiology of DOA.

Cited by 23 publications

References 37 publications

A Data Mining Metabolomics Exploration of Glaucoma

A Data Mining Metabolomics Exploration of Glaucoma

Nicotinamide Deficiency in Primary Open-Angle Glaucoma

The Metabolomic Bioenergetic Signature of Opa1-Disrupted Mouse Embryonic Fibroblasts Highlights Aspartate Deficiency

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