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Metabo-lipidomics of Fibroblasts and Mitochondrial-Endoplasmic Reticulum Extracts from ALS Patients Shows Alterations in Purine, Pyrimidine, Energetic, and Phospholipid Metabolisms

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Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by a wide metabolic remodeling, as shown by recent metabolomics and lipidomics studies performed in samples from patient cohorts and experimental animal models. Here, we explored the metabolome and lipidome of fibroblasts from sporadic ALS patients (n = 13) comparatively to age- and sex-matched controls (n = 11), and the subcellular fraction containing the mitochondria and endoplasmic reticulum (mito-ER), given that mitochondrial dysfunctions and ER stress are important features of ALS patho-mechanisms. We also assessed the mitochondrial oxidative respiration and the mitochondrial genomic (mtDNA) sequence, although without yielding significant differences. Compared to controls, ALS fibroblasts did not exhibit a mitochondrial respiration defect nor an increased proportion of mitochondrial DNA mutations. In addition, non-targeted metabolomics and lipidomics analyses identified 124 and 127 metabolites, and 328 and 220 lipids in whole cells and the mito-ER fractions, respectively, along with partial least-squares–discriminant analysis (PLS-DA) models being systematically highly predictive of the disease. The most discriminant metabolomic features were the alteration of purine, pyrimidine, and energetic metabolisms, suggestive of oxidative stress and of pro-inflammatory status. The most important lipidomic feature in the mito-ER fraction was the disturbance of phosphatidylcholine PC (36:4p) levels, which we had previously reported in the cerebrospinal fluid of ALS patients and in the brain from an ALS mouse model. Thus, our results reveal that fibroblasts from sporadic ALS patients share common metabolic remodeling, consistent with other metabolic studies performed in ALS, opening perspectives for further exploration in this cellular model in ALS.

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Abbreviations

ALS:

amyotrophic lateral sclerosis

sALS:

sporadic ALS

ER:

endoplasmic reticulum

mtDNA:

mitochondrial DNA

PCA:

principal component analysis

PLS-DA:

partial least square discriminant analysis

OXPHOS:

oxidative phosphorylation

FVC:

forced vital capacity

BMI:

body mass index

HRMS:

high-resolution mass spectrometry

UPLC:

ultra-performance liquid chromatography

ESI:

electrospray ionization

QC:

quality control

VIP:

variable importance in projection

OCR:

oxygen consumption rate

RCR:

respiration capacity rate

SM:

sphingomyelins

PC:

phosphatidylcholines

PE:

phosphatidylethanolamines

ROS:

reactive oxygen species

CSF:

cerebrospinal fluid

Cer:

ceramides

DHA:

docosahexaenoic acid

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Acknowledgements

We thank University Hospitals of Angers and Limoges for patients’ recruitment and fibroblasts’ sampling.

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Authors and Affiliations

  1. Département de Biochimie et Génétique, CHU d’Angers, Angers, France

    Charlotte Veyrat-Durebex, Céline Bris, Stéphanie Chupin & Pascal Reynier

  2. Unité Mixte de Recherche MITOVASC, CNRS 6015-INSERM 1083, Université d’Angers, Angers, France

    Charlotte Veyrat-Durebex, Céline Bris, Philippe Codron, Cinzia Bocca, Julien Cassereau, Guy Lenaers, Pascal Reynier & Hélène Blasco

  3. Laboratoire de Biochimie et Biologie Moléculaire, CHRU Hôpital Bretonneau, 2, Bd Tonnellé, 37044, Tours, France

    Charlotte Veyrat-Durebex, Patrick Vourc’h, Christian R Andres & Hélène Blasco

  4. Centre de Ressources et de Compétences SLA, Service de Neurologie, CHU Angers, Angers, France

    Philippe Codron & Julien Cassereau

  5. Université de Tours, Inserm U1253, Tours, France

    Philippe Corcia, Patrick Vourc’h, Rudolf Hergesheimer, Christian R Andres & Hélène Blasco

  6. Centre de Référence SLA, Service de Neurologie, CHRU Bretonneau, Tours, France

    Philippe Corcia

  7. Fédération des CRCSLA Tours et Limoges, LITORALS, Tours, France

    Philippe Corcia, Benoit Funalot & Philippe Couratier

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  1. Charlotte Veyrat-Durebex
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  2. Céline Bris
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  3. Philippe Codron
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Contributions

C.V-D and H.B designed and supervised the study, performed statistical analysis and wrote the manuscript; C. Br performed mtDNA experiments and analyzed mtDNA sequence; C.V-D and C.Bo performed metabolomic and lipidomic assays, S.C performed cell cultures and mitochondrial function assessment; P.Cod and B.F recruited ALS patients and performed fibroblast sampling; J.C and P. Cou supervised patients’ recruitment; P.V supervised genetic determination of genes involved in ALS; R.H gave technical and intellectual support and critical advice for English writing; P.Cor, P.V, and C.R.A gave technical and intellectual support; G.L and P.R gave intellectual support and conceptual advice for manuscript writing. All authors offered conceptual advice and comments on the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Charlotte Veyrat-Durebex or Hélène Blasco.

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Ethical Approval and Consent to Participate

All the participants in this current study provided their informed consent for the use of their fibroblasts for research. The ethic committees of the Centre for Human Research of Angers and Limoges Hospitals approved the study and the consent process.

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All authors declare that they have no conflict of interest.

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Table S1

Table of mtDNA pathogenic reported variants. (XLSX 10 kb)

Table S2

List of identified metabolites in whole cells and mito-ER extracts. (XLSX 15 kb)

Table S3

List of identified lipids in whole cells and mito-ER extracts. (XLSX 23 kb)

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Veyrat-Durebex, C., Bris, C., Codron, P. et al. Metabo-lipidomics of Fibroblasts and Mitochondrial-Endoplasmic Reticulum Extracts from ALS Patients Shows Alterations in Purine, Pyrimidine, Energetic, and Phospholipid Metabolisms. Mol Neurobiol 56, 5780–5791 (2019). https://doi.org/10.1007/s12035-019-1484-7

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