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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

  • Charlotte Veyrat-DurebexEmail author
  • Céline Bris
  • Philippe Codron
  • Cinzia Bocca
  • Stéphanie Chupin
  • Philippe Corcia
  • Patrick Vourc’h
  • Rudolf Hergesheimer
  • Julien Cassereau
  • Benoit Funalot
  • Christian R Andres
  • Guy Lenaers
  • Philippe Couratier
  • Pascal Reynier
  • Hélène BlascoEmail author
Article

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.

Keywords

Amyotrophic lateral sclerosis Metabolomics Lipidomics Fibroblasts Mitochondria Oxidative stress 

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

Notes

Acknowledgements

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

Authors’ 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.

Compliance with Ethical Standards

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.

Conflict of Interest

All authors declare that they have no conflict of interest.

Supplementary material

12035_2019_1484_MOESM1_ESM.xlsx (10 kb)
Table S1 Table of mtDNA pathogenic reported variants. (XLSX 10 kb)
12035_2019_1484_MOESM2_ESM.xlsx (16 kb)
Table S2 List of identified metabolites in whole cells and mito-ER extracts. (XLSX 15 kb)
12035_2019_1484_MOESM3_ESM.xlsx (23 kb)
Table S3 List of identified lipids in whole cells and mito-ER extracts. (XLSX 23 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Charlotte Veyrat-Durebex
    • 1
    • 2
    • 3
    Email author
  • Céline Bris
    • 1
    • 2
  • Philippe Codron
    • 2
    • 4
  • Cinzia Bocca
    • 2
  • Stéphanie Chupin
    • 1
  • Philippe Corcia
    • 5
    • 6
    • 7
  • Patrick Vourc’h
    • 3
    • 5
  • Rudolf Hergesheimer
    • 5
  • Julien Cassereau
    • 2
    • 4
  • Benoit Funalot
    • 7
  • Christian R Andres
    • 3
    • 5
  • Guy Lenaers
    • 2
  • Philippe Couratier
    • 7
  • Pascal Reynier
    • 1
    • 2
  • Hélène Blasco
    • 2
    • 3
    • 5
    Email author
  1. 1.Département de Biochimie et GénétiqueCHU d’AngersAngersFrance
  2. 2.Unité Mixte de Recherche MITOVASC, CNRS 6015-INSERM 1083Université d’AngersAngersFrance
  3. 3.Laboratoire de Biochimie et Biologie MoléculaireCHRU Hôpital BretonneauToursFrance
  4. 4.Centre de Ressources et de Compétences SLA, Service de NeurologieCHU AngersAngersFrance
  5. 5.Université de Tours, Inserm U1253ToursFrance
  6. 6.Centre de Référence SLA, Service de Neurologie, CHRU BretonneauToursFrance
  7. 7.Fédération des CRCSLA Tours et Limoges, LITORALSToursFrance

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