Skin fibroblast metabolomic profiling reveals that lipid dysfunction predicts the severity of Friedreich's ataxia
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved..
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a triplet guanine-adenine-adenine (GAA) repeat expansion in intron 1 of the FXN gene, which leads to decreased levels of the frataxin protein. Frataxin is involved in the formation of iron-sulfur (Fe-S) cluster prosthetic groups for various metabolic enzymes. To provide a better understanding of the metabolic status of patients with FRDA, here we used patient-derived fibroblast cells as a surrogate tissue for metabolic and lipidomic profiling by liquid chromatography-high resolution mass spectrometry. We found elevated HMG-CoA and β-hydroxybutyrate-CoA levels, implying dysregulated fatty acid oxidation, which was further demonstrated by elevated acyl-carnitine levels. Lipidomic profiling identified dysregulated levels of several lipid classes in FRDA fibroblast cells when compared with non-FRDA fibroblast cells. For example, levels of several ceramides were significantly increased in FRDA fibroblast cells; these results positively correlated with the GAA repeat length and negatively correlated with the frataxin protein levels. Furthermore, stable isotope tracing experiments indicated increased ceramide synthesis, especially for long-chain fatty acid-ceramides, in FRDA fibroblast cells compared with ceramide synthesis in healthy control fibroblast cells. In addition, PUFA-containing triglycerides and phosphatidylglycerols were enriched in FRDA fibroblast cells and negatively correlated with frataxin levels, suggesting lipid remodeling as a result of FXN deficiency. Altogether, we demonstrate patient-derived fibroblast cells exhibited dysregulated metabolic capabilities, and their lipid dysfunction predicted the severity of FRDA, making them a useful surrogate to study the metabolic status in FRDA.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:63 |
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| Enthalten in: |
Journal of lipid research - 63(2022), 9 vom: 01. Sept., Seite 100255 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Dezhen [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 04.10.2022 Date Revised 25.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jlr.2022.100255 |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Skin fibroblast metabolomic profiling reveals that lipid dysfunction predicts the severity of Friedreich's ataxia |
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| 520 | |a Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a triplet guanine-adenine-adenine (GAA) repeat expansion in intron 1 of the FXN gene, which leads to decreased levels of the frataxin protein. Frataxin is involved in the formation of iron-sulfur (Fe-S) cluster prosthetic groups for various metabolic enzymes. To provide a better understanding of the metabolic status of patients with FRDA, here we used patient-derived fibroblast cells as a surrogate tissue for metabolic and lipidomic profiling by liquid chromatography-high resolution mass spectrometry. We found elevated HMG-CoA and β-hydroxybutyrate-CoA levels, implying dysregulated fatty acid oxidation, which was further demonstrated by elevated acyl-carnitine levels. Lipidomic profiling identified dysregulated levels of several lipid classes in FRDA fibroblast cells when compared with non-FRDA fibroblast cells. For example, levels of several ceramides were significantly increased in FRDA fibroblast cells; these results positively correlated with the GAA repeat length and negatively correlated with the frataxin protein levels. Furthermore, stable isotope tracing experiments indicated increased ceramide synthesis, especially for long-chain fatty acid-ceramides, in FRDA fibroblast cells compared with ceramide synthesis in healthy control fibroblast cells. In addition, PUFA-containing triglycerides and phosphatidylglycerols were enriched in FRDA fibroblast cells and negatively correlated with frataxin levels, suggesting lipid remodeling as a result of FXN deficiency. Altogether, we demonstrate patient-derived fibroblast cells exhibited dysregulated metabolic capabilities, and their lipid dysfunction predicted the severity of FRDA, making them a useful surrogate to study the metabolic status in FRDA | ||
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| 700 | 1 | |a Ho, Elaine S |e verfasserin |4 aut | |
| 700 | 1 | |a Cotticelli, M Grazia |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Peining |e verfasserin |4 aut | |
| 700 | 1 | |a Napierala, Jill S |e verfasserin |4 aut | |
| 700 | 1 | |a Hauser, Lauren A |e verfasserin |4 aut | |
| 700 | 1 | |a Napierala, Marek |e verfasserin |4 aut | |
| 700 | 1 | |a Himes, Blanca E |e verfasserin |4 aut | |
| 700 | 1 | |a Wilson, Robert B |e verfasserin |4 aut | |
| 700 | 1 | |a Lynch, David R |e verfasserin |4 aut | |
| 700 | 1 | |a Mesaros, Clementina |e verfasserin |4 aut | |
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