Skin fibroblast metabolomic profiling reveals that lipid dysfunction predicts the severity of Friedreich’s ataxia

Dezhen Wang, Elaine S. Ho, M. Grazia Cotticelli, Peining Xu, Jill S. Napierala, Lauren A. Hauser, Marek Napierala, Blanca E. Himes, Robert B. Wilson, David R. Lynch, Clementina Mesaros

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageEnglish (US)
Article number100255
JournalJournal of lipid research
Issue number9
StatePublished - Sep 2022
Externally publishedYes


  • ceramides
  • fatty acids oxidation
  • frataxin
  • lipid remodeling
  • lipidomics
  • neurodegenerative disorders
  • phospholipids
  • stable isotope tracing
  • triglycerides
  • triplet repeat expansion

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology


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