Tissue specificity of a human mitochondrial disease: Differentiation- enhanced mis-splicing of the fe-s scaffold gene iscu renders patient cells more sensitive to oxidative stress in ISCU myopathy

Daniel R. Crooks, Suh Young Jeong, Wing Hang Tong, Manik C. Ghosh, Hayden Olivierre, Ronald G. Haller, Tracey A. Rouault

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Iron-sulfur (Fe-S) cluster cofactors are formed on the scaffold protein ISCU. ISCU myopathy is a disease caused by an intronic mutation that leads to abnormally spliced ISCU mRNA. We found that two predominant mis-spliced ISCU mRNAs produce a truncated and short-lived ISCU protein product in multiple patient cell types. Expression of the muscle-specific transcription factor MyoD further diminished normal splicing of ISCU mRNA in patient myoblasts, demonstrating that the process of muscle differentiation enhances the loss of normal ISCUmRNA splicing. ISCU protein was nearly undetectable in patient skeletal muscle, but was higher in patient myoblasts, fibroblasts, and lymphoblasts.Wenext treated patient cells with pro-oxidants to mimic the oxidative stress associated with muscle activity. Brief hydrogen peroxide treatment or incubation in an enriched oxygen atmosphere led to a marked further reduction of ISCU protein levels, which could be prevented by pretreatment with the antioxidant ascorbate. Thus, we conclude that skeletal muscle differentiation of patient cells causes a higher degree of abnormal ISCU splicing and that oxidative stress resulting from skeletal muscle work destabilizes the small amounts of normal ISCU protein generated in patient skeletal muscles.

Original languageEnglish (US)
Pages (from-to)40119-40130
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number48
DOIs
StatePublished - Nov 23 2012

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sulofenur
Mitochondrial Diseases
Organ Specificity
Oxidative stress
Muscular Diseases
Scaffolds
Oxidative Stress
Genes
Tissue
Muscle
Skeletal Muscle
Myoblasts
Proteins
Muscles
Messenger RNA
Fibroblasts

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Tissue specificity of a human mitochondrial disease : Differentiation- enhanced mis-splicing of the fe-s scaffold gene iscu renders patient cells more sensitive to oxidative stress in ISCU myopathy. / Crooks, Daniel R.; Jeong, Suh Young; Tong, Wing Hang; Ghosh, Manik C.; Olivierre, Hayden; Haller, Ronald G.; Rouault, Tracey A.

In: Journal of Biological Chemistry, Vol. 287, No. 48, 23.11.2012, p. 40119-40130.

Research output: Contribution to journalArticle

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