The presence of multiple cellular defects associated with a novel G50E iron-sulfur cluster scaffold protein (ISCU) mutation leads to development of mitochondrial myopathy

J Biol Chem. 2014 Apr 11;289(15):10359-77. doi: 10.1074/jbc.M113.526665. Epub 2014 Feb 26.


Iron-sulfur (Fe-S) clusters are versatile cofactors involved in regulating multiple physiological activities, including energy generation through cellular respiration. Initially, the Fe-S clusters are assembled on a conserved scaffold protein, iron-sulfur cluster scaffold protein (ISCU), in coordination with iron and sulfur donor proteins in human mitochondria. Loss of ISCU function leads to myopathy, characterized by muscle wasting and cardiac hypertrophy. In addition to the homozygous ISCU mutation (g.7044G→C), compound heterozygous patients with severe myopathy have been identified to carry the c.149G→A missense mutation converting the glycine 50 residue to glutamate. However, the physiological defects and molecular mechanism associated with G50E mutation have not been elucidated. In this report, we uncover mechanistic insights concerning how the G50E ISCU mutation in humans leads to the development of severe ISCU myopathy, using a human cell line and yeast as the model systems. The biochemical results highlight that the G50E mutation results in compromised interaction with the sulfur donor NFS1 and the J-protein HSCB, thus impairing the rate of Fe-S cluster synthesis. As a result, electron transport chain complexes show significant reduction in their redox properties, leading to loss of cellular respiration. Furthermore, the G50E mutant mitochondria display enhancement in iron level and reactive oxygen species, thereby causing oxidative stress leading to impairment in the mitochondrial functions. Thus, our findings provide compelling evidence that the respiration defect due to impaired biogenesis of Fe-S clusters in myopathy patients leads to manifestation of complex clinical symptoms.

Keywords: Electron Transport System (ETS); Hsp70; Iron-Sulfur Cluster; Iron-Sulfur Protein; J-protein; Mitochondrial Diseases; Molecular Chaperone; Myopathy; Reactive Oxygen Species (ROS).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Respiration
  • Escherichia coli / metabolism
  • HSP70 Heat-Shock Proteins / metabolism
  • HeLa Cells
  • Heterozygote
  • Humans
  • Iron / chemistry
  • Iron-Sulfur Proteins / genetics*
  • Iron-Sulfur Proteins / metabolism*
  • Membrane Potentials
  • Mitochondrial Myopathies / genetics*
  • Mitochondrial Myopathies / metabolism
  • Molecular Sequence Data
  • Mutagenesis
  • Mutation, Missense*
  • Oxidation-Reduction
  • Oxidative Stress
  • Reactive Oxygen Species / metabolism
  • Saccharomyces cerevisiae / metabolism
  • Sequence Homology, Amino Acid
  • Sulfur / chemistry


  • HSP70 Heat-Shock Proteins
  • ISCU protein, human
  • Iron-Sulfur Proteins
  • Reactive Oxygen Species
  • Sulfur
  • Iron