Multiple Cellular Defects Associated with a Novel G50E ISCU Mutation leads to Development of Mitochondrial Myopathy [Cell Biology]

February 26th, 2014 by Saha, P. P., Kumar S. K., P., Srivastava, S., Sinha, D., Pareek, G., D'Silva, P.

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 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 homozygous ISCU mutation (g.7044G>C), compound heterozygous patients with severe myopathy have been identified to carry (c.149G>A) missense mutation converting 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 development of severe ISCU myopathy, using human cell line and yeast as the model systems. The biochemical results highlight that, G50E mutation results in compromised interaction with the sulfur donor NFS1 and J-protein HSCB protein, thus impairing the rate of Fe-S cluster synthesis. As a result, electron transport chain (ETC) 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 (ROS), thereby causing oxidative stress leading to impairment in the mitochondrial functions. Thus, our findings provide compelling evidence that respiration defect due to impaired biogenesis of Fe-S clusters in myopathy patients, leads to manifestation of complex clinical symptoms.