Executive Summary : | "The mammalian system relies on over 200 proteins, including the Fe/S cluster, for enzyme catalysis, electron transfer reactions, and metabolic pathways regulation. The mitochondrial matrix's core machinery, including proteins like ISCU, ISD11, NFS1, Frataxin, and ACP, primarily synthesizes these clusters. Genetic defects can lead to severe mitochondrial-specific pathological conditions, which can be fatal. A mutation in ISCU, the scaffold protein, leads to ISCU-specific mitochondrial myopathy in humans. A previous study revealed the molecular insights of ISCUG50E, a missense mutation predominantly reported in the western population. Newer missense mutations (H43N, Y43A, R47A, G96A) have been identified with severe mitochondrial myopathic symptoms in patients from Western, Asian, and Middle Eastern countries. ISCU mitochondrial myopathy is characterized by lifelong exercise intolerance, pain, shortness of breath, fatigue, and tachycardia. Secondary complications include rhabdomyolysis and myoglobinuria, including renal failure. Understanding the effect of these mutations on Fe/S cluster biosynthesis and iron homeostasis will help better manage disease progression.
Another protein essential in Fe/S cluster biogenesis is NFS1, which is an interacting partner of ISCU. A missense mutation (R72Q) in NFS1 causes a rare disease called IMC23D (Infantile mitochondrial complex II/III deficiency), which causes early fatality in infants and children below ten years. The goal is to delineate the molecular details using mammalian cell lines and yeast as model systems. Investigating the effect on iron regulation in mutants and their secondary effects on disease manifestations will lead to a better understanding of Fe/S cluster biogenesis and iron regulation in eukaryotic cells, which will help in better disease management and treatment." |