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NOVEL ROLES FOR IRON-SULFUR CLUSTERS IN RED BLOOD CELL DEVELOPMENT AND HUMAN DISEASE

Iron-sulfur (Fe-S) clusters are versatile enzyme cofactors that are essential to all living organisms due to their diverse electron transfer and catalytic capabilities. In this collection of studies, we investigated the function of Fe-S clusters in several physiological settings that are relevant to human health and disease. We identified cellular conditions in which the biosynthesis of heme, the iron-containing cofactor present in hemoglobin and other enzymes, may be directly influenced by cellular Fe-S cluster assembly processes. This interdependence of the heme biosynthesis and Fe-S cluster assembly pathways relied on the provision of Fe-S clusters to the terminal heme biosynthetic enzyme, ferrochelatase. We also studied the tissue specificity and pathophysiology of a rare inherited human disease known as ISCU Myopathy, caused by deficiency of Fe-S clusters due to low expression of the Fe-S scaffold protein, ISCU. We found that tissue-specific splicing and oxidative stress lead to pathological depletion of ISCU protein in patient skeletal muscle, while other patient tissues are spared, perhaps in part because they express higher levels of ISCU protein. We performed global gene expression analysis on ISCU Myopathy patient skeletal muscle biopsies, and found evidence for a coordinated pattern of changes in biochemical pathways and muscle tissue architecture due to chronic Fe-S cluster deficiency. These changes included an increase in the proportion of oxidative muscle fibers iv relative to glycolytic fibers and enhanced capillary perfusion, providing a possible basis for the muscle hypertrophy observed in these patients. We also found evidence for activation of a starvation response and ketogenesis in patient muscles, which probably reflected a coordinated response to cellular energy starvation and over-accumulation of acetyl-coenzyme A. Finally, we found that ISCU Myopathy patient muscles synthesize and secrete elevated levels of the starvation response hormone FGF-21, leading to measurable increases in FGF-21 levels in patient blood samples. Our findings suggest that FGF-21 may serve an important future role in diagnosing mitochondrial myopathies, and in assessing potential therapeutic treatments. Together these studies illuminate the role occupied by Fe-S clusters in the interface between inorganic chemistry and human health, and demonstrate novel roles and future possibilities for these ancient cofactors.