Our goal is to define mitochondrial iron metabolism in eukaryotes at the molecular and biochemical level by studying proteins required for mitochondrial iron transport and utilization. We have identified mitochondrial iron importers in yeast, Mrs3/Mrs4, and vertebrates, Mitoferrin1 and Mitoferrin2. We demonstrated that the mitoferrins show tissue specific expression patterns and tissue specific functions. We have generated mice with floxed alleles of both Mitoferrin1 and Mitoferrin2. We will utilize specific expression of Cre recombinase to identify the tissue specific function of the mitoferrins. We will examine the mechanism of mitochondrial dysfunction by deleting mitoferrins in vitro in specific cell types through the use of recombinant Tat-Cre. Through genetic screens we identified genes that are required for hemoglobinization in developing erythrocytes. We will determine the function of these genes. We will determine if Abcb10 has roles other than stabilizing Mfrn1, if deletion of Atpif1 affects ferrochelatase activity through altered mitochondrial pH and if reductio of SLC25A39, the Mtm1 yeast homologue, affects mitochondrial superoxide dismutase activity. We determined that the mitochondrial iron pool is tightly regulated, but can be increased by overexpression of mitochondrial iron importers. We will determine the physiological consequences of increased levels of mitochondrial iron in both yeast and mammalian cells. We had identified Mmt1 and Mmt2 as mitochondrial iron exporters. We discovered that MMT1 and MMT2 are transcriptionally upregulated by low iron and by oxidant stress. We have identified Yap1 as the oxidant stress activated transcription factor for MMT1. We will identify the transcriptional factor responsible for the low iron induction of MMT1/MMT2 and the physiological function of mitochondrial iron export. We will determine if mammalian mitochondria can act as a iron reservoir and if there are mammalian mitochondrial iron exporters.
Mitochondrial iron metabolism is essential for life. Malregulation of mitochondrial iron metabolism leads to disease. We will determine the mechanisms that regulate mitochondrial iron import and export. Our studies will provide information that may be used to manage and diagnose human diseases due to altered mitochondrial iron metabolism.
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