The major site of iron utilization in mammalian cells is the mitochondrion. Mitochondria are instrumental in the biosynthesis of heme and iron sulfur clusters, which contain iron, and are employed as cofactors in numerous proteins, including hemoglobin, the cytochromes, and many enzymes that play roles in key metabolic processes. The vast majority of iron in mammals is present as heme, primarily in hemoglobin in erythrocytes, underscoring the importance of understanding mitochondrial iron utilization to describing the normal pathways of iron metabolism. Disorders of iron and heme metabolism are prevalent in humans, and are most commonly the consequence of systemic iron deficiency or iron overload. The sideroblastic anemias (SAs) are an uncommon, but informative, group of diseases associated with ineffective mitochondrial iron utilization and pathologic mitochondrial iron accumulation. In collaboration, we have identified mutations in the mitochondrial solute carrier protein family 25, member A38 (SLC25A38) as an autosomal recessive cause of inherited congenital sideroblastic anemia (CSA) that is clinically very similar to X-linked sideroblastic anemia due to mutations in the heme synthesis enzyme 5- aminolevulinic acid (ALA) synthase. We have developed preliminary data indicating that, like ALAS2, SLC25A38 is likely involved in mitochondrial heme biosynthesis. Specifically, evidence would suggest that SLC25A38 transports glycine, one of the substrates of the reaction catalyzed by ALAS2, into the erythroid mitochondrion to support very high-level heme synthesis. Furthermore, SLC25A28 may act by exchanging glycine for ALA across the mitochondrial inner membrane, coupling substrate import to product export, thereby streamlining the initial mitochondrial phase of heme biosynthesis. This grant endeavors to directly test these hypotheses. Furthermore, because the genetic cause of nearly half of cases of CSA go undiscovered, we propose developing a patient registry to complement our already large clinical research database of CSA patients and use these samples to go on to discover novel CSA loci using genome-wide screens. Acquired idiopathic (neoplastic) sideroblastic anemia, also called refractory anemia with ringed sideroblasts (RARS) is a myelodysplastic syndrome that is relatively more common (~7.5 new cases/yr/106 people) than CSA. As perplexing as CSA is, RARS is more so, as we know very little about its pathogenesis, and much less about the somatic molecular genetic events that underlie this phenotype. Here, we will attempt to leverage our knowledge of the CSAs to gain insight into the pathogenesis of RARS. Furthermore, we will independently address the dearth of information regarding the molecular underpinnings of RARS by sequencing entire genomes. In both cases, we expect to learn more about mitochondrial iron metabolism, the SAs and approaches to therapy.

Public Health Relevance

The body uses iron largely to make heme, the molecule in hemoglobin in red blood cells (RBCs) that binds oxygen, and delivers it to the tissues. Heme synthesis occurs, in part, in the mitochondrial compartment within the cell. In a rare group of inherited disorders called sideroblastic anemias (SAs), iron precipitates in mitochondria, impairing RBC production. Sometimes, the defect that leads to this abnormality is an inherited mutation in a protein involved in the synthesis of heme. We recently identified a new form of inherited or congenital SA (CSA). Our data indicate that the mutated protein is likely involved in transporting the precursors required to make heme into and out of mitochondria. In this grant, we will determine the exact role of this protein in order to understand more about mitochondrial heme and iron metabolism and how we might treat patients with CSA. In addition, we will recruit patients with unknown causes of CSA as well as acquired neoplastic forms of SA in order to identify additional genetic and acquired causes of the disorder that will further our understanding of the SAs and iron utilization by mitochondria, in general.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK087992-05
Application #
8838772
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Bishop, Terry Rogers
Project Start
2011-05-01
Project End
2017-04-30
Budget Start
2015-05-01
Budget End
2017-04-30
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
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