Mitoferrin-1

Function

The molecular details of iron trafficking for heme and Iron-sulfur cluster synthesis are still unclear, however, Mitoferrin-1 has been shown to form oligomeric complexes with the ATP-binding cassette transporter ABCB10 and Ferrochelatase (or protoporphyrin ferrochelatase). Furthermore, ABC10 binding enhances the stability and functionality of Mfrn1, suggesting that transcriptional and post-translational mechanisms further regulate cellular and mitochondrial iron homeostasis. Recombinant Mfrn1 in vitro has micromolar affinity for the following first-row transition metals: iron (II), manganese (II), cobalt (II), and nickel (II). Mfrn1 iron transport was reconstituted in proteoliposomes, where the protein was also able to transport manganese, cobalt, copper, and zinc, yet it discriminated against nickel, despite the aforementioned affinity. Notably, Mfrn1 appears to transport free iron ions as opposed to any sort of chelated iron complex. Additionally, Mfrn1 selects against divalent alkali ions. Mfrn1 and its paralog Mfrn2 have complementary functionalities, though the precise relationship is still uncertain. For example, heme production is restored by expression of Mfrn2 in cells silenced for Mfrn1 and by ectopic expression of Mfrn1 in nonerythroid cells silenced for Mfrn2, where Mfrn1 accumulates due to an increased protein half-life. In contrast, ectopic expression of Mfrn2 failed to restore heme product in erythroid cells silenced for Mfrn1 because Mfrn2 was unable to accumulate in mitochondria.

Clinical Significance

Mitoferrin-1 has been implicated in diseases associated with defective iron homeostasis, resulting in iron or porphyrin imbalances. Abnormal Mfrn1 expression, for example, may contribute to Erythropoietic protoporphyria, a porphyrin disease linked to mutations in the Ferrochelatase enzyme. Selective deletion of Mfrn1 in adult mice led to severe anemia rather than porphyria likely because Iron-responsive element-binding protein (specifically IRE-BP1) transcriptionally regulates porphyrin biogenesis, inhibiting it in the absence of Mfrn1. Mfrn1 has also been implicated in depression and myelodysplastic syndrome.

Animal Studies

The importance of Mitoferrins in heme and Fe-S cluster biosynthesis was first discovered in the anemic zebrafish mutant frascati. Studies in mice revealed that total deletion of Mfrn1 resulted in embryonic lethality, while selective deletion in adults caused severe anemia as stated above. Expression mouse Mfrn1 rescued knockout zebrafish, indicating that the gene is highly evolutionarily conserved. The transcription factor, GATA-1, directly regulates Mfrn1 expression in zebrafish via distal cis-regulatory Mfrn1 elements. In C. elegans, reduced Mfrn1 expression results in abnormal development and increased lifespans of roughly 50-80%.

References

References

1. (January 2013). "Mitoferrin-2-dependent mitochondrial iron uptake sensitizes human head and neck squamous carcinoma cells to photodynamic therapy". The Journal of Biological Chemistry.
2. (March 2006). "Mitoferrin is essential for erythroid iron assimilation". Nature.
3. "Entrez Gene: SLC25A37 solute carrier family 25, member 37".
4. (July 2010). "Two to tango: regulation of Mammalian iron metabolism". Cell.
5. (March 2014). "Iron regulatory protein-1 protects against mitoferrin-1-deficient porphyria". The Journal of Biological Chemistry.
6. (July 2010). "Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis". Blood.
7. (September 2009). "Abcb10 physically interacts with mitoferrin-1 (Slc25a37) to enhance its stability and function in the erythroid mitochondria". Proceedings of the National Academy of Sciences of the United States of America.
8. (March 2018). "In vitro reconstitution, functional dissection, and mutational analysis of metal ion transport by mitoferrin-1". The Journal of Biological Chemistry.
9. (February 2009). "Regulation of mitochondrial iron import through differential turnover of mitoferrin 1 and mitoferrin 2". Molecular and Cellular Biology.
10. (March 2006). "Mitoferrin is essential for erythroid iron assimilation". Nature.
11. (July 2011). "Abnormal mitoferrin-1 expression in patients with erythropoietic protoporphyria". Experimental Hematology.
12. (May 2011). "Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria". Blood.
13. (December 2016). "Identification of SLC25A37 as a major depressive disorder risk gene". Journal of Psychiatric Research.
14. (January 2015). "Distinct iron architecture in SF3B1-mutant myelodysplastic syndrome patients is linked to an SLC25A37 splice variant with a retained intron". Leukemia.
15. (April 2011). "Identification of distal cis-regulatory elements at mouse mitoferrin loci using zebrafish transgenesis". Molecular and Cellular Biology.
16. (January 11, 2018). "Reduction of mitoferrin results in abnormal development and extended lifespan in Caenorhabditis elegans". PLOS ONE.