Mitoferrin-1 Explained

Mitoferrin-1 (Mfrn1) is a 38 kDa protein^[1] that is encoded by the SLC25A37 gene in humans.^{[2] [3]} It is a member of the Mitochondrial carrier (MC) Superfamily, however, its metal cargo makes it distinct from other members of this family. Mfrn1 plays a key role in mitochondrial iron homeostasis as an iron transporter, importing ferrous iron from the intermembrane space of the mitochondria to the mitochondrial matrix for the biosynthesis of heme groups and Fe-S clusters.^[4] This process is tightly regulated, given the redox potential of Mitoferrin's iron cargo. Mfrn1 is paralogous to Mitoferrin-2 (Mfrn2), a 39 kDa protein encoded by the SLC25A28 gene in humans.^[1] Mfrn1 is highly expressed in differentiating erythroid cells and in other tissues at low levels, while Mfrn2 is expressed ubiquitously in non-erythroid tissues.^{[5] [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).^[6] Furthermore, ABC10 binding enhances the stability and functionality of Mfrn1, suggesting that transcriptional and post-translational mechanisms further regulate cellular and mitochondrial iron homeostasis.^[7] Recombinant Mfrn1 in vitro has micromolar affinity for the following first-row transition metals: iron (II), manganese (II), cobalt (II), and nickel (II).^[8] 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.^[8] Notably, Mfrn1 appears to transport free iron ions as opposed to any sort of chelated iron complex.^[8] Additionally, Mfrn1 selects against divalent alkali ions.^[8] 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.^[9] 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.^[9]

Clinical Significance

Mitoferrin-1 has been implicated in diseases associated with defective iron homeostasis, resulting in iron or porphyrin imbalances.^[10] Abnormal Mfrn1 expression, for example, may contribute to Erythropoietic protoporphyria,^[11] a porphyrin disease linked to mutations in the Ferrochelatase enzyme.^[11] Selective deletion of Mfrn1 in adult mice led to severe anemia rather than porphyria^[12] likely because Iron-responsive element-binding protein (specifically IRE-BP1) transcriptionally regulates porphyrin biogenesis, inhibiting it in the absence of Mfrn1.^[5] Mfrn1 has also been implicated in depression^[13] and myelodysplastic syndrome.^[14]

Animal Studies

The importance of Mitoferrins in heme and Fe-S cluster biosynthesis was first discovered in the anemic zebrafish mutant frascati.^[2] Studies in mice revealed that total deletion of Mfrn1 resulted in embryonic lethality, while selective deletion in adults caused severe anemia as stated above.^[12] Expression mouse Mfrn1 rescued knockout zebrafish, indicating that the gene is highly evolutionarily conserved.^[10] The transcription factor, GATA-1, directly regulates Mfrn1 expression in zebrafish via distal cis-regulatory Mfrn1 elements.^[15] In C. elegans, reduced Mfrn1 expression results in abnormal development and increased lifespans of roughly 50-80%.^[16]

See also

• Solute carrier family

Further reading

• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Hu RM, Han ZG, Song HD, Peng YD, Huang QH, Ren SX, Gu YJ, Huang CH, Li YB, Jiang CL, Fu G, Zhang QH, Gu BW, Dai M, Mao YF, Gao GF, Rong R, Ye M, Zhou J, Xu SH, Gu J, Shi JX, Jin WR, Zhang CK, Wu TM, Huang GY, Chen Z, Chen MD, Chen JL . Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning . Proceedings of the National Academy of Sciences of the United States of America . 97 . 17 . 9543–8 . August 2000 . 10931946 . 16901 . 10.1073/pnas.160270997 . free . 2000PNAS...97.9543H .
• Li QZ, Eckenrode S, Ruan QG, Wang CY, Shi JD, McIndoe RA, She JX . Rapid decrease of RNA level of a novel mouse mitochondria solute carrier protein (Mscp) gene at 4-5 weeks of age . Mammalian Genome . 12 . 11 . 830–6 . November 2001 . 11845285 . 10.1007/s00335001-2075-1 . 1743722 .
• Otsuki T, Ota T, Nishikawa T, Hayashi K, Suzuki Y, Yamamoto J, Wakamatsu A, Kimura K, Sakamoto K, Hatano N, Kawai Y, Ishii S, Saito K, Kojima S, Sugiyama T, Ono T, Okano K, Yoshikawa Y, Aotsuka S, Sasaki N, Hattori A, Okumura K, Nagai K, Sugano S, Isogai T . Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries . DNA Research . 12 . 2 . 117–26 . 2007 . 16303743 . 10.1093/dnares/12.2.117 . free .

Notes and References

1. Hung HI, Schwartz JM, Maldonado EN, Lemasters JJ, Nieminen AL . Mitoferrin-2-dependent mitochondrial iron uptake sensitizes human head and neck squamous carcinoma cells to photodynamic therapy . The Journal of Biological Chemistry . 288 . 1 . 677–86 . January 2013 . 23135267 . 10.1074/jbc.M112.422667 . 3537066 . free .
2. Shaw GC, Cope JJ, Li L, Corson K, Hersey C, Ackermann GE, Gwynn B, Lambert AJ, Wingert RA, Traver D, Trede NS, Barut BA, Zhou Y, Minet E, Donovan A, Brownlie A, Balzan R, Weiss MJ, Peters LL, Kaplan J, Zon LI, Paw BH . Mitoferrin is essential for erythroid iron assimilation . Nature . 440 . 7080 . 96–100 . March 2006 . 16511496 . 10.1038/nature04512 . 2006Natur.440...96S . 4429335 .
3. Web site: Entrez Gene: SLC25A37 solute carrier family 25, member 37.
4. Hentze MW, Muckenthaler MU, Galy B, Camaschella C . Two to tango: regulation of Mammalian iron metabolism . Cell . 142 . 1 . 24–38 . July 2010 . 20603012 . 10.1016/j.cell.2010.06.028 . 23971474 . free .
5. Chung J, Anderson SA, Gwynn B, Deck KM, Chen MJ, Langer NB, Shaw GC, Huston NC, Boyer LF, Datta S, Paradkar PN, Li L, Wei Z, Lambert AJ, Sahr K, Wittig JG, Chen W, Lu W, Galy B, Schlaeger TM, Hentze MW, Ward DM, Kaplan J, Eisenstein RS, Peters LL, Paw BH . Iron regulatory protein-1 protects against mitoferrin-1-deficient porphyria . The Journal of Biological Chemistry . 289 . 11 . 7835–43 . March 2014 . 24509859 . 10.1074/jbc.M114.547778 . 4022844 . free .
6. Chen W, Dailey HA, Paw BH . Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis . Blood . 116 . 4 . 628–30 . July 2010 . 20427704 . 10.1182/blood-2009-12-259614 . 3324294 .
7. Chen W, Paradkar PN, Li L, Pierce EL, Langer NB, Takahashi-Makise N, Hyde BB, Shirihai OS, Ward DM, Kaplan J, Paw BH . 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 . 106 . 38 . 16263–8 . September 2009 . 19805291 . 10.1073/pnas.0904519106 . 2752562 . free .
8. Christenson ET, Gallegos AS, Banerjee A . In vitro reconstitution, functional dissection, and mutational analysis of metal ion transport by mitoferrin-1 . The Journal of Biological Chemistry . 293 . 10 . 3819–3828 . March 2018 . 29305420 . 10.1074/jbc.M117.817478 . 5846140. free .
9. Paradkar PN, Zumbrennen KB, Paw BH, Ward DM, Kaplan J . Regulation of mitochondrial iron import through differential turnover of mitoferrin 1 and mitoferrin 2 . Molecular and Cellular Biology . 29 . 4 . 1007–16 . February 2009 . 19075006 . 10.1128/MCB.01685-08 . 2643804 .
10. Shaw GC, Cope JJ, Li L, Corson K, Hersey C, Ackermann GE, Gwynn B, Lambert AJ, Wingert RA, Traver D, Trede NS, Barut BA, Zhou Y, Minet E, Donovan A, Brownlie A, Balzan R, Weiss MJ, Peters LL, Kaplan J, Zon LI, Paw BH . Mitoferrin is essential for erythroid iron assimilation . Nature . 440 . 7080 . 96–100 . March 2006 . 16511496 . 10.1038/nature04512 . 2006Natur.440...96S . 4429335 .
11. Wang Y, Langer NB, Shaw GC, Yang G, Li L, Kaplan J, Paw BH, Bloomer JR . Abnormal mitoferrin-1 expression in patients with erythropoietic protoporphyria . Experimental Hematology . 39 . 7 . 784–94 . July 2011 . 21627978 . 10.1016/j.exphem.2011.05.003 . 3143264 .
12. Troadec MB, Warner D, Wallace J, Thomas K, Spangrude GJ, Phillips J, Khalimonchuk O, Paw BH, Ward DM, Kaplan J . Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria . Blood . 117 . 20 . 5494–502 . May 2011 . 21310927 . 10.1182/blood-2010-11-319483 . 3109720 .
13. Huo YX, Huang L, Zhang DF, Yao YG, Fang YR, Zhang C, Luo XJ . Identification of SLC25A37 as a major depressive disorder risk gene . Journal of Psychiatric Research . 83 . 168–175 . December 2016 . 27643475 . 10.1016/j.jpsychires.2016.09.011 .
14. Visconte V, Avishai N, Mahfouz R, Tabarroki A, Cowen J, Sharghi-Moshtaghin R, Hitomi M, Rogers HJ, Hasrouni E, Phillips J, Sekeres MA, Heuer AH, Saunthararajah Y, Barnard J, Tiu RV . Distinct iron architecture in SF3B1-mutant myelodysplastic syndrome patients is linked to an SLC25A37 splice variant with a retained intron . Leukemia . 29 . 1 . 188–95 . January 2015 . 24854990 . 10.1038/leu.2014.170 . 10475563 .
15. Amigo JD, Yu M, Troadec MB, Gwynn B, Cooney JD, Lambert AJ, Chi NC, Weiss MJ, Peters LL, Kaplan J, Cantor AB, Paw BH . Identification of distal cis-regulatory elements at mouse mitoferrin loci using zebrafish transgenesis . Molecular and Cellular Biology . 31 . 7 . 1344–56 . April 2011 . 21248200 . 10.1128/MCB.01010-10 . 3135305 .
16. Ren Y, Yang S, Tan G, Ye W, Liu D, Qian X, Ding Z, Zhong Y, Zhang J, Jiang D, Zhao Y, Lu J . Reduction of mitoferrin results in abnormal development and extended lifespan in Caenorhabditis elegans . PLOS ONE . 7 . 1 . e29666 . January 11, 2018 . 22253756 . 10.1371/journal.pone.0029666 . 3256167. free .