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.
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%.
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