Identification of a mammalian mitochondrial porphyrin transporter

Abstract

The movement of anionic porphyrins (for example, haem) across intracellular membranes is crucial to many biological processes, but their mitochondrial translocation and coordination with haem biosynthesis is not understood. Transport of porphyrins into isolated mitochondria is energy-dependent1,2,3, as expected for the movement of anions into a negatively charged environment. ATP-binding cassette transporters actively facilitate the transmembrane movement of substances. We found that the mitochondrial ATP-binding cassette transporter ABCB6 is upregulated (messenger RNA and protein in human and mouse cells) by elevation of cellular porphyrins and postulated that ABCB6 has a function in porphyrin transport. We also predicted that ABCB6 is functionally linked to haem biosynthesis, because its mRNA is found in both human bone marrow and CD71+ early erythroid cells (by database searching), and because our results show that ABCB6 is highly expressed in human fetal liver, and Abcb6 in mouse embryonic liver. Here we demonstrate that ABCB6 is uniquely located in the outer mitochondrial membrane and is required for mitochondrial porphyrin uptake. After ABCB6 is upregulated in response to increased intracellular porphyrin, mitochondrial porphyrin uptake activates de novo porphyrin biosynthesis. This process is blocked when the Abcb6 gene is silenced. Our results challenge previous assumptions about the intracellular movement of porphyrins and the factors controlling haem biosynthesis.

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Figure 1: ABCB6 is highly expressed in human and murine fetal liver, and is upregulated in the presence of haemin and during erythroid differentiation.
Figure 2: ABCB6 expression is regulated by intracellular protoporphyrin levels.
Figure 3: ABCB6 binds and transports haem.
Figure 4: ABCB6 regulates porphyrin biosynthesis.

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Acknowledgements

We thank S. Naron for editorial assistance; J. Groff for preparation of the illustrations; A. Smith for comments and suggestions; S. Orkin for providing the G1ER cells; B. Sarkadi and C. Ozvegy-Laczka for assistance with the ATPase assays; and Y. Fan for bioinformatics analysis of Abcb6. This work was supported by NIH grants and by the American Lebanese Syrian Associated Charities (ALSAC).

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Correspondence to John D. Schuetz.

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Krishnamurthy, P., Du, G., Fukuda, Y. et al. Identification of a mammalian mitochondrial porphyrin transporter. Nature 443, 586–589 (2006). https://doi.org/10.1038/nature05125

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