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. 2010 Jul 29;116(4):628-30.
doi: 10.1182/blood-2009-12-259614. Epub 2010 Apr 28.

Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis

Wen Chen  1 , Harry A Dailey, Barry H Paw
Affiliations

Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis

Wen Chen et al. Blood. .

Abstract

In erythroid cells, ferrous iron is imported into the mitochondrion by mitoferrin-1 (Mfrn1). Previously, we showed that Mfrn1 interacts with Abcb10 to enhance mitochondrial iron importation. Herein we have derived stable Friend mouse erythroleukemia (MEL) cell clones expressing either Mfrn1-FLAG or Abcb10-FLAG and by affinity purification and mass spectrometry have identified ferrochelatase (Fech) as an interacting protein for both Mfrn1 and Abcb10. Fech is the terminal heme synthesis enzyme to catalyze the insertion of the imported iron into protoporphyrin IX to produce heme. The Mfrn1-Fech and Abcb10-Fech interactions were confirmed by immunoprecipitation/Western blot analysis with endogenous proteins in MEL cells and heterologous proteins expressed in HEK293 cells. Moreover, Fech protein is induced in parallel with Mfrn1 and Abcb10 during MEL cell erythroid differentiation. Our findings imply that Fech forms an oligomeric complex with Mfrn1 and Abcb10 to synergistically integrate mitochondrial iron importation and use for heme biosynthesis.

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Figures

Figure 1
Figure 1
Physical interactions between Fech with either Mfrn1 or Abcb10 proteins are confirmed in endogenous MEL cells and transfected heterologous cells. (A) IP/Western blot analysis of interactions of endogenous Fech with Mfrn1 and Abcb10 in differentiated MEL cells stably expressing empty vector, engineered Mfrn1-FLAG, or Abcb10-FLAG. (B) IP/Western blot analysis of interactions of heterologous Fech with Mfrn1 and Abcb10 from transiently cotransfected HEK293 cells with control vector, Mfrn1-FLAG, or Abcb10-FLAG. Protein input lysate is shown on the respective left columns. Fech is selectively copurified in the presence of Mfrn1 or Abcb10.
Figure 2
Figure 2
Interacting Fech, Mfrn1, and Abcb10 proteins are coordinately induced during MEL cell erythroid differentiation. (A) Endogenous Fech, Mfrn1, and Abcb10 are coinduced in chemically differentiated MEL cells. Mitochondrial lysates collected from MEL cells exposed to 1.5% dimethyl sulfoxide (DMSO) for various lengths of days were serially probed with antisera against Fech (i), antisera against Mfrn1 (ii), antisera against Abcb10 (iii), and antisera against loading control Hsp60 (iv). Endogenous Fech and Mfrn1 proteins are induced (i,ii) and Abcb10 protein is proteolytically processed to a mature isoform in MEL cells during erythroid differentiation (iii). (B) A schematic model for Mfrn1, Abcb10, and Fech forming an oligomeric protein complex, which facilitates the importation of mitochondrial iron for heme biosynthesis in the developing red blood cells.
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