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Prepublished online as a Blood First Edition Paper on December 12, 2002; DOI 10.1182/blood-2002-04-1212.
Submitted June 27, 2002
Accepted October 31, 2002
Involvement of ABC7 in the Biosynthesis of Heme in Erythroid Cells: Interaction of ABC7 with ferrochelatase
Shigeru Taketani*, Kazuhiro Kakimoto, Hiromi Ueta, Ryuichi Masaki, and Takako Furukawa
Biotechnology, Kyoto Institute of Technology, Kyoto, Japan
Physiology, Kansai Medical University, Moriguchi, Osaka, Japan
Biomedical Imaging Research Center, Fukui Medical University, Fukui, Japan
* Corresponding author; email: taketani{at}ipc.kit.ac.jp.
A mitochondrial half-type ATP-binding cassette (ABC) protein, ABC7 plays a role in iron homeostasis in mitochondria and defects in human ABC7 were shown to be responsible for the inherited disease X-linked sideroblastic anemia/ataxia. We examined the role of ABC7 in the biosynthesis of heme in erythroid cells where hemoglobin is a major product of iron-containing compounds. RNA blots showed that the amount of ABC7 mRNA in dimethylsulfoxide (Me2SO)-treated mouse erythroleukemia (MEL) cells increased markedly in parallel with the induction of the mRNA expression of ferrochelatase, the last enzyme in the pathway to synthesize heme. The transfection of the antisense oligonucleotide to mouse ABC7 mRNA into Me2SO-treated MEL cells led to a decrease of the intracellular level of heme, as compared with sense oligonucleotide-transfected cells. ABC7 protein was shown to be co-localized with ferrochelatase in mitochondria, as assessed by immunostaining. Furthermore, in vitro and in vivo pull down assays revealed that the ABC7 protein interacted with the carboxy terminal region of ferrochelatase where an iron-sulfur cluster is located. The transient expression of ABC7 in mouse embryo liver BNL-CL2 cells resulted in an increase in the activity and level of ferrochelatase and thioredoxin, a cytosolic protein containing iron-sulfur. These increases were also observed in MEL cells stably expressing ABC7. When ABC7 transfectants were treated with Me2SO, an increase in cellular heme concomitant with a marked induction of the expression of ferrochelatase was observed. The extent of these increases was 2.5-fold greater than in control cells. The results indicated that ABC7 positively regulates not only the expression of extramitochondrial thioredoxin but also that of an intramitochondrial iron-sulfur-containing protein, ferrochelatase Thus, the expression of ABC7 contributes to the production of heme during the differentiation of erythroid cells.
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