Regulation of the expression of human ferrochelatase by intracellular iron levels

Taketani, Shigeru; Adachi, Yasushi; Nakahashi, Yoshitsugu

doi:10.1046/j.1432-1327.2000.01519.x

Cited by 57 publications

(71 citation statements)

References 37 publications

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“…The mammalian enzyme contains a 2Fe-2S cluster in the carboxyl terminal region (Wu et al 2001;Ohgari et al 2005). The iron-sulfur cluster is essential for promotion of the high enzyme activity although the cluster is not part of the binding region of the ferrous ion substrate (Furukawa et al 1995;Taketani et al 2000Taketani et al , 2003. Given that the expression of ferrochelatase is regulated by the level of intracellular iron, via the iron-sulfur cluster, and that an iron-transporter ABC7 interacting with the Fe-S cluster region in ferrochelatase regulates the level of ferrochelatase protein, ferrochelatase is an iron sensor in mitochondria (Taketani et al 2000(Taketani et al , 2003.…”

Section: Biosynthesis and Regulation Of Heme Metabolism In Mitochondriamentioning

confidence: 99%

“…The iron-sulfur cluster is essential for promotion of the high enzyme activity although the cluster is not part of the binding region of the ferrous ion substrate (Furukawa et al 1995;Taketani et al 2000Taketani et al , 2003. Given that the expression of ferrochelatase is regulated by the level of intracellular iron, via the iron-sulfur cluster, and that an iron-transporter ABC7 interacting with the Fe-S cluster region in ferrochelatase regulates the level of ferrochelatase protein, ferrochelatase is an iron sensor in mitochondria (Taketani et al 2000(Taketani et al , 2003. Furthermore, the cellular content of heme decreased when erythroid and non-erythroid cells were treated with an iron chelater, desferioxamine, indicating that the decrease in ferrochelatase activity causes the decrease in heme biosynthesis (Taketani et al 2000).…”

Section: Biosynthesis and Regulation Of Heme Metabolism In Mitochondriamentioning

confidence: 99%

“…Given that the expression of ferrochelatase is regulated by the level of intracellular iron, via the iron-sulfur cluster, and that an iron-transporter ABC7 interacting with the Fe-S cluster region in ferrochelatase regulates the level of ferrochelatase protein, ferrochelatase is an iron sensor in mitochondria (Taketani et al 2000(Taketani et al , 2003. Furthermore, the cellular content of heme decreased when erythroid and non-erythroid cells were treated with an iron chelater, desferioxamine, indicating that the decrease in ferrochelatase activity causes the decrease in heme biosynthesis (Taketani et al 2000). However, protoporphyrin did not accumulate in iron-deficient cells or patients with ABC7 deficient-sideroblastic anemia/ataxia.…”

Section: Biosynthesis and Regulation Of Heme Metabolism In Mitochondriamentioning

confidence: 99%

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Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Taketani

2005

Tohoku J. Exp. Med.

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100

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Iron is fastidiously utilized by living cells, since it is an essential element, but is toxic in excess. Cells take up iron via a transferrin-transferrin receptor-dependent endocytotic process. The iron thus taken up is used for essential biological functions including oxygen transport, electron transfer, and DNA synthesis. The intracellular level of iron is tightly controlled, through regulation of the cellular uptake of iron and the sequestering of low molecular labile iron into the storage protein ferritin. The known proteins of iron transport and storage, transferrin, transferrin receptor and ferritin, have been recently linked with a number of newly identified proteins that are responsible for inherited diseases of iron metabolisms and play critical roles in the maintenance of iron homeostasis. These proteins are involved in regulation of intracellular levels of iron, iron transport, and heme transport and the oxygen-dependent regulation of gene expression. On the other hand, most iron is transported into mitochondria and immediately used for the biosynthesis of heme in erythroid cells. The heme biosynthesis in mitochondria is coupled with the supply of iron, and the heme, exported from mitochondria, is utilized as prosthetic groups of hemeproteins. Furthermore, non-erythroid and erythroid cells possess the different regulatory systems for the biosynthesis of heme; iron positively regulates the biosynthesis in erythroid cells while heme negatively regulates it in non-erythroid cells. Because of the toxicity and insolubility of heme, the intracellular level of uncommitted heme is maintained at a low concentration (< 10 -9 M). The influx and efflux of heme also help to prevent cytotoxicity. Finally, heme-binding transcriptional factors such as Bach1 and NPAS2 regulate the transcription of several genes involved in the synthesis and degradation of heme-hemeproteins. The discovery of new molecules related to disorders of iron and heme metabolism is ascribable to a complete mechanistic understanding of the cellular network of iron homeostasis. The network of interactions that link iron and heme metabolisms with functions of cellular regulation involving oxidative stress and inflammations contributes to new insights into clinical aspects of disorders.

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Section: Biosynthesis and Regulation Of Heme Metabolism In Mitochondriamentioning

confidence: 99%

Section: Biosynthesis and Regulation Of Heme Metabolism In Mitochondriamentioning

confidence: 99%

Section: Biosynthesis and Regulation Of Heme Metabolism In Mitochondriamentioning

confidence: 99%

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Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Taketani

2005

Tohoku J. Exp. Med.

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100

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“…In addition, heme synthesis is susceptible to exogenous lead, aluminum, and other environmental toxins (15,16). Ferrochelatase is inactivated when its iron-sulfur cluster disassembles because intracellular iron levels are low (17) or nitric oxide (NO) is present (18). Iron deficiency is by far the most studied; it impairs cognitive function in children, impacts the morphology and the physiology of brain even before changes in hemoglobin appear (19), damages mitochondria (20), and causes oxidative stress (20).…”

mentioning

confidence: 99%

“…Iron deficiency in children is associated with difficulties in performing cognitive tasks and retardation in the development of the CNS (21,22). Prenatal iron deficiency causes loss of cytochrome c oxidase (complex IV) in selected regions in the brain of rats (23) and causes a decrease in ferrochelatase (17). Iron deficiency also occurs in the elderly (24), but surprisingly little work has been reported concerning heme and iron deficiency in brain dysfunction with age.…”

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confidence: 99%

Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging

Atamna¹,

Killilea²,

Killilea³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

199

150

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Heme, a major functional form of iron in the cell, is synthesized in the mitochondria by ferrochelatase inserting ferrous iron into protoporphyrin IX. Heme deficiency was induced with N-methylprotoporphyrin IX, a selective inhibitor of ferrochelatase, in two human brain cell lines, SHSY5Y (neuroblastoma) and U373 (astrocytoma), as well as in rat primary hippocampal neurons. Heme deficiency in brain cells decreases mitochondrial complex IV, activates nitric oxide synthase, alters amyloid precursor protein, and corrupts iron and zinc homeostasis. The metabolic consequences resulting from heme deficiency seem similar to dysfunctional neurons in patients with Alzheimer's disease. Heme-deficient SHSY5Y or U373 cells die when induced to differentiate or to proliferate, respectively. The role of heme in these observations could result from its interaction with heme regulatory motifs in specific proteins or secondary to the compromised mitochondria. Common causes of heme deficiency include aging, deficiency of iron and vitamin B6, and exposure to toxic metals such as aluminum. Iron and B6 deficiencies are especially important because they are widespread, but they are also preventable with supplementation. Thus, heme deficiency or dysregulation may be an important and preventable component of the neurodegenerative process.iron ͉ complex IV ͉ amyloid precursor protein (APP) ͉ nitric oxide synthase ͉ oxidative stress

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The Role of Heme and Iron-Sulfur Clusters in Mitochondrial Biogenesis, Maintenance, and Decay with Age

Atamna

Walter

Ames

2002

Archives of Biochemistry and Biophysics

108

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Regulation of the expression of human ferrochelatase by intracellular iron levels

Cited by 57 publications

References 37 publications

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging

The Role of Heme and Iron-Sulfur Clusters in Mitochondrial Biogenesis, Maintenance, and Decay with Age

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