Abcb10 Role in Heme Biosynthesis <i>In Vivo</i>: Abcb10 Knockout in Mice Causes Anemia with Protoporphyrin IX and Iron Accumulation

Yamamoto, Masayuki; Arimura, Hiroshi; Fukushige, Tomoko; Minami, Kentarou; Nishizawa, Yuji; Tanimoto, Akihide; Kanekura, Takuro; Nakagawa, Masayuki; Akiyama, Shin–ichi; Furukawa, Tatsuhiko

doi:10.1128/mcb.00865-13

Cited by 62 publications

(57 citation statements)

References 30 publications

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“…Mice with one ABCB10 gene removed survived to become adults and were apparently normal, but their hearts were more susceptible to damage by oxidative stress during ischaemia and reperfusion [25]. A recent study using conditional knockouts of the ABCB10 gene in haematopoietic cells showed a dramatic accumulation of protoporphyrin IX (PPIX) in erythrocytes and accumulation of iron inside the mitochondria [53].…”

Section: Abcb10 In Mammalsmentioning

confidence: 99%

“…In the absence of ABCB10, Mfrn1 (but not Mfrn2) is destabilized and Fe import is decreased. The ABCB10-Mfrn complex also interacts with ferrochelatase, but this interaction is weaker [21] and is not required for ferrochelatase stability [53]. The suggestion that the main role for ABCB10 is to stabilize Mfrn1 is challenged by the observation that there are no conserved regions on the external surface of ABCB10 [6].…”

Section: Abcb10 In Mammalsmentioning

confidence: 99%

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Structures and functions of mitochondrial ABC transporters

Schaedler

Faust

Shintre

et al. 2015

Biochemical Society Transactions

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A small number of physiologically important ATP-binding cassette (ABC) transporters are found in mitochondria. Most are half transporters of the B group forming homodimers and their topology suggests they function as exporters. The results of mutant studies point towards involvement in iron cofactor biosynthesis. In particular, ABC subfamily B member 7 (ABCB7) and its homologues in yeast and plants are required for iron-sulfur (Fe-S) cluster biosynthesis outside of the mitochondria, whereas ABCB10 is involved in haem biosynthesis. They also play a role in preventing oxidative stress. Mutations in ABCB6 and ABCB7 have been linked to human disease. Recent crystal structures of yeast Atm1 and human ABCB10 have been key to identifying substrate-binding sites and transport mechanisms. Combined with in vitro and in vivo studies, progress is being made to find the physiological substrates of the different mitochondrial ABC transporters. Sequence analysis of mitochondrial ABC transportersMitochondria of most eukaryote species harbour 2-4 different ABC transporters that belong to the B subfamily of half transporters. The proteins contain an N-terminal transmembrane domain (TMD) and a C-terminal nucleotidebinding domain (NBD), which form homodimers for full functionality [1]. Plant and algal genomes additionally encode a unique ABC transporter, termed cytochrome c maturation (Ccm)AB, in which the TMD and NBD are encoded by separate genes. CcmAB is placed in the ABCI subfamily, see section 'CcmAB in plant mitochondria'. Phylogenetic relationship of mitochondrial transporters of the ABCB subfamilyAs a starting point for the discussion of recent crystal structures and functional data, we have reanalysed the phylogenetic relationships of B-type mitochondrial ABC transporters and their closest prokaryotic homologues (Figure 1). The CcmAB proteins were excluded from the phylogenetic analysis due to their large evolutionary distance from the other mitochondrial ABC transporters.Key words: ATP-binding cassette (ABC) transporter, glutathione, haem, iron, mitochondria, oxidative stress. Abbreviations: ABC, ATP-binding cassette; Aft, Activator of ferrous transport; ATM, ABC transporter of the mitochondria; Ccm, cytochrome c maturation; dALA, δ-amino levulinic acid; IRP1, iron regulatory protein 1; Mdl, multi-drug resistance-like; Mfrn, mitoferrin; NBD, nt-binding domain; PPIX, protoporphyrin IX; TMD, transmembrane domain; TMH, transmembrane helix. 1 To whom correspondence should be addressed (email janneke.balk@jic.ac.uk).The ABCB7 group, which includes the ABC transporters of the mitochondria Atm1 in yeast and ATM3 in Arabidopsis, can be found in virtually all eukaryotic species. Human ABCB7 and Arabidopsis ATM3 can largely rescue the phenotypes of yeast atm1 mutants [2][3][4], providing experimental support that members of this subfamily may have the same function. Human ABCB6 can also partially complement a yeast atm1 mutant [5] but differences in the intracellular localization of ABCB6 and Atm1 may point to distinct phys...

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Section: Abcb10 In Mammalsmentioning

confidence: 99%

Section: Abcb10 In Mammalsmentioning

confidence: 99%

Structures and functions of mitochondrial ABC transporters

Schaedler

Faust

Shintre

et al. 2015

Biochemical Society Transactions

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“…This interaction ensures that the imported iron is preferentially utilized for heme production. Deletion of Abcb10 in mice impaired heme biosynthesis, erythropoiesis, and caused embryonic lethality [59]. Tissue-specific knockout of Abcb10 in mouse hematopoietic cells resulted in accumulation of iron and PPIX in reticulocytes, confirming its role in the final step of heme synthesis pathway [59].…”

Section: Regulation Of Heme Synthesis Enzymesmentioning

confidence: 98%

“…A study suggested that ABCB10 might mediate this translocating event [60]. However, other biochemical and genetic studies indicate that ABCB10 is more likely to be involved in the final step of heme synthesis, as discussed above [59,61].…”

Section: Transport Of Heme Synthesis Intermediatesmentioning

confidence: 99%

Regulation of heme biosynthesis and transport in metazoa

Sun

Cheng

Chen

2015

Sci. China Life Sci.

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Heme is an iron-containing tetrapyrrole that plays a critical role in regulating a variety of biological processes including oxygen and electron transport, gas sensing, signal transduction, biological clock, and microRNA processing. Most metazoan cells synthesize heme via a conserved pathway comprised of eight enzyme-catalyzed reactions. Heme can also be acquired from food or extracellular environment. Cellular heme homeostasis is maintained through the coordinated regulation of synthesis, transport, and degradation. This review presents the current knowledge of the synthesis and transport of heme in metazoans and highlights recent advances in the regulation of these pathways. heme, iron, synthesis, transport, regulation Citation:Sun FX, Cheng YJ, Chen CY. Regulation of heme biosynthesis and transport in metazoa.

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“…ABCB10 physically interacts with MFRN1 and increases the half-life of MFRN1 (Chen et al, 2009). Deficiency of ABCB10 impairs mitochondrial iron import and causes PPIX accumulation (Yamamoto et al, 2014). At the same time, ABCB10 deficiency in mice results in iron accumulation in cytoplasm and leads to sideroblastic anemia (Yamamoto et al, 2014).…”

Section: Disregulation Of Ppix Homeostasismentioning

confidence: 99%

Protoporphyrin IX: the Good, the Bad, and the Ugly

Sachar

Anderson

2015

Journal of Pharmacology and Experimental Therapeutics

190

159

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Protoporphyrin IX (PPIX) is ubiquitously present in all living cells in small amounts as a precursor of heme. PPIX has some biologic functions of its own, and PPIX-based strategies have been used for cancer diagnosis and treatment (the good). PPIX serves as the substrate for ferrochelatase, the final enzyme in heme biosynthesis, and its homeostasis is tightly regulated during heme synthesis. Accumulation of PPIX in human porphyrias can cause skin photosensitivity, biliary stones, hepatobiliary damage, and even liver failure (the bad and the ugly). In this work, we review the mechanisms that are associated with the broad aspects of PPIX. Because PPIX is a hydrophobic molecule, its disposition is by hepatic rather than renal excretion. Large amounts of PPIX are toxic to the liver and can cause cholestatic liver injury. Application of PPIX in cancer diagnosis and treatment is based on its photodynamic effects.

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Abcb10 Role in Heme Biosynthesis In Vivo: Abcb10 Knockout in Mice Causes Anemia with Protoporphyrin IX and Iron Accumulation

Cited by 62 publications

References 30 publications

Structures and functions of mitochondrial ABC transporters

Structures and functions of mitochondrial ABC transporters

Regulation of heme biosynthesis and transport in metazoa

Protoporphyrin IX: the Good, the Bad, and the Ugly

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