title: ATP-dependent mitochondrial porphyrin importer ABCB6 protects against phenylhydrazine toxicity.
abstract: Abcb6 is a mammalian mitochondrial ATP-binding cassette (ABC) transporter that regulates de novo porphyrin synthesis. In previous studies, haploinsufficient (Abcb6(+/-)) embryonic stem cells showed impaired porphyrin synthesis. Unexpectedly, Abcb6(-/-) mice derived from these stem cells appeared phenotypically normal. We hypothesized that other ATP-dependent and/or -independent mechanisms conserve porphyrins. Here, we demonstrate that Abcb6(-/-) mice lack mitochondrial ATP-driven import of coproporphyrin III. Gene expression analysis revealed that loss of Abcb6 results in up-regulation of compensatory porphyrin and iron pathways, associated with elevated protoporphyrin IX (PPIX). Phenylhydrazine-induced stress caused higher mortality in Abcb6(-/-) mice, possibly because of sustained elevation of PPIX and an inability to convert PPIX to heme despite elevated ferrochelatase levels. Therefore, Abcb6 is the sole ATP-dependent porphyrin importer, and loss of Abcb6 produces up-regulation of heme and iron pathways necessary for normal development. However, under extreme demand for porphyrins (e.g. phenylhydrazine stress), these adaptations appear inadequate, which suggests that under these conditions Abcb6 is important for optimal survival.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Dagny L
authors.initials: DL
authors.lastname: Ulrich
authors.forename: John
authors.initials: J
authors.lastname: Lynch
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Fukuda
authors.forename: Deepa
authors.initials: D
authors.lastname: Nachagari
authors.forename: Guoqing
authors.initials: G
authors.lastname: Du
authors.forename: Daxi
authors.initials: D
authors.lastname: Sun
authors.forename: Yiping
authors.initials: Y
authors.lastname: Fan
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Tsurkan
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003306:Coproporphyrins / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006418:Heme / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D016877:Oxidants / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010659:Phenylhydrazines / Q000633:toxicity*; D011166:Porphyrins / Q000378:metabolism*; D011524:Protoporphyrins / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; C514489:Abcb6 protein, mouse; D003306:Coproporphyrins; D051741:Kruppel-Like Transcription Factors; D016877:Oxidants; D010659:Phenylhydrazines; D011166:Porphyrins; D011524:Protoporphyrins; C080774:erythroid Kruppel-like factor; C030299:phenylhydrazine; C026971:coproporphyrin III; C017803:zinc protoporphyrin; D006418:Heme; D000255:Adenosine Triphosphate; C028025:protoporphyrin IX