Identification of a mammalian mitochondrial porphyrin transporter.
The movement of anionic porphyrins (for example, haem) across intracellular membranes is crucial to many biological processes, but their mitochondrial translocation and coordination with haem biosynthesis is not understood. Transport of porphyrins into isolated mitochondria is energy-dependent, as expected for the movement of anions into a negatively charged environment. ATP-binding cassette transporters actively facilitate the transmembrane movement of substances. We found that the mitochondrial ATP-binding cassette transporter ABCB6 is upregulated (messenger RNA and protein in human and mouse cells) by elevation of cellular porphyrins and postulated that ABCB6 has a function in porphyrin transport. We also predicted that ABCB6 is functionally linked to haem biosynthesis, because its mRNA is found in both human bone marrow and CD71+ early erythroid cells (by database searching), and because our results show that ABCB6 is highly expressed in human fetal liver, and Abcb6 in mouse embryonic liver. Here we demonstrate that ABCB6 is uniquely located in the outer mitochondrial membrane and is required for mitochondrial porphyrin uptake. After ABCB6 is upregulated in response to increased intracellular porphyrin, mitochondrial porphyrin uptake activates de novo porphyrin biosynthesis. This process is blocked when the Abcb6 gene is silenced. Our results challenge previous assumptions about the intracellular movement of porphyrins and the factors controlling haem biosynthesis.
Krishnamurthy
Partha C
PC
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, Tennessee 38105-2794, USA.
Du
Guoqing
G
Fukuda
Yu
Y
Sun
Daxi
D
Sampath
Janardhan
J
Mercer
Kelly E
KE
Wang
Junfeng
J
Sosa-Pineda
Beatriz
B
Murti
K Gopal
KG
Schuetz
John D
JD
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002454:Cell Differentiation; D005333:Fetus / Q000378:metabolism; D005786:Gene Expression Regulation; D006418:Heme / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D011166:Porphyrins / Q000096:biosynthesis / Q000378:metabolism*; D011485:Protein Binding; D011524:Protoporphyrins / Q000378:metabolism
C107991:ABCB6 protein, human; D018528:ATP-Binding Cassette Transporters; C514489:Abcb6 protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011166:Porphyrins; D011524:Protoporphyrins; D006418:Heme