Cell survival under stress is enhanced by a mitochondrial ATP-binding cassette transporter that regulates hemoproteins.
The ATP-binding cassette (ABC) transporter ABCB6 localizes to the mitochondria, where it imports porphyrins and up-regulates de novo porphyrin synthesis. If ABCB6 also increases the intracellular heme concentration, it may broadly affect the regulation and physiology of cellular hemoproteins. We tested whether the ability of ABCB6 to accelerate de novo porphyrin biosynthesis alters mitochondrial and extramitochondrial heme levels. ABCB6 overexpression increased the quantity of cytosolic heme but did not affect mitochondrial heme levels. We then tested whether the increased extramitochondrial heme would increase the concentration and/or activity of cellular hemoproteins (hemoglobin, catalase, and cytochrome c oxidase). ABCB6 overexpression increased the activity and quantity of hemoproteins found in several subcellular compartments, and reduction of ABCB6 function (by small interfering RNA or knockout) reversed these findings. In complementary studies, suppression of ABCB6 expression sensitized cells to stress induced by peroxide and cyanide, whereas overexpression of ABCB6 protected against both stressors. Our findings show that the ability of ABCB6 to increase cytosolic heme levels produces phenotypic changes in hemoproteins that protect cells from certain stresses. Collectively, these findings have implications for the health and survival of both normal and abnormal cells, which rely on heme for multiple cellular processes.
Lynch
John
J
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, USA.
Fukuda
Yu
Y
Krishnamurthy
Partha
P
Du
Guoqing
G
Schuetz
John D
JD
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D005822:Genetic Vectors; D006418:Heme / Q000378:metabolism; D006420:Hemeproteins / Q000235:genetics / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D020014:K562 Cells / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D011166:Porphyrins / Q000378:metabolism
C107991:ABCB6 protein, human; D018528:ATP-Binding Cassette Transporters; D006420:Hemeproteins; D006454:Hemoglobins; D026901:Membrane Transport Proteins; D011166:Porphyrins; D006418:Heme