Regulation of mitochondrial iron import through differential turnover of mitoferrin 1 and mitoferrin 2.
Mitoferrin 1 and mitoferrin 2 are homologous members of the mitochondrial solute carrier family. Mitoferrin 1 is required for mitochondrial iron delivery in developing erythrocytes. Here we show that mitoferrin 1 and mitoferrin 2 contribute to mitochondrial iron delivery in a variety of cells. Reductions in mitoferrin 1 and/or mitoferrin 2 levels by RNA interference result in decreased mitochondrial iron accumulation, heme synthesis, and iron-sulfur cluster synthesis. The ectopic expression of mitoferrin 1 in nonerythroid cells silenced for mitoferrin 2 or the expression of mitoferrin 2 in cells silenced for mitoferrin 1 restored heme synthesis to "baseline" levels. The ectopic expression of mitoferrin 2, however, did not support hemoglobinization in erythroid cells deficient in mitoferrin 1. Mitoferrin 2 could not restore heme synthesis in developing erythroid cells because of an inability of the protein to accumulate in mitochondria. The half-life of mitoferrin 1 was increased in developing erythroid cells, while the half-life of mitoferrin 2 did not change. These results suggest that mitochondrial iron accumulation is tightly regulated and that controlling mitoferrin levels within the mitochondrial membrane provides a mechanism to regulate mitochondrial iron levels.
Paradkar
Prasad N
PN
Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
Zumbrennen
Kimberley B
KB
Paw
Barry H
BH
Ward
Diane M
DM
Kaplan
Jerry
J
D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D027682:Cation Transport Proteins; D006224:Cricetinae; D003412:Cricetulus; D003600:Cytosol / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D041681:NIH 3T3 Cells; D011499:Protein Processing, Post-Translational
D027682:Cation Transport Proteins; D007506:Iron-Sulfur Proteins; D026901:Membrane Transport Proteins; C486056:Slc25a28 protein, mouse; C509051:mitoferrin protein, mouse; D049452:Green Fluorescent Proteins; D007501:Iron