Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter.
Mitochondria are integral components of cellular calcium (Ca2+) signaling. Calcium stimulates mitochondrial adenosine 5'-triphosphate production, but can also initiate apoptosis. In turn, cytoplasmic Ca2+ concentrations are regulated by mitochondria. Although several transporter and ion-channel mechanisms have been measured in mitochondria, the molecules that govern Ca2+ movement across the inner mitochondrial membrane are unknown. We searched for genes that regulate mitochondrial Ca2+ and H+ concentrations using a genome-wide Drosophila RNA interference (RNAi) screen. The mammalian homolog of one Drosophila gene identified in the screen, Letm1, was found to specifically mediate coupled Ca2+/H+ exchange. RNAi knockdown, overexpression, and liposome reconstitution of the purified Letm1 protein demonstrate that Letm1 is a mitochondrial Ca2+/H+ antiporter.
Department of Cardiology, Howard Hughes Medical Institute, Children's Hospital Boston, Manton Center for Orphan Disease, and Department of Neurobiology, Harvard Medical School, Enders Building 1309, 320 Longwood Avenue, Boston, MA 02115, USA.
Dawei
D
Jiang
Linlin
L
Zhao
David E
DE
Clapham
D000818:Animals; D017920:Antiporters / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D015894:Genome, Human; D049750:Genome, Insect; D006367:HeLa Cells; D006801:Humans; D006859:Hydrogen / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D017136:Ion Transport; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D011510:Proteolipids / Q000378:metabolism; D034622:RNA Interference
D017920:Antiporters; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; D029721:Drosophila Proteins; C488528:LETM1 protein, human; C544264:Letm1 protein, Drosophila; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011510:Proteolipids; C027614:calcium-hydrogen antiporters; C020485:proteoliposomes; D006859:Hydrogen; D002118:Calcium