Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) forms a Ca/H antiporter.

Leucine zipper-EF-hand-containing transmembrane protein1 (LETM1) is located in the mitochondrial inner membrane and is defective in Wolf-Hirschhorn syndrome. LETM1 contains only one transmembrane helix, but it behaves as a putative transporter. Our data shows that LETM1 knockdown or overexpression robustly increases or decreases mitochondrial Ca level in HeLa cells, respectively. Also the residue Glu221 of mouse LETM1 is identified to be necessary for Ca flux. The mutation of Glu221 to glutamine abolishes the Ca-transport activity of LETM1 in cells. Furthermore, the purified LETM1 exhibits Ca/H anti-transport activity, and the activity is enhanced as the proton gradient is increased. More importantly, electron microscopy studies reveal a hexameric LETM1 with a central cavity, and also, observe two different conformational states under alkaline and acidic conditions, respectively. Our results indicate that LETM1 is a Ca/H antiporter and most likely responsible for mitochondrial Ca output.