Genome-Wide RNAi Screen Identifies Letm1 as a Mitochondrial Ca2+/H+ Antiporter

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Science  02 Oct 2009:
Vol. 326, Issue 5949, pp. 144-147
DOI: 10.1126/science.1175145

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For over 40 years, Ca2+/H+ antiport has been reported across plasma cell membranes and mitochondrial inner membranes, but the molecules responsible for the exchange have not been known. Jiang et al. (p. 144; see the Perspective by Demaurex and Poburko) conducted a genome-wide RNA interference screen in Drosophila and identified a nuclear-encoded mitochondrial protein, Letm1 (leucine zipper EF–hand-containing transmembrane protein 1), as a mitochondrial Ca2+/H+ antiporter critical for mitochondrial Ca2+ uptake. Furthermore, the gene's mammalian homolog is deleted in Wolf-Hirschhorn syndrome, a disorder characterized by mental retardation, microcephaly, seizures, hypotonia, and cleft lip or palate.


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.

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