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

Science. 2009 Oct 2;326(5949):144-7. doi: 10.1126/science.1175145.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiporters / genetics*
  • Antiporters / metabolism
  • Calcium / metabolism*
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / metabolism*
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Cell Line
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / metabolism
  • Genome, Human
  • Genome, Insect
  • HeLa Cells
  • Humans
  • Hydrogen / metabolism
  • Hydrogen-Ion Concentration
  • Ion Transport
  • Membrane Potential, Mitochondrial
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Proteolipids / metabolism
  • RNA Interference*

Substances

  • Antiporters
  • Calcium-Binding Proteins
  • Cation Transport Proteins
  • Drosophila Proteins
  • LETM1 protein, human
  • Letm1 protein, Drosophila
  • Membrane Proteins
  • Mitochondrial Proteins
  • Proteolipids
  • calcium-hydrogen antiporters
  • proteoliposomes
  • Hydrogen
  • Calcium