Letm1, the mitochondrial Ca2+/H+ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf-Hirschhorn syndrome.

[wolf-hirschhorn syndrome]

Mitochondrial metabolism , respiration , and ATP production necessitate ion transport across the inner mitochondrial membrane . Leucine zipper-EF-hand containing transmembrane protein 1 (Letm 1 ), one of the genes deleted in Wolf-Hirschhorn syndrome , encodes a putative mitochondrial Ca (2 +)/H (+) antiporter . Cellular Letm 1 knockdown reduced Ca (2 +)mito uptake , H (+)mito extrusion and impaired mitochondrial ATP generation capacity . Homozygous deletion of Letm 1 in mice resulted in embryonic lethality before day 6 .5 of embryogenesis and ~50 % of the heterozygotes died before day 13 .5 of embryogenesis . The surviving heterozygous mice exhibited altered glucose metabolism , impaired control of brain ATP levels , and increased seizure activity . We conclude that loss of Letm 1 contributes to the pathology of Wolf-Hirschhorn syndrome in humans and may contribute to seizure phenotypes by reducing glucose oxidation and other specific metabolic alterations .