Abstract
Mitochondrial metabolism, respiration, and ATP production necessitate ion transport across the inner mitochondrial membrane. Leucine zipper-EF-hand containing transmembrane protein 1 (Letm1), one of the genes deleted in Wolf-Hirschhorn syndrome, encodes a putative mitochondrial Ca(2+)/H(+) antiporter. Cellular Letm1 knockdown reduced Ca(2+)mito uptake, H(+)mito extrusion and impaired mitochondrial ATP generation capacity. Homozygous deletion of Letm1 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 Letm1 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.