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

Proc Natl Acad Sci U S A
Authors
Keywords
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.

Year of Publication
2013
Journal
Proc Natl Acad Sci U S A
Volume
110
Issue
24
Pages
E2249-54
Date Published
2013 Jun 11
ISSN
1091-6490
URL
DOI
10.1073/pnas.1308558110
PubMed ID
23716663
PubMed Central ID
PMC3683736
Links
Grant list
P30 HD018655 / HD / NICHD NIH HHS / United States
Howard Hughes Medical Institute / United States
Canadian Institutes of Health Research / Canada