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

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.
Authors	Dawei Jiang, Linlin Zhao, Clary B Clish, David E Clapham
Journal	Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 24 Pg. E2249-54 (Jun 11 2013) ISSN: 1091-6490 [Electronic] United States
PMID	23716663 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antiporters Calcium-Binding Proteins LETM1 protein, human Membrane Proteins Mitochondrial Proteins Protons Adenosine Triphosphate Glucose Kainic Acid Calcium
Topics	Adenosine Triphosphate (metabolism) Animals Antiporters (genetics, metabolism) Brain (metabolism) Calcium (metabolism) Calcium-Binding Proteins (genetics, metabolism) Cells, Cultured Embryo, Mammalian (cytology, embryology, metabolism) Female Glucose (metabolism) HEK293 Cells Humans Kainic Acid (toxicity) Male Membrane Potential, Mitochondrial Membrane Proteins (genetics, metabolism) Mice Mice, Knockout Microscopy, Confocal Microscopy, Electron Mitochondria (metabolism, physiology, ultrastructure) Mitochondrial Proteins (genetics, metabolism) Protons RNA Interference Seizures (chemically induced, genetics, physiopathology) Wolf-Hirschhorn Syndrome (genetics, metabolism)

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