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. 2013 Jun 11;110(24):E2249-54. doi: 10.1073/pnas.1308558110. Epub 2013 May 28.

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.

Keywords: calcium signaling; epilepsy; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Antiporters / genetics
  • Antiporters / metabolism
  • Brain / metabolism*
  • Calcium / metabolism
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cells, Cultured
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / embryology
  • Embryo, Mammalian / metabolism
  • Female
  • Glucose / metabolism*
  • HEK293 Cells
  • Humans
  • Kainic Acid / toxicity
  • Male
  • Membrane Potential, Mitochondrial
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Microscopy, Electron
  • Mitochondria / metabolism
  • Mitochondria / physiology
  • Mitochondria / ultrastructure
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Protons
  • RNA Interference
  • Seizures / chemically induced
  • Seizures / genetics
  • Seizures / physiopathology
  • Wolf-Hirschhorn Syndrome / genetics
  • Wolf-Hirschhorn Syndrome / metabolism*

Substances

  • Antiporters
  • Calcium-Binding Proteins
  • LETM1 protein, human
  • Membrane Proteins
  • Mitochondrial Proteins
  • Protons
  • Adenosine Triphosphate
  • Glucose
  • Kainic Acid
  • Calcium