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Proc Natl Acad Sci U S A DOI:10.1073/pnas.1308558110

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

Publication TypeJournal Article
Year of Publication2013
AuthorsJiang, D, Zhao, L, Clish, CB, Clapham, DE
JournalProc Natl Acad Sci U S A
Volume110
Issue24
PagesE2249-54
Date Published2013 Jun 11
ISSN1091-6490
KeywordsAdenosine Triphosphate, Animals, Antiporters, Brain, Calcium, Calcium-Binding Proteins, Cells, Cultured, Embryo, Mammalian, Female, Glucose, HEK293 Cells, Humans, Kainic Acid, Male, Membrane Potential, Mitochondrial, Membrane Proteins, Mice, Mice, Knockout, Microscopy, Confocal, Microscopy, Electron, Mitochondria, Mitochondrial Proteins, Protons, RNA Interference, Seizures, 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.

URLhttp://www.pnas.org/cgi/pmidlookup?view=long&pmid=23716663
DOI10.1073/pnas.1308558110
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23716663?dopt=Abstract

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID23716663
PubMed Central IDPMC3683736
Grant ListP30 HD018655 / HD / NICHD NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
/ / Canadian Institutes of Health Research / Canada