Inverse correlation between expression of the Wolfs Hirschhorn candidate gene Letm1 and mitochondrial volume in C. elegans and in mammalian cells
Deletion of the Letm1 gene correlates with the occurrence of epilepsy in patients with Wolf–Hirschhorn syndrome. The Letm1 gene encodes a mitochondrial protein that is homologous to yeast Mdm38. Yeast Mdm38 is localized to the mitochondrial inner membrane where it was proposed to act as a K+/H+ anti...
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Published in | Human molecular genetics Vol. 16; no. 17; pp. 2061 - 2071 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
Oxford
Oxford University Press
01.09.2007
Oxford Publishing Limited (England) |
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Abstract | Deletion of the Letm1 gene correlates with the occurrence of epilepsy in patients with Wolf–Hirschhorn syndrome. The Letm1 gene encodes a mitochondrial protein that is homologous to yeast Mdm38. Yeast Mdm38 is localized to the mitochondrial inner membrane where it was proposed to act as a K+/H+ antiporter or alternatively as a chaperone for selected mitochondrial inner membrane proteins. Here, we present cellular and biochemical analysis of Letm1 in mammalian cells and an analysis of a C. elegans mutant that could serve as a model for Wolf–Hirschhorn syndrome. We localized the Letm1 protein to the mitochondrial inner membrane of mammalian cells, where it exists in a 550-kDa complex. We show that Letm1 can bind to itself in vitro, raising the possibility that it can form higher order multimers in vivo. Reduced levels of Letm1 in human cells and in C. elegans lead to swellings along the lengths of mitochondria, consistent with the phenotype observed in yeast. Electron micrographs show mitochondria with swollen matrices that are less electron-dense than matrices in normal mitochondria. The opposite effect is achieved by overexpression of Letm1. Overexpression increases the electron density of the mitochondrial matrix and swelling of cristae. Our results are therefore consistent with a protein that regulates the volume of the mitochondrial matrix. |
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AbstractList | Deletion of the Letm1 gene correlates with the occurrence of epilepsy in patients with Wolf-Hirschhorn syndrome. The Letm1 gene encodes a mitochondrial protein that is homologous to yeast Mdm38. Yeast Mdm38 is localized to the mitochondrial inner membrane where it was proposed to act as a K+/H+ antiporter or alternatively as a chaperone for selected mitochondrial inner membrane proteins. Here, we present cellular and biochemical analysis of Letm1 in mammalian cells and an analysis of a C. elegans mutant that could serve as a model for Wolf-Hirschhorn syndrome. We localized the Letm1 protein to the mitochondrial inner membrane of mammalian cells, where it exists in a 550-kDa complex. We show that Letm1 can bind to itself in vitro, raising the possibility that it can form higher order multimers in vivo. Reduced levels of Letm1 in human cells and in C. elegans lead to swellings along the lengths of mitochondria, consistent with the phenotype observed in yeast. Electron micrographs show mitochondria with swollen matrices that are less electron-dense than matrices in normal mitochondria. The opposite effect is achieved by overexpression of Letm1. Overexpression increases the electron density of the mitochondrial matrix and swelling of cristae. Our results are therefore consistent with a protein that regulates the volume of the mitochondrial matrix. |
Author | van der Bliek, Alexander M. Hasegawa, Ayako |
Author_xml | – sequence: 1 givenname: Ayako surname: Hasegawa fullname: Hasegawa, Ayako organization: 1Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Box 951737, Los Angeles, CA 90095USA – sequence: 2 givenname: Alexander M. surname: van der Bliek fullname: van der Bliek, Alexander M. email: avan@mednet.ucla.edu organization: E-mail: avan@mednet.ucla.edu |
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Snippet | Deletion of the Letm1 gene correlates with the occurrence of epilepsy in patients with Wolf–Hirschhorn syndrome. The Letm1 gene encodes a mitochondrial protein... Deletion of the Letm1 gene correlates with the occurrence of epilepsy in patients with Wolf-Hirschhorn syndrome. The Letm1 gene encodes a mitochondrial protein... |
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SubjectTerms | Animals Biological and medical sciences Caenorhabditis elegans - metabolism Caenorhabditis elegans Proteins - analysis Caenorhabditis elegans Proteins - genetics Caenorhabditis elegans Proteins - metabolism Calcium-Binding Proteins - genetics Calcium-Binding Proteins - metabolism Cell Membrane - metabolism Cells, Cultured Fluorescent Antibody Technique Fundamental and applied biological sciences. Psychology Genetics of eukaryotes. Biological and molecular evolution HeLa Cells Humans Membrane Proteins - genetics Membrane Proteins - metabolism Mitochondria - metabolism Mitochondria - ultrastructure Mitochondrial Proteins - analysis Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism Mitochondrial Size Molecular and cellular biology Mutation Wolfram Syndrome - genetics |
Title | Inverse correlation between expression of the Wolfs Hirschhorn candidate gene Letm1 and mitochondrial volume in C. elegans and in mammalian cells |
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