Inverse correlation between expression of the Wolfs Hirschhorn candidate gene Letm1 and mitochondrial volume in C. elegans and in mammalian cells

• Published in: Human molecular genetics Vol. 16; no. 17; pp. 2061 - 2071
• Main Authors: Hasegawa, Ayako, van der Bliek, Alexander M.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.09.2007; Oxford Publishing Limited (England)
• Subjects: 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; Correlation; Gene expression; Caenorhabditis elegans; Vertebrata; Mitochondria; Mammalia; Volume; Helmintha; Genetics; Nemathelminthia; Candidate gene; Invertebrata; Nematoda
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddm154

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.