1. The LETM1/YOL027 gene family encodes a factor of the mitochondrial K+ homeostasis with a potential role in the Wolf-Hirschhorn syndrome.
- Author
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Nowikovsky K, Froschauer EM, Zsurka G, Samaj J, Reipert S, Kolisek M, Wiesenberger G, and Schweyen RJ
- Subjects
- Amino Acid Sequence, Animals, Calcium-Binding Proteins genetics, Cloning, Molecular, DNA, Complementary metabolism, Gene Deletion, Green Fluorescent Proteins, Homeostasis, Humans, Intracellular Membranes metabolism, Luminescent Proteins metabolism, Membrane Potentials, Membrane Proteins genetics, Microscopy, Confocal, Microscopy, Electron, Microscopy, Fluorescence, Mitochondrial Proteins, Molecular Sequence Data, Mutation, Phenotype, Plasmids metabolism, Potassium chemistry, Potassium Acetate pharmacology, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins genetics, Sequence Homology, Amino Acid, Subcellular Fractions metabolism, Syndrome, Time Factors, Calcium-Binding Proteins metabolism, Membrane Proteins metabolism, Mitochondria metabolism, Multigene Family, Muscular Diseases genetics, Potassium metabolism, Saccharomyces cerevisiae Proteins metabolism
- Abstract
The yeast open reading frames YOL027 and YPR125 and their orthologs in various eukaryotes encode proteins with a single predicted trans-membrane domain ranging in molecular mass from 45 to 85 kDa. Hemizygous deletion of their human homolog LETM1 is likely to contribute to the Wolf-Hirschhorn syndrome phenotype. We show here that in yeast and human cells, these genes encode integral proteins of the inner mitochondrial membrane. Deletion of the yeast YOL027 gene (yol027Delta mutation) results in mitochondrial dysfunction. This mutant phenotype is complemented by the expression of the human LETM1 gene in yeast, indicating a functional conservation of LetM1/Yol027 proteins from yeast to man. Mutant yol027Delta mitochondria have increased cation contents, particularly K+ and low-membrane-potential Deltapsi. They are massively swollen in situ and refractory to potassium acetate-induced swelling in vitro, which is indicative of a defect in K+/H+ exchange activity. Thus, YOL027/LETM1 are the first genes shown to encode factors involved in both K+ homeostasis and organelle volume control.
- Published
- 2004
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