The LETM1/YOL027 Gene Family Encodes a Factor of the Mitochondrial K+ Homeostasis with a Potential Role in the Wolf-Hirschhorn Syndrome

• Published in: The Journal of biological chemistry 2004-07, Vol.279 (29), p.30307-30315
• Main Authors: Nowikovsky, Karin, Froschauer, Elisabeth M, Zsurka, Gabor, Samaj, Jozef, Reipert, Siegfried, Kolisek, Martin, Wiesenberger, Gerlinde, Schweyen, Rudolf J
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cloning, Molecular; DNA, Complementary - metabolism; Gene Deletion; Green Fluorescent Proteins; Homeostasis; Humans; Intracellular Membranes - metabolism; Luminescent Proteins - metabolism; Membrane Potentials; Membrane Proteins - genetics; Membrane Proteins - metabolism; Microscopy, Confocal; Microscopy, Electron; Microscopy, Fluorescence; Mitochondria - metabolism; Mitochondrial Proteins; Molecular Sequence Data; Multigene Family; Muscular Diseases - genetics; Mutation; Phenotype; Plasmids - metabolism; Potassium - chemistry; Potassium - metabolism; Potassium Acetate - pharmacology; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Sequence Homology, Amino Acid; Subcellular Fractions - metabolism; Syndrome; Time Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M403607200

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 ( yol027 Δ 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 yol027 Δ mitochondria have increased cation contents, particularly K + and low-membrane-potential Δψ. 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.