The LETM1/YOL027 gene family encodes a factor of the mitochondrial K+ homeostasis with a potential role in the Wolf-Hirschhorn syndrome

J Biol Chem. 2004 Jul 16;279(29):30307-15. doi: 10.1074/jbc.M403607200. Epub 2004 May 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Calcium-Binding Proteins
  • DNA, Complementary
  • LETM1 protein, human
  • Luminescent Proteins
  • MDM38 protein, S cerevisiae
  • Membrane Proteins
  • Mitochondrial Proteins
  • Saccharomyces cerevisiae Proteins
  • Green Fluorescent Proteins
  • Potassium Acetate
  • Potassium