The calcium-binding aspartate/glutamate carriers, citrin and aralar1, are new substrates for the DDP1/TIMM8a-TIMM13 complex

Hum Mol Genet. 2004 Sep 15;13(18):2101-11. doi: 10.1093/hmg/ddh217. Epub 2004 Jul 14.


The biogenesis of the mitochondrial inner membrane is dependent on two distinct 70 kDa protein complexes. TIMM8a partners with TIMM13 in the mitochondrial intermembrane space to form a 70 kDa complex and facilitates the import of the inner membrane substrate TIMM23. We have identified a new class of substrates, citrin and aralar1, which are Ca2+-binding aspartate/glutamate carriers (AGCs) of the mitochondrial inner membrane, using cross-linking and immunoprecipitation assays in isolated mitochondria. The AGCs function in the aspartate-malate NADH shuttle that moves reducing equivalents from the cytosol to the mitochondrial matrix. Mohr-Tranebjaerg syndrome (MTS/DFN-1, deafness/dystonia syndrome) results from a mutation in deafness/dystonia protein 1/translocase of mitochondrial inner membrane 8a (DDP1/TIMM8a) and loss of the 70 kDa complex. A lymphoblast cell line derived from an MTS patient had decreased NADH levels and defects in mitochondrial protein import. Protein expression studies indicate that DDP1 and TIMM13 show non-uniform expression in mammals, and expression is prominent in the large neurons in the brain, which is in agreement with the expression pattern of aralar1. Thus, insufficient NADH shuttling, linked with changes in Ca2+ concentration, in sensitive cells of the central nervous system might contribute to the pathologic process associated with MTS.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium-Binding Proteins / metabolism*
  • Cell Line
  • Deafness / genetics
  • Deafness / metabolism
  • Dystonia / genetics
  • Dystonia / metabolism
  • Heredodegenerative Disorders, Nervous System / genetics
  • Heredodegenerative Disorders, Nervous System / metabolism*
  • Humans
  • Immunoprecipitation
  • Intracellular Membranes / metabolism
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Mitochondria / metabolism
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Mitochondrial Proteins / metabolism*
  • Organic Anion Transporters / metabolism*
  • Purkinje Cells / immunology
  • Purkinje Cells / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Syndrome


  • Calcium-Binding Proteins
  • Membrane Transport Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Mitochondrial Proteins
  • Organic Anion Transporters
  • Slc25a12 protein, mouse
  • TIMM13 protein, human
  • TIMM8A protein, human
  • citrin