Human Molecular Genetics Advance Access originally published online on July 14, 2004
Human Molecular Genetics 2004 13(18):2101-2111; doi:10.1093/hmg/ddh217
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Human Molecular Genetics, Vol. 13, No. 18 © Oxford University Press 2004; all rights reserved
The calcium-binding aspartate/glutamate carriers, citrin and aralar1, are new substrates for the DDP1/TIMM8a–TIMM13 complex
1Department of Chemistry and Biochemistry, 2Molecular Biology Institute, PO Box 951569, UCLA, Los Angeles, CA 90095-15691, USA, 3Boys Town National Research Hospital, Genetics Department, 555 N. 30th Street, Omaha, NE 68131, USA and 4Department of Medial Genetics, IMBG, University of Copenhagen, Denmark
Received May 10, 2004; Accepted July 6, 2004
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.
* To whom correspondence should be addressed. Tel: +1 3107944834; Fax: +1 3102064038; Email: koehler{at}chem.ucla.edu
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