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J. Biol. Chem., Vol. 279, Issue 14, 13540-13546, April 2, 2004

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Organization and Function of the Small Tim Complexes Acting along the Import Pathway of Metabolite Carriers into Mammalian Mitochondria^*

Nicole Mühlenbein, Sabine Hofmann, Uli Rothbauer, and Matthias F. Bauer¶||

From the Institut für Diabetesforschung, Akademisches Krankenhaus München-Schwabing, Kölner Platz 1, D-80804 München, Germany and the ^¶Institut für Klinische Chemie, Molekulare Diagnostik und Mitochondriale Genetik, Akademisches Krankenhaus München-Schwabing, Kölner Platz 1, D-80804 München, Germany

Tim9, Tim10a, and Tim10b are members of the family of small Tim proteins located in the intermembrane space of mammalian mitochondria. In yeast, members of this family act along the TIM22 import pathway during import of metabolite carriers and other integral inner membrane proteins. Here, we show that the human small proteins form two distinct hetero-oligomeric complexes. A 70-kDa complex that contains Tim9 and Tim10a and a Tim9-10a-10b that is part of a higher molecular weight assembly of 450 kDa. This distribution among two complexes suggests Tim10b to be the functional homologue of yeast Tim12. Both human complexes are tightly associated with the inner membrane and, compared with yeast, soluble 70-kDa complexes appear to be completely absent in the intermembrane space. Thus, the function of soluble 70-kDa complexes as trans-site receptors for incoming carrier proteins is not conserved from lower to higher eukaryotes. During import, the small Tim complexes directly interact with human adenine nucleotide translocator (ANT) in transit in a metal-dependent manner. For insertion of carrier preproteins into the inner membrane, the human small Tim proteins directly interact with human Tim22, the putative insertion pore of the TIM22 translocase. However, in contrast to yeast, only a small fraction of Tim9-Tim10a-Tim10b complex is in a stable association with Tim22. We conclude that different mechanisms and specific requirements for import and insertion of mammalian carrier preproteins have evolved in higher eukaryotes.

Received for publication, November 14, 2003 , and in revised form, January 15, 2004.

^* This work was supported by the Deutsche Forschungsgemeinschaft (to M. F. B.) (Ba1438/3 and 4) and (to S. H.) (Ho2374/1-1) and by the Bundesministerium für Bildung und Forschung (BMBF: 01KW9953-MITOP Project). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors have contributed equally to this work.

^|| To whom correspondence should be addressed: Institut für Klinische Chemie, Molekularbiologische Diagnostik und Mitochondriale Genetik, KH München-Schwabing, Kölner Platz 1, D-80804 München, Germany. Tel.: 49-(0)89-3068-2670; Fax: 49-(0)89-3068-3911; E-mail: bauer{at}bio.med.uni-muenchen.de.

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