MCB Accepts, published online ahead of print on 2 November 2009

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Mol. Cell. Biol. doi:10.1128/MCB.00749-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Distinct forms of mitochondrial TOM-TIM supercomplexes define signal-dependent states of preprotein sorting

Agnieszka Chacinska, Martin van der Laan, Carola S. Mehnert, Bernard Guiard, David U. Mick, Dana P. Hutu, Kaye N. Truscott, Nils Wiedemann, Chris Meisinger, Nikolaus Pfanner^*, and Peter Rehling^*

Institut für Biochemie und Molekularbiologie, ZBMZ, Universität Freiburg, 79104 Freiburg, Germany; Centre for Biological Signalling Studies (bioss), Universität Freiburg, 79104 Freiburg, Germany; Fakultät für Biologie, Universität Freiburg, 79104 Freiburg, Germany; Centre de Génétique Moléculaire, CNRS, 91190 Gif-sur-Yvette, France; Abteilung für Biochemie II, Universität Göttingen, 37073 Göttingen, Germany; Department of Biochemistry, La Trobe University, Melbourne 3086, Australia

^* To whom correspondence should be addressed. Email: nikolaus.pfanner{at}biochemie.uni-freiburg.de. peter.rehling{at}medizin.uni-goettingen.de.

Mitochondrial import of cleavable preproteins occurs at translocation contact sites where the translocase of the outer membrane (TOM) associates with the presequence translocase of the inner membrane (TIM23) in a supercomplex. Different views exist on the mechanism of how TIM23 mediates preprotein sorting to either the matrix or inner membrane. On the one hand, two TIM23 forms were proposed, a matrix transport-form containing the motor PAM (TIM23-PAM) and a sorting form containing Tim21 (TIM23^SORT). On the other hand, it was reported that TIM23 and PAM are permanently associated in a single-entity translocase. We have accumulated distinct transport intermediates of preproteins to analyze the translocases in their active, preprotein-carrying state. We identified two different forms of active TOM-TIM23 supercomplexes, TOM-TIM23^SORT and TOM-TIM23-PAM. The two supercomplexes do not represent separate pathways but are in dynamic exchange during preprotein translocation and sorting. Depending on the signals of the preproteins, switches between the different forms of supercomplex and TIM23 are required for the completion of preprotein import.