On the mechanism of preprotein import by the mitochondrial presequence translocase

Institut für Biochemie und Molekularbiologie, Universität Freiburg, D-79104 Freiburg, Germany.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 06/2010; 1803(6):732-9. DOI: 10.1016/j.bbamcr.2010.01.013
Source: PubMed


Mitochondria are organelles of endosymbiontic origin that contain more than one thousand different proteins. The vast majority of these proteins is synthesized in the cytosol and imported into one of four mitochondrial subcompartments: outer membrane, intermembrane space, inner membrane and matrix. Several import pathways exist and are committed to different classes of precursor proteins. The presequence translocase of the inner mitochondrial membrane (TIM23 complex) mediates import of precursor proteins with cleavable amino-terminal presequences. Presequences direct precursors across the inner membrane. The combination of this presequence with adjacent regions determines if a precursor is fully translocated into the matrix or laterally sorted into the inner mitochondrial membrane. The membrane-embedded TIM23(SORT) complex mediates the membrane potential-dependent membrane insertion of precursor proteins with a stop-transfer sequence downstream of the mitochondrial targeting signal. In contrast, translocation of precursor proteins into the matrix requires the recruitment of the presequence translocase-associated motor (PAM) to the TIM23 complex. This ATP-driven import motor consists of mitochondrial Hsp70 and several membrane-associated co-chaperones. These two structurally and functionally distinct forms of the TIM23 complex (TIM23(SORT) and TIM23(MOTOR)) are in a dynamic equilibrium with each other. In this review, we discuss recent advances in our understanding of the mechanisms of matrix translocation and membrane insertion by the TIM23 machinery.

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Available from: Martin Van der Laan, Sep 28, 2015
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    • "In this regard, a previous report shows that over-expression or knockout of Mfn2 modulates and affects mRNA levels of several mitochondrial proteins [51], [52]. We have described an arachidonic acid [55] generation/exportation system that includes an Acyl-CoA synthetase 4 (Acsl4) [38], [40], [56]. Acsl4 is anchored at the MAM (mitochondrial associated-membrane) structures [57] and its activity determines the production rate of AA which is necessary for StAR gene expression [22]. "
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    ABSTRACT: The rate-limiting step in the biosynthesis of steroid hormones, known as the transfer of cholesterol from the outer to the inner mitochondrial membrane, is facilitated by StAR, the Steroidogenic Acute Regulatory protein. We have described that mitochondrial ERK1/2 phosphorylates StAR and that mitochondrial fusion, through the up-regulation of a fusion protein Mitofusin 2, is essential during steroidogenesis. Here, we demonstrate that mitochondrial StAR together with mitochondrial active ERK and PKA are necessary for maximal steroid production. Phosphorylation of StAR by ERK is required for the maintenance of this protein in mitochondria, observed by means of over-expression of a StAR variant lacking the ERK phosphorylation residue. Mitochondrial fusion regulates StAR levels in mitochondria after hormone stimulation. In this study, Mitofusin 2 knockdown and mitochondrial fusion inhibition in MA-10 Leydig cells diminished StAR mRNA levels and concomitantly mitochondrial StAR protein. Together our results unveil the requirement of mitochondrial fusion in the regulation of the localization and mRNA abundance of StAR. We here establish the relevance of mitochondrial phosphorylation events in the correct localization of this key protein to exert its action in specialized cells. These discoveries highlight the importance of mitochondrial fusion and ERK phosphorylation in cholesterol transport by means of directing StAR to the outer mitochondrial membrane to achieve a large number of steroid molecules per unit of StAR.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "In addition to the TIM23-PAM complex, another version, called TIM23 SORT , exists that is functionally different from TIM23-PAM [6] [27] [29] (Fig. 1C). TIM23 SORT is capable of the IMM insertion of presequence proteins if the presequence is followed by the hydrophobic transmembrane sorting signal. "
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    ABSTRACT: Mitochondria are involved in many essential cellular activities. These broad functions explicate the need for the well-orchestrated biogenesis of mitochondrial proteins to avoid death and pathological consequences, both in unicellular and more complex organisms. Yeast as a model organism has been pivotal in identifying components and mechanisms that drive the transport and sorting of nuclear-encoded mitochondrial proteins. The machinery components that are involved in the import of mitochondrial proteins are generally evolutionarily conserved within the eukaryotic kingdom. However, topological and functional differences have been observed. We review the similarities and differences in mitochondrial translocases from yeast to human. Additionally, we provide a systematic overview of the contribution of mitochondrial import machineries to human pathologies, including cancer, mitochondrial diseases, and neurodegeneration.
    Full-text · Article · May 2014 · FEBS Letters
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    • "Alternatively, TIM22 is responsible for the import of proteins via the carrier import pathway, which is specific for the import of inner membrane proteins containing internal mitochondrial targeting signals (Fig. 1). Along with the Sorting and Assembly Machinery (SAM) complex on the outer membrane and the Mitochondrial Intermembrane space Assembly (MIA) in the intermembrane space, these complexes are responsible for the import of the majority of proteins into the mitochondria [3] [9]. In the last few years, studies on the mechanisms of protein import into mitochondria have revealed interactions between the protein import complexes with other multi-subunit protein complexes. "
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    ABSTRACT: Background: Mitochondria play essential roles in the life and death of almost all eukaryotic cells, ranging from single-celled to multi-cellular organisms that display tissue and developmental differentiation. As mitochondria only arose once in evolution, much can be learned from studying single celled model systems such as yeast and applying this knowledge to other organisms. However, two billion years of evolution have also resulted in substantial divergence in mitochondrial function between eukaryotic organisms. Scope of review: Here we review our current understanding of the mechanisms of mitochondrial protein import between plants and yeast (Saccharomyces cerevisiae) and identify a high level of conservation for the essential subunits of plant mitochondrial import apparatus. Furthermore, we investigate examples whereby divergence and acquisition of functions have arisen and highlight the emerging examples of interactions between the import apparatus and components of the respiratory chain. Major conclusions: After more than three decades of research into the components and mechanisms of mitochondrial protein import of plants and yeast, the differences between these systems are examined. Specifically, expansions of the small gene families that encode the mitochondrial protein import apparatus in plants are detailed, and their essential role in seed viability is revealed. General significance: These findings point to the essential role of the inner mitochondrial protein translocases in Arabidopsis, establishing their necessity for seed viability and the crucial role of mitochondrial biogenesis during germination. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.
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