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Journal articles on the topic 'TIM23 complex'

Author: Grafiati
Published: 6 September 2023

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1

Ryan, Kathleen R., Roxanne S. Leung, and Robert E. Jensen. "Characterization of the Mitochondrial Inner Membrane Translocase Complex: the Tim23p Hydrophobic Domain Interacts with Tim17p but Not with Other Tim23p Molecules." Molecular and Cellular Biology 18, no. 1 (January 1, 1998): 178–87. http://dx.doi.org/10.1128/mcb.18.1.178.

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ABSTRACT Tim23p is a mitochondrial inner membrane protein essential for the import of proteins from the cytosol. Tim23p contains an amino-terminal hydrophilic segment and a carboxyl-terminal hydrophobic domain (Tim23Cp). To study the functions and interactions of the two parts of Tim23p separately, we constructed tim23N, encoding only the hydrophilic region of Tim23p, and tim23C, encoding only the hydrophobic domain of Tim23p. Only the Tim23C protein is imported into mitochondria, indicating that the mitochondrial targeting information in Tim23p resides in its membrane spans or intervening loops. Tim23Cp, however, cannot substitute for full-length Tim23p, suggesting that the hydrophilic portion of Tim23p also performs an essential function in mitochondrial protein import. We found that overexpression of Tim23Cp is toxic to yeast cells that carry the tim23-1 mutation. Excess Tim23Cp causes Tim23-1p to disappear, leavingtim23-1 cells without a full-length version of the Tim23 protein. If Tim17p, another inner membrane import component, is overexpressed along with Tim23Cp, the toxicity of Tim23Cp is largely reversed and the Tim23-1 protein no longer disappears. In coimmunoprecipitations from solubilized mitochondria, Tim17p associates with the Tim23C protein. In addition, we show that Tim23p and Tim17p can be chemically cross-linked to each other in intact mitochondria. We conclude that the hydrophobic domain encoded by tim23Ctargets Tim23p to the mitochondria and mediates the direct interaction between Tim23p and Tim17p. In contrast, Tim23Cp cannot be coimmunoprecipitated with Tim23p, raising the possibility that the hydrophobic domain of Tim23p does not interact with other Tim23 molecules.
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2

Alder, Nathan N., Jennifer Sutherland, Ashley I. Buhring, Robert E. Jensen, and Arthur E. Johnson. "Quaternary Structure of the Mitochondrial TIM23 Complex Reveals Dynamic Association between Tim23p and Other Subunits." Molecular Biology of the Cell 19, no. 1 (January 2008): 159–70. http://dx.doi.org/10.1091/mbc.e07-07-0669.

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Tim23p is an essential channel-forming component of the multisubunit TIM23 complex of the mitochondrial inner membrane that mediates protein import. Radiolabeled Tim23p monocysteine mutants were imported in vitro, incorporated into functional TIM23 complexes, and subjected to chemical cross-linking. Three regions of proximity between Tim23p and other subunits of the TIM23 complex were identified: Tim17p and the first transmembrane segment of Tim23p; Tim50p and the C-terminal end of the Tim23p hydrophilic region; and the entire hydrophilic domains of Tim23p molecules. These regions of proximity reversibly change in response to changes in membrane potential across the inner membrane and also when a translocating substrate is trapped in the TIM23 complex. These structural changes reveal that the macromolecular arrangement within the TIM23 complex is dynamic and varies with the physiological state of the mitochondrion.
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3

Gebert, Michael, Sandra G. Schrempp, Carola S. Mehnert, Anna K. Heißwolf, Silke Oeljeklaus, Raffaele Ieva, Maria Bohnert, et al. "Mgr2 promotes coupling of the mitochondrial presequence translocase to partner complexes." Journal of Cell Biology 197, no. 5 (May 21, 2012): 595–604. http://dx.doi.org/10.1083/jcb.201110047.

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Many mitochondrial proteins are synthesized with N-terminal presequences in the cytosol. The presequence translocase of the inner mitochondrial membrane (TIM23) translocates preproteins into and across the membrane and associates with the matrix-localized import motor. The TIM23 complex consists of three core components and Tim21, which interacts with the translocase of the outer membrane (TOM) and the respiratory chain. We have identified a new subunit of the TIM23 complex, the inner membrane protein Mgr2. Mitochondria lacking Mgr2 were deficient in the Tim21-containing sorting form of the TIM23 complex. Mgr2 was required for binding of Tim21 to TIM23CORE, revealing a binding chain of TIM23CORE-Mgr2/Tim21–respiratory chain. Mgr2-deficient yeast cells were defective in growth at elevated temperature, and the mitochondria were impaired in TOM-TIM23 coupling and the import of presequence-carrying preproteins. We conclude that Mgr2 is a coupling factor of the presequence translocase crucial for cell growth at elevated temperature and for efficient protein import.
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4

Kerscher, Oliver, Jason Holder, Maithreyan Srinivasan, Roxanne S. Leung, and Robert E. Jensen. "The Tim54p–Tim22p Complex Mediates Insertion of Proteins into the Mitochondrial Inner Membrane." Journal of Cell Biology 139, no. 7 (December 29, 1997): 1663–75. http://dx.doi.org/10.1083/jcb.139.7.1663.

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We have identified a new protein, Tim54p, located in the yeast mitochondrial inner membrane. Tim54p is an essential import component, required for the insertion of at least two polytopic proteins into the inner membrane, but not for the translocation of precursors into the matrix. Several observations suggest that Tim54p and Tim22p are part of a protein complex in the inner membrane distinct from the previously characterized Tim23p-Tim17p complex. First, multiple copies of the TIM22 gene, but not TIM23 or TIM17, suppress the growth defect of a tim54-1 temperature-sensitive mutant. Second, Tim22p can be coprecipitated with Tim54p from detergent-solubilized mitochondria, but Tim54p and Tim22p do not interact with either Tim23p or Tim17p. Finally, the tim54-1 mutation destabilizes the Tim22 protein, but not Tim23p or Tim17p. Our results support the idea that the mitochondrial inner membrane carries two independent import complexes: one required for the translocation of proteins across the inner membrane (Tim23p–Tim17p), and the other required for the insertion of proteins into the inner membrane (Tim54p–Tim22p).
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5

Lohret, Timothy A., Robert E. Jensen, and Kathleen W. Kinnally. "Tim23, a Protein Import Component of the Mitochondrial Inner Membrane, Is Required for Normal Activity of the Multiple Conductance Channel, MCC." Journal of Cell Biology 137, no. 2 (April 21, 1997): 377–86. http://dx.doi.org/10.1083/jcb.137.2.377.

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We previously showed that the conductance of a mitochondrial inner membrane channel, called MCC, was specifically blocked by peptides corresponding to mitochondrial import signals. To determine if MCC plays a role in protein import, we examined the relationship between MCC and Tim23p, a component of the protein import complex of the mitochondrial inner membrane. We find that antibodies against Tim23p, previously shown to inhibit mitochondrial protein import, inhibit MCC activity. We also find that MCC activity is altered in mitochondria isolated from yeast carrying the tim23-1 mutation. In contrast to wild-type MCC, we find that the conductance of MCC from the tim23-1 mutant is not significantly blocked by mitochondrial presequence peptides. Tim23 antibodies and the tim23-1 mutation do not, however, alter the activity of PSC, a presequence-peptide sensitive channel in the mitochondrial outer membrane. Our results show that Tim23p is required for normal MCC activity and raise the possibility that precursors are translocated across the inner membrane through the pore of MCC.
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6

Yablonska, Svitlana, Vinitha Ganesan, Lisa M. Ferrando, JinHo Kim, Anna Pyzel, Oxana V. Baranova, Nicolas K. Khattar, et al. "Mutant huntingtin disrupts mitochondrial proteostasis by interacting with TIM23." Proceedings of the National Academy of Sciences 116, no. 33 (July 25, 2019): 16593–602. http://dx.doi.org/10.1073/pnas.1904101116.

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Mutant huntingtin (mHTT), the causative protein in Huntington’s disease (HD), associates with the translocase of mitochondrial inner membrane 23 (TIM23) complex, resulting in inhibition of synaptic mitochondrial protein import first detected in presymptomatic HD mice. The early timing of this event suggests that it is a relevant and direct pathophysiologic consequence of mHTT expression. We show that, of the 4 TIM23 complex proteins, mHTT specifically binds to the TIM23 subunit and that full-length wild-type huntingtin (wtHTT) and mHTT reside in the mitochondrial intermembrane space. We investigated differences in mitochondrial proteome between wtHTT and mHTT cells and found numerous proteomic disparities between mHTT and wtHTT mitochondria. We validated these data by quantitative immunoblotting in striatal cell lines and human HD brain tissue. The level of soluble matrix mitochondrial proteins imported through the TIM23 complex is lower in mHTT-expressing cell lines and brain tissues of HD patients compared with controls. In mHTT-expressing cell lines, membrane-bound TIM23-imported proteins have lower intramitochondrial levels, whereas inner membrane multispan proteins that are imported via the TIM22 pathway and proteins integrated into the outer membrane generally remain unchanged. In summary, we show that, in mitochondria, huntingtin is located in the intermembrane space, that mHTT binds with high-affinity to TIM23, and that mitochondria from mHTT-expressing cells and brain tissues of HD patients have reduced levels of nuclearly encoded proteins imported through TIM23. These data demonstrate the mechanism and biological significance of mHTT-mediated inhibition of mitochondrial protein import, a mechanism likely broadly relevant to other neurodegenerative diseases.
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7

Tamura, Yasushi, Yoshihiro Harada, Takuya Shiota, Koji Yamano, Kazuaki Watanabe, Mihoko Yokota, Hayashi Yamamoto, Hiromi Sesaki, and Toshiya Endo. "Tim23–Tim50 pair coordinates functions of translocators and motor proteins in mitochondrial protein import." Journal of Cell Biology 184, no. 1 (January 12, 2009): 129–41. http://dx.doi.org/10.1083/jcb.200808068.

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Mitochondrial protein traffic requires coordinated operation of protein translocator complexes in the mitochondrial membrane. The TIM23 complex translocates and inserts proteins into the mitochondrial inner membrane. Here we analyze the intermembrane space (IMS) domains of Tim23 and Tim50, which are essential subunits of the TIM23 complex, in these functions. We find that interactions of Tim23 and Tim50 in the IMS facilitate transfer of precursor proteins from the TOM40 complex, a general protein translocator in the outer membrane, to the TIM23 complex. Tim23–Tim50 interactions also facilitate a late step of protein translocation across the inner membrane by promoting motor functions of mitochondrial Hsp70 in the matrix. Therefore, the Tim23–Tim50 pair coordinates the actions of the TOM40 and TIM23 complexes together with motor proteins for mitochondrial protein import.
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8

Mokranjac, Dejana, Martin Sichting, Dušan Popov-Čeleketić, Koyeli Mapa, Lada Gevorkyan-Airapetov, Keren Zohary, Kai Hell, Abdussalam Azem, and Walter Neupert. "Role of Tim50 in the Transfer of Precursor Proteins from the Outer to the Inner Membrane of Mitochondria." Molecular Biology of the Cell 20, no. 5 (March 2009): 1400–1407. http://dx.doi.org/10.1091/mbc.e08-09-0934.

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Transport of essentially all matrix and a number of inner membrane proteins is governed, entirely or in part, by N-terminal presequences and requires a coordinated action of the translocases of outer and inner mitochondrial membranes (TOM and TIM23 complexes). Here, we have analyzed Tim50, a subunit of the TIM23 complex that is implicated in transfer of precursors from TOM to TIM23. Tim50 is recruited to the TIM23 complex via Tim23 in an interaction that is essentially independent of the rest of the translocase. We find Tim50 in close proximity to the intermembrane space side of the TOM complex where it recognizes both types of TIM23 substrates, those that are to be transported into the matrix and those destined to the inner membrane, suggesting that Tim50 recognizes presequences. This function of Tim50 depends on its association with TIM23. We conclude that the efficient transfer of precursors between TOM and TIM23 complexes requires the concerted action of Tim50 with Tim23.
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9

Davis, Alison J., Naresh B. Sepuri, Jason Holder, Arthur E. Johnson, and Robert E. Jensen. "Two Intermembrane Space Tim Complexes Interact with Different Domains of Tim23p during Its Import into Mitochondria." Journal of Cell Biology 150, no. 6 (September 18, 2000): 1271–82. http://dx.doi.org/10.1083/jcb.150.6.1271.

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Tim23p (translocase of the inner membrane) is an essential import component located in the mitochondrial inner membrane. To determine how the Tim23 protein itself is transported into mitochondria, we used chemical cross-linking to identify proteins adjacent to Tim23p during its biogenesis. In the absence of an inner membrane potential, Tim23p is translocated across the mitochondrial outer membrane, but not inserted into the inner membrane. At this intermediate stage, we find that Tim23p forms cross-linked products with two distinct protein complexes of the intermembrane space, Tim8p–Tim13p and Tim9p–Tim10p. Tim9p and Tim10p cross-link to the COOH-terminal domain of the Tim23 protein, which carries all of the targeting signals for Tim23p. Therefore, our results suggest that the Tim9p–Tim10p complex plays a key role in Tim23p import. In contrast, Tim8p and Tim13p cross-link to the hydrophilic NH2-terminal segment of Tim23p, which does not carry essential import information and, thus, the role of Tim8p–Tim13p is unclear. Tim23p contains two matrix-facing, positively charged loops that are essential for its insertion into the inner membrane. The positive charges are not required for interaction with the Tim9p–Tim10p complex, but are essential for cross-linking of Tim23p to components of the inner membrane insertion machinery, including Tim54p, Tim22p, and Tim12p.
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10

Callegari, Sylvie, Luis Daniel Cruz-Zaragoza, and Peter Rehling. "From TOM to the TIM23 complex – handing over of a precursor." Biological Chemistry 401, no. 6-7 (May 26, 2020): 709–21. http://dx.doi.org/10.1515/hsz-2020-0101.

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AbstractMitochondrial precursor proteins with amino-terminal presequences are imported via the presequence pathway, utilizing the TIM23 complex for inner membrane translocation. Initially, the precursors pass the outer membrane through the TOM complex and are handed over to the TIM23 complex where they are sorted into the inner membrane or translocated into the matrix. This handover process depends on the receptor proteins at the inner membrane, Tim50 and Tim23, which are critical for efficient import. In this review, we summarize key findings that shaped the current concepts of protein translocation along the presequence import pathway, with a particular focus on the precursor handover process from TOM to the TIM23 complex. In addition, we discuss functions of the human TIM23 pathway and the recently uncovered pathogenic mutations in TIM50.
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11

Hutu, Dana P., Bernard Guiard, Agnieszka Chacinska, Dorothea Becker, Nikolaus Pfanner, Peter Rehling, and Martin van der Laan. "Mitochondrial Protein Import Motor: Differential Role of Tim44 in the Recruitment of Pam17 and J-Complex to the Presequence Translocase." Molecular Biology of the Cell 19, no. 6 (June 2008): 2642–49. http://dx.doi.org/10.1091/mbc.e07-12-1226.

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The presequence translocase of the mitochondrial inner membrane (TIM23 complex) mediates the import of preproteins with amino-terminal presequences. To drive matrix translocation the TIM23 complex recruits the presequence translocase-associated motor (PAM) with the matrix heat shock protein 70 (mtHsp70) as central subunit. Activity and localization of mtHsp70 are regulated by four membrane-associated cochaperones: the adaptor protein Tim44, the stimulatory J-complex Pam18/Pam16, and Pam17. It has been proposed that Tim44 serves as molecular platform to localize mtHsp70 and the J-complex at the TIM23 complex, but it is unknown how Pam17 interacts with the translocase. We generated conditional tim44 yeast mutants and selected a mutant allele, which differentially affects the association of PAM modules with TIM23. In tim44-804 mitochondria, the interaction of the J-complex with the TIM23 complex is impaired, whereas unexpectedly the binding of Pam17 is increased. Pam17 interacts with the channel protein Tim23, revealing a new interaction site between TIM23 and PAM. Thus, the motor PAM is composed of functional modules that bind to different sites of the translocase. We suggest that Tim44 is not simply a scaffold for binding of motor subunits but plays a differential role in the recruitment of PAM modules to the inner membrane translocase.
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12

Matta, Srujan Kumar, Abhishek Kumar, and Patrick D’Silva. "Mgr2 regulates mitochondrial preprotein import by associating with channel-forming Tim23 subunit." Molecular Biology of the Cell 31, no. 11 (May 15, 2020): 1112–23. http://dx.doi.org/10.1091/mbc.e19-12-0677.

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Mgr2 regulates the gating behavior of the TIM23 complex and mgr2∆ and causes aberrations in mitochondrial dynamics. Here, we show that Mgr2 directly associates with channel-forming Tim23. Additionally, the Mgr2 transmembrane region plays a crucial role in coupling the TIM23 complex with OXPHOS machinery and thus regulates mitochondrial protein import and dynamics.
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13

Kurz, Martin, Heiko Martin, Joachim Rassow, Nikolaus Pfanner, and Michael T. Ryan. "Biogenesis of Tim Proteins of the Mitochondrial Carrier Import Pathway: Differential Targeting Mechanisms and Crossing Over with the Main Import Pathway." Molecular Biology of the Cell 10, no. 7 (July 1999): 2461–74. http://dx.doi.org/10.1091/mbc.10.7.2461.

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Two major routes of preprotein targeting into mitochondria are known. Preproteins carrying amino-terminal signals mainly use Tom20, the general import pore (GIP) complex and the Tim23–Tim17 complex. Preproteins with internal signals such as inner membrane carriers use Tom70, the GIP complex, and the special Tim pathway, involving small Tims of the intermembrane space and Tim22–Tim54 of the inner membrane. Little is known about the biogenesis and assembly of the Tim proteins of this carrier pathway. We report that import of the preprotein of Tim22 requires Tom20, although it uses the carrier Tim route. In contrast, the preprotein of Tim54 mainly uses Tom70, yet it follows the Tim23–Tim17 pathway. The positively charged amino-terminal region of Tim54 is required for membrane translocation but not for targeting to Tom70. In addition, we identify two novel homologues of the small Tim proteins and show that targeting of the small Tims follows a third new route where surface receptors are dispensable, yet Tom5 of the GIP complex is crucial. We conclude that the biogenesis of Tim proteins of the carrier pathway cannot be described by either one of the two major import routes, but involves new types of import pathways composed of various features of the hitherto known routes, including crossing over at the level of the GIP.
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14

Richter, Frank, Sven Dennerlein, Miroslav Nikolov, Daniel C. Jans, Nataliia Naumenko, Abhishek Aich, Thomas MacVicar, et al. "ROMO1 is a constituent of the human presequence translocase required for YME1L protease import." Journal of Cell Biology 218, no. 2 (December 31, 2018): 598–614. http://dx.doi.org/10.1083/jcb.201806093.

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The mitochondrial presequence translocation machinery (TIM23 complex) is conserved between the yeast Saccharomyces cerevisiae and humans; however, functional characterization has been mainly performed in yeast. Here, we define the constituents of the human TIM23 complex using mass spectrometry and identified ROMO1 as a new translocase constituent with an exceptionally short half-life. Analyses of a ROMO1 knockout cell line revealed aberrant inner membrane structure and altered processing of the GTPase OPA1. We show that in the absence of ROMO1, mitochondria lose the inner membrane YME1L protease, which participates in OPA1 processing and ROMO1 turnover. While ROMO1 is dispensable for general protein import along the presequence pathway, we show that it participates in the dynamics of TIM21 during respiratory chain biogenesis and is specifically required for import of YME1L. This selective import defect can be linked to charge distribution in the unusually long targeting sequence of YME1L. Our analyses establish an unexpected link between mitochondrial protein import and inner membrane protein quality control.
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15

Tamura, Yasushi, Yoshihiro Harada, Koji Yamano, Kazuaki Watanabe, Daigo Ishikawa, Chié Ohshima, Shuh-ichi Nishikawa, Hayashi Yamamoto, and Toshiya Endo. "Identification of Tam41 maintaining integrity of the TIM23 protein translocator complex in mitochondria." Journal of Cell Biology 174, no. 5 (August 28, 2006): 631–37. http://dx.doi.org/10.1083/jcb.200603087.

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Newly synthesized mitochondrial proteins are imported into mitochondria with the aid of protein translocator complexes in the outer and inner mitochondrial membranes. We report the identification of yeast Tam41, a new member of mitochondrial protein translocator systems. Tam41 is a peripheral inner mitochondrial membrane protein facing the matrix. Disruption of the TAM41 gene led to temperature-sensitive growth of yeast cells and resulted in defects in protein import via the TIM23 translocator complex at elevated temperature both in vivo and in vitro. Although Tam41 is not a constituent of the TIM23 complex, depletion of Tam41 led to a decreased molecular size of the TIM23 complex and partial aggregation of Pam18 and -16. Import of Pam16 into mitochondria without Tam41 was retarded, and the imported Pam16 formed aggregates in vitro. These results suggest that Tam41 facilitates mitochondrial protein import by maintaining the functional integrity of the TIM23 protein translocator complex from the matrix side of the inner membrane.
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16

Demishtein-Zohary, Keren, Milit Marom, Walter Neupert, Dejana Mokranjac, and Abdussalam Azem. "GxxxG motifs hold the TIM23 complex together." FEBS Journal 282, no. 11 (April 10, 2015): 2178–86. http://dx.doi.org/10.1111/febs.13266.

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17

Hwang, David K., Steven M. Claypool, Danielle Leuenberger, Heather L. Tienson, and Carla M. Koehler. "Tim54p connects inner membrane assembly and proteolytic pathways in the mitochondrion." Journal of Cell Biology 178, no. 7 (September 24, 2007): 1161–75. http://dx.doi.org/10.1083/jcb.200706195.

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Tim54p, a component of the inner membrane TIM22 complex, does not directly mediate the import of inner membrane substrates but is required for assembly/stability of the 300-kD TIM22 complex. In addition, Δtim54 yeast exhibit a petite-negative phenotype (also observed in yeast harboring mutations in the F1Fo ATPase, the ADP/ATP carrier, mitochondrial morphology components, or the i–AAA protease, Yme1p). Interestingly, other import mutants in our strain background are not petite-negative. We report that Tim54p is not involved in maintenance of mitochondrial DNA or mitochondrial morphology. Rather, Tim54p mediates assembly of an active Yme1p complex, after Yme1p is imported via the TIM23 pathway. Defective Yme1p assembly is likely the major contributing factor for the petite-negativity in strains lacking functional Tim54p. Thus, Tim54p has two independent functions: scaffolding/stability for the TIM22 membrane complex and assembly of Yme1p into a proteolytically active complex. As such, Tim54p links protein import, assembly, and turnover pathways in the mitochondrion.
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18

Beverly, Kristen N., Michael R. Sawaya, Einhard Schmid, and Carla M. Koehler. "The Tim8–Tim13 Complex Has Multiple Substrate Binding Sites and Binds Cooperatively to Tim23." Journal of Molecular Biology 382, no. 5 (October 2008): 1144–56. http://dx.doi.org/10.1016/j.jmb.2008.07.069.

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19

Gevorkyan-Airapetov, Lada, Keren Zohary, Dušan Popov-Čeleketić, Koyeli Mapa, Kai Hell, Walter Neupert, Abdussalam Azem, and Dejana Mokranjac. "Interaction of Tim23 with Tim50 Is Essential for Protein Translocation by the Mitochondrial TIM23 Complex." Journal of Biological Chemistry 284, no. 8 (November 18, 2008): 4865–72. http://dx.doi.org/10.1074/jbc.m807041200.

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20

Schulz, Christian, Oleksandr Lytovchenko, Jonathan Melin, Agnieszka Chacinska, Bernard Guiard, Piotr Neumann, Ralf Ficner, Olaf Jahn, Bernhard Schmidt, and Peter Rehling. "Tim50’s presequence receptor domain is essential for signal driven transport across the TIM23 complex." Journal of Cell Biology 195, no. 4 (November 7, 2011): 643–56. http://dx.doi.org/10.1083/jcb.201105098.

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N-terminal targeting signals (presequences) direct proteins across the TOM complex in the outer mitochondrial membrane and the TIM23 complex in the inner mitochondrial membrane. Presequences provide directionality to the transport process and regulate the transport machineries during translocation. However, surprisingly little is known about how presequence receptors interact with the signals and what role these interactions play during preprotein transport. Here, we identify signal-binding sites of presequence receptors through photo-affinity labeling. Using engineered presequence probes, photo cross-linking sites on mitochondrial proteins were mapped mass spectrometrically, thereby defining a presequence-binding domain of Tim50, a core subunit of the TIM23 complex that is essential for mitochondrial protein import. Our results establish Tim50 as the primary presequence receptor at the inner membrane and show that targeting signals and Tim50 regulate the Tim23 channel in an antagonistic manner.
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21

Koehler, Carla M., Michael P. Murphy, Nikolaus A. Bally, Danielle Leuenberger, Wolfgang Oppliger, Luisita Dolfini, Tina Junne, Gottfried Schatz, and Eran Or. "Tim18p, a New Subunit of the TIM22 Complex That Mediates Insertion of Imported Proteins into the Yeast Mitochondrial Inner Membrane." Molecular and Cellular Biology 20, no. 4 (February 15, 2000): 1187–93. http://dx.doi.org/10.1128/mcb.20.4.1187-1193.2000.

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ABSTRACT Import of carrier proteins from the cytoplasm into the mitochondrial inner membrane of yeast is mediated by a distinct system consisting of two soluble 70-kDa protein complexes in the intermembrane space and a 300-kDa complex in the inner membrane, the TIM22 complex. The TIM22 complex contains the peripheral subunits Tim9p, Tim10p, and Tim12p and the integral membrane subunits Tim22p and Tim54p. We identify here an additional subunit, an 18-kDa integral membrane protein termed Tim18p. This protein is made as a 21.9-kDa precursor which is imported into mitochondria and processed to its mature form. When mitochondria are gently solubilized, Tim18p comigrates with the other subunits of the TIM22 complex on nondenaturing gels and is coimmunoprecipitated with Tim54p and Tim12p. Tim18p does not cofractionate with the TIM23 complex upon immunoprecipitation or nondenaturing gel electrophoresis. Deletion of Tim18p decreases the growth rate of yeast cells by a factor of two and is synthetically lethal with temperature-sensitive mutations in Tim9p or Tim10p. It also impairs the import of several precursor proteins into isolated mitochondria, and lowers the apparent mass of the TIM22 complex. We suggest that Tim18p functions in the assembly and stabilization of the TIM22 complex but does not directly participate in protein insertion into the inner membrane.
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Mokranjac, Dejana, and Walter Neupert. "The many faces of the mitochondrial TIM23 complex." Biochimica et Biophysica Acta (BBA) - Bioenergetics 1797, no. 6-7 (June 2010): 1045–54. http://dx.doi.org/10.1016/j.bbabio.2010.01.026.

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23

Mokranjac, D., and W. Neupert. "Protein import into mitochondria." Biochemical Society Transactions 33, no. 5 (October 26, 2005): 1019–23. http://dx.doi.org/10.1042/bst0331019.

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Mitochondria comprise approx. 1000–3000 different proteins, almost all of which must be imported from the cytosol into the organelle. So far, six complex molecular machines, protein translocases, were identified that mediate this process. The TIM23 complex is a major translocase in the inner mitochondrial membrane. It uses two energy sources, namely membrane potential and ATP, to facilitate preprotein translocation across the inner membrane and insertion into the inner membrane. Recent research has led to the discovery of a number of new constituents of the TIM23 complex and to the unravelling of the mechanisms of preprotein translocation.
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24

Mokranjac, Dejana. "How to get to the other side of the mitochondrial inner membrane – the protein import motor." Biological Chemistry 401, no. 6-7 (May 26, 2020): 723–36. http://dx.doi.org/10.1515/hsz-2020-0106.

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AbstractBiogenesis of mitochondria relies on import of more than 1000 different proteins from the cytosol. Approximately 70% of these proteins follow the presequence pathway – they are synthesized with cleavable N-terminal extensions called presequences and reach the final place of their function within the organelle with the help of the TOM and TIM23 complexes in the outer and inner membranes, respectively. The translocation of proteins along the presequence pathway is powered by the import motor of the TIM23 complex. The import motor of the TIM23 complex is localized at the matrix face of the inner membrane and is likely the most complicated Hsp70-based system identified to date. How it converts the energy of ATP hydrolysis into unidirectional translocation of proteins into mitochondria remains one of the biggest mysteries of this translocation pathway. Here, the knowns and the unknowns of the mitochondrial protein import motor are discussed.
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25

Tamura, Yasushi, Toshiya Endo, Miho Iijima, and Hiromi Sesaki. "Ups1p and Ups2p antagonistically regulate cardiolipin metabolism in mitochondria." Journal of Cell Biology 185, no. 6 (June 8, 2009): 1029–45. http://dx.doi.org/10.1083/jcb.200812018.

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Cardiolipin, a unique phospholipid composed of four fatty acid chains, is located mainly in the mitochondrial inner membrane (IM). Cardiolipin is required for the integrity of several protein complexes in the IM, including the TIM23 translocase, a dynamic complex which mediates protein import into the mitochondria through interactions with the import motor presequence translocase–associated motor (PAM). In this study, we report that two homologous intermembrane space proteins, Ups1p and Ups2p, control cardiolipin metabolism and affect the assembly state of TIM23 and its association with PAM in an opposing manner. In ups1Δ mitochondria, cardiolipin levels were decreased, and the TIM23 translocase showed altered conformation and decreased association with PAM, leading to defects in mitochondrial protein import. Strikingly, loss of Ups2p restored normal cardiolipin levels and rescued TIM23 defects in ups1Δ mitochondria. Furthermore, we observed synthetic growth defects in ups mutants in combination with loss of Pam17p, which controls the integrity of PAM. Our findings provide a novel molecular mechanism for the regulation of cardiolipin metabolism.
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VERGNOLLE, Maïlys A. S., Helen SAWNEY, Tina JUNNE, Luisita DOLFINI, and Kostas TOKATLIDIS. "A cryptic matrix targeting signal of the yeast ADP/ATP carrier normally inserted by the TIM22 complex is recognized by the TIM23 machinery." Biochemical Journal 385, no. 1 (December 14, 2004): 173–80. http://dx.doi.org/10.1042/bj20040650.

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The yeast ADP/ATP carrier (AAC) is a mitochondrial protein that is targeted to the inner membrane via the TIM10 and TIM22 translocase complexes. AAC is devoid of a typical mitochondrial targeting signal and its targeting and insertion are thought to be guided by internal amino acid sequences. Here we show that AAC contains a cryptic matrix targeting signal that can target up to two thirds of the N-terminal part of the protein to the matrix. This event is coordinated by the TIM23 translocase and displays all the features of the matrix-targeting pathway. However, in the context of the whole protein, this signal is ‘masked’ and rendered non-functional as the polypeptide is targeted to the inner membrane via the TIM10 and TIM22 translocases. Our data suggest that after crossing the outer membrane the whole polypeptide chain of AAC is necessary to commit the precursor to the TIM22-mediated inner membrane insertion pathway.
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Demishtein-Zohary, Keren, and Abdussalam Azem. "The TIM23 mitochondrial protein import complex: function and dysfunction." Cell and Tissue Research 367, no. 1 (September 3, 2016): 33–41. http://dx.doi.org/10.1007/s00441-016-2486-7.

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Weems, Ebony, Ujjal K. Singha, VaNae Hamilton, Joseph T. Smith, Karin Waegemann, Dejana Mokranjac, and Minu Chaudhuri. "Functional Complementation Analyses Reveal that the Single PRAT Family Protein of Trypanosoma brucei Is a Divergent Homolog of Tim17 in Saccharomyces cerevisiae." Eukaryotic Cell 14, no. 3 (January 9, 2015): 286–96. http://dx.doi.org/10.1128/ec.00203-14.

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ABSTRACT Trypanosoma brucei , a parasitic protozoan that causes African trypanosomiasis, possesses a single member of the presequence and amino acid transporter (PRAT) protein family, which is referred to as TbTim17. In contrast, three homologous proteins, ScTim23, ScTim17, and ScTim22, are found in Saccharomyces cerevisiae and higher eukaryotes. Here, we show that TbTim17 cannot rescue Tim17, Tim23, or Tim22 mutants of S. cerevisiae . We expressed S. cerevisiae Tim23, Tim17, and Tim22 in T. brucei . These heterologous proteins were properly imported into mitochondria in the parasite. Further analysis revealed that although ScTim23 and ScTim17 were integrated into the mitochondrial inner membrane and assembled into a protein complex similar in size to TbTim17, only ScTim17 was stably associated with TbTim17. In contrast, ScTim22 existed as a protease-sensitive soluble protein in the T. brucei mitochondrion. In addition, the growth defect caused by TbTim17 knockdown in T. brucei was partially restored by the expression of ScTim17 but not by the expression of either ScTim23 or ScTim22, whereas the expression of TbTim17 fully complemented the growth defect caused by TbTim17 knockdown, as anticipated. Similar to the findings for cell growth, the defect in the import of mitochondrial proteins due to depletion of TbTim17 was in part restored by the expression of ScTim17 but was not complemented by the expression of either ScTim23 or ScTim22. Together, these results suggest that TbTim17 is divergent compared to ScTim23 but that its function is closer to that of ScTim17. In addition, ScTim22 could not be sorted properly in the T. brucei mitochondrion and thus failed to complement the function of TbTim17.
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Gallas, Michelle R., Mary K. Dienhart, Rosemary A. Stuart, and Roy M. Long. "Characterization of Mmp37p, aSaccharomyces cerevisiaeMitochondrial Matrix Protein with a Role in Mitochondrial Protein Import." Molecular Biology of the Cell 17, no. 9 (September 2006): 4051–62. http://dx.doi.org/10.1091/mbc.e06-04-0366.

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Many mitochondrial proteins are encoded by nuclear genes and after translation in the cytoplasm are imported via translocases in the outer and inner membranes, the TOM and TIM complexes, respectively. Here, we report the characterization of the mitochondrial protein, Mmp37p (YGR046w) and demonstrate its involvement in the process of protein import into mitochondria. Haploid cells deleted of MMP37 are viable but display a temperature-sensitive growth phenotype and are inviable in the absence of mitochondrial DNA. Mmp37p is located in the mitochondrial matrix where it is peripherally associated with the inner membrane. We show that Mmp37p has a role in the translocation of proteins across the mitochondrial inner membrane via the TIM23-PAM complex and further demonstrate that substrates containing a tightly folded domain in close proximity to their mitochondrial targeting sequences display a particular dependency on Mmp37p for mitochondrial import. Prior unfolding of the preprotein, or extension of the region between the targeting signal and the tightly folded domain, relieves their dependency for Mmp37p. Furthermore, evidence is presented to show that Mmp37 may affect the assembly state of the TIM23 complex. On the basis of these findings, we hypothesize that the presence of Mmp37p enhances the early stages of the TIM23 matrix import pathway to ensure engagement of incoming preproteins with the mtHsp70p/PAM complex, a step that is necessary to drive the unfolding and complete translocation of the preprotein into the matrix.
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Kutik, Stephan, Michael Rissler, Xue Li Guan, Bernard Guiard, Guanghou Shui, Natalia Gebert, Philip N. Heacock, et al. "The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis." Journal of Cell Biology 183, no. 7 (December 29, 2008): 1213–21. http://dx.doi.org/10.1083/jcb.200806048.

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The mitochondrial inner membrane contains different translocator systems for the import of presequence-carrying proteins and carrier proteins. The translocator assembly and maintenance protein 41 (Tam41/mitochondrial matrix protein 37) was identified as a new member of the mitochondrial protein translocator systems by its role in maintaining the integrity and activity of the presequence translocase of the inner membrane (TIM23 complex). Here we demonstrate that the assembly of proteins imported by the carrier translocase, TIM22 complex, is even more strongly affected by the lack of Tam41. Moreover, respiratory chain supercomplexes and the inner membrane potential are impaired by lack of Tam41. The phenotype of Tam41-deficient mitochondria thus resembles that of mitochondria lacking cardiolipin. Indeed, we found that Tam41 is required for the biosynthesis of the dimeric phospholipid cardiolipin. The pleiotropic effects of the translocator maintenance protein on preprotein import and respiratory chain can be attributed to its role in biosynthesis of mitochondrial cardiolipin.
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Dienhart, Mary K., and Rosemary A. Stuart. "The Yeast Aac2 Protein Exists in Physical Association with the Cytochromebc1-COX Supercomplex and the TIM23 Machinery." Molecular Biology of the Cell 19, no. 9 (September 2008): 3934–43. http://dx.doi.org/10.1091/mbc.e08-04-0402.

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The ADP/ATP carrier (AAC) proteins play a central role in cellular metabolism as they facilitate the exchange of ADP and ATP across the mitochondrial inner membrane. We present evidence here that in yeast (Saccharomyces cerevisiae) mitochondria the abundant Aac2 isoform exists in physical association with the cytochrome c reductase (cytochrome bc1)-cytochrome c oxidase (COX) supercomplex and its associated TIM23 machinery. Using a His-tagged Aac2 derivative and affinity purification studies, we also demonstrate here that the Aac2 isoform can be affinity-purified with other AAC proteins. Copurification of the Aac2 protein with the TIM23 machinery can occur independently of its association with the fully assembled cytochrome bc1-COX supercomplex. In the absence of the Aac2 protein, the assembly of the cytochrome bc1-COX supercomplex is perturbed, whereby a decrease in the III2-IV2assembly state relative to the III2-IV form is observed. We propose that the association of the Aac2 protein with the cytochrome bc1-COX supercomplex is important for the function of the OXPHOS complexes and for the assembly of the COX complex. The physiological implications of the association of AAC with the cytochrome bc1-COX-TIM23 supercomplex are also discussed.
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32

Tsofack, Serges P., Danielle C. Croucher, Benjamin G. Barwick, Zhihua Li, Ahmed Aman, Dennis Tao, Ellen nong Wei, Laura Garcia Prat, Aaron D. Schimmer, and Suzanne Trudel. "Disrupting Mitohormesis As a Novel Therapeutic Strategy for Multiple Myeloma (MM) Including Those with High Risk Disease and Proteosome Inhibitor Resistance." Blood 138, Supplement 1 (November 5, 2021): 722. http://dx.doi.org/10.1182/blood-2021-148673.

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Abstract Background: Moderate mitochondrial stress induced by multiple mediators but most notably ROS can lead to activation of persistent mito-protective mechanisms termed "Mitohormesis". As a result of massive protein synthesis, malignant plasma cells (PCs) from MM patients (pts) undergo substantial ER stress but in addition high rates of Ig synthesis contributes to overproduction of ROS. We hypothesized that MM cells exploit mitohormesis to maintain ROS in the hometic zone, thereby increasing mitochondrial fitness to avoid apoptosis. We therefore set out to determine if the processes of mitohormesis are activated in MM and whether unmitigated mitochondrial stress can be exploited as a therapeutic strategy in MM. Results: Protective stress mechanisms of mitohormesis include the activation of the mitochondrial UPR (UPR MT),a mitochondrial-to-nuclear signaling pathway mediated by CHOP and ATF5 that upregulates mitochondrial import proteins, chaperones and proteases to maintain mitochondrial proteastasis. We first demonstrated that UPR MT activation occurs with progression from precursor to overt MM. Using a UPR MTgene signature derived from published gene-sets we observed upregulation of UPR MT genes in single-cell RNA sequencing (scRNA-seq) data generated from PCs derived from Vκ*MYC mice (a transgenic mouse model of MM) spanning the spectrum of the disease. UPR MT gene signature scores in PCs from mice increased with disease progression with the highest levels found in late-MM> int-MM> early MM>wild type mice. Similarly, analysis of publicly available gene expression datasets (GSE6477) that includes normal donors, MGUS and newly diagnosed MM (NDMM) revealed higher expression of UPR MT genes in the majority of NDMM, weak expression in MGUS and absence in normal PCs. To assess the impact of UPR MT expression on pt outcomes we calculated a UPR MT index score derived from the median expression of 12 mtUPR classifier genes across the MMRF CoMMpass dataset of NDMM pts. Stratifying pts by UPR MT expression score we found that pts in the top quartile had a significantly shorter PFS and OS compared to pts with the lowest quartile weighted score. Next, we postulated that perturbation of the mitochondrial import protein, Translocase of the Inner Membrane 23 (TIM23) would exaggerate mitochondrial stress as mitochondrial import efficiency is a key regulator of the UPR MT. First, we demonstrated that TIM23 complex genes are enriched in pts from the CoMMpass dataset with poor risk (1q gain and PR gene signature) and that shorter PFS and OS is associated with a higher weighted score of TIM23 complex genes. We then demonstrated that genetic (shRNA) knockdown or pharmacologic inhibition of TIM23 with MB-10, a small molecule inhibitor of TIM23 induced apoptosis of MM cell lines and primary pt PCs. Further non-transformed cell lines, CD138 - non-MM cells and normal donor hematopoietic progenitor cells were less susceptible to the effects of MB-10. Consistent with activation of the UPR MT, treatment of MM cells resulted in increased cytosolic ATF4, CHOP and a shift of ATF5 to the nuclear fraction. Activation of the CHOP-dependent branch of the UPR MT resulted in in upregulation of mitochondrial-targeted proteins, cpn10 and ClpP. Interestingly, MB-10 also induced XBP1 splicing demonstrating that inhibition of TIM23 complex can simultaneously activate the IRE1/XBP1 branch of integrated stress response (ISR), This led us to hypothesize that targeting TIM23 as an alternative means of activating the ISR could overcome acquired resistance to proteosome inhibitors (PIs). Indeed, PI-resistant and parental isogenic cell lines were equally susceptible to MB-10 as measured by IC50 values of cell growth. Finally, we demonstrated that doxycycline inducible knockdown of TIM23 in a mouse xenograft model induced tumor regression with significantly small tumor volumes at the end of 17 days of doxycycline treatment compared to tumors expressing an inducible control vector. Conclusions: These data demonstrate that mitohormesis and UPR MT activation is associated with MM progression and worse clinical outcomes. Further we show that disrupting mitochondrial protein import results in unmitigated mitochondrial stress that switches the UPR MT from an adaptive cytoprotective to cytotoxic proapoptotic response. Thus, targeting mitochondrial import proteins such as TIM23 may represent novel therapeutic targets for MM. Disclosures Schimmer: Takeda Pharmaceuticals: Consultancy, Research Funding; Medivir AB: Research Funding; Novartis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Otsuka Pharmaceuticals: Consultancy, Honoraria; UHN: Patents & Royalties. Trudel: Janssen: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Roche: Consultancy; Sanofi: Honoraria; Pfizer: Honoraria, Research Funding; Genentech: Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding.
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33

Li, Jingzhi, and Bingdong Sha. "The structure of Tim50(164–361) suggests the mechanism by which Tim50 receives mitochondrial presequences." Acta Crystallographica Section F Structural Biology Communications 71, no. 9 (August 25, 2015): 1146–51. http://dx.doi.org/10.1107/s2053230x15013102.

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Mitochondrial preproteins are transported through the translocase of the outer membrane (TOM) complex. Tim50 and Tim23 then transfer preproteins with N-terminal targeting presequences through the intermembrane space (IMS) across the inner membrane. The crystal structure of the IMS domain of Tim50 [Tim50(164–361)] has previously been determined to 1.83 Å resolution. Here, the crystal structure of Tim50(164–361) at 2.67 Å resolution that was crystallized using a different condition is reported. Compared with the previously determined Tim50(164–361) structure, significant conformational changes occur within the protruding β-hairpin of Tim50 and the nearby helix A2. These findings indicate that the IMS domain of Tim50 exhibits significant structural plasticity within the putative presequence-binding groove, which may play important roles in the function of Tim50 as a receptor protein in the TIM complex that interacts with the presequence and multiple other proteins. More interestingly, the crystal packing indicates that helix A1 from the neighboring monomer docks into the putative presequence-binding groove of Tim50(164–361), which may mimic the scenario of Tim50 and the presequence complex. Tim50 may recognize and bind the presequence helix by utilizing the inner side of the protruding β-hairpin through hydrophobic interactions. Therefore, the protruding β-hairpin of Tim50 may play critical roles in receiving the presequence and recruiting Tim23 for subsequent protein translocations.
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34

Paschen, S. A. "The role of the TIM8-13 complex in the import of Tim23 into mitochondria." EMBO Journal 19, no. 23 (December 1, 2000): 6392–400. http://dx.doi.org/10.1093/emboj/19.23.6392.

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35

Marom, Milit, Dana Dayan, Keren Demishtein-Zohary, Dejana Mokranjac, Walter Neupert, and Abdussalam Azem. "Direct Interaction of Mitochondrial Targeting Presequences with Purified Components of the TIM23 Protein Complex." Journal of Biological Chemistry 286, no. 51 (October 3, 2011): 43809–15. http://dx.doi.org/10.1074/jbc.m111.261040.

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36

Alder, Nathan N., Robert E. Jensen, and Arthur E. Johnson. "Fluorescence Mapping of Mitochondrial TIM23 Complex Reveals a Water-Facing, Substrate-Interacting Helix Surface." Cell 134, no. 3 (August 2008): 439–50. http://dx.doi.org/10.1016/j.cell.2008.06.007.

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37

Bajaj, Rakhi, Łukasz Jaremko, Mariusz Jaremko, Stefan Becker, and Markus Zweckstetter. "Molecular Basis of the Dynamic Structure of the TIM23 Complex in the Mitochondrial Intermembrane Space." Structure 22, no. 10 (October 2014): 1501–11. http://dx.doi.org/10.1016/j.str.2014.07.015.

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38

Popov‐Čeleketić, Dušan, Karin Waegemann, Koyeli Mapa, Walter Neupert, and Dejana Mokranjac. "Role of the import motor in insertion of transmembrane segments by the mitochondrial TIM23 complex." EMBO reports 12, no. 6 (May 6, 2011): 542–48. http://dx.doi.org/10.1038/embor.2011.72.

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39

Malhotra, Ketan, Arnab Modak, Shivangi Nangia, Tyler H. Daman, Umut Gunsel, Victoria L. Robinson, Dejana Mokranjac, Eric R. May, and Nathan N. Alder. "Cardiolipin mediates membrane and channel interactions of the mitochondrial TIM23 protein import complex receptor Tim50." Science Advances 3, no. 9 (September 2017): e1700532. http://dx.doi.org/10.1126/sciadv.1700532.

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40

Lepe, Javier, Naomi Lomeli, Chris Douglas, Kaijun Di, and Daniela Bota. "TMET-05. MAGMAS FACILITATES METABOLIC CHANGES INDUCED BY STRESSORS IN GLIOBLASTOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii262. http://dx.doi.org/10.1093/neuonc/noac209.1010.

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Abstract The dynamic nature of tumor microenvironments contributes to tumor heterogeneity generating subpopulations of cells that are resistant to treatment in glioblastoma (GBM). The high recurrent rate of GBM tumors in patients can partially be explained by the presence of glioma stem cells (GSCs), which are thought to give rise to resistant clones against chemotherapy. As solid tumors expand, cancer cells can disrupt the tumor microenviroment by disrupting the blood brain barrier. Pericytes and astrocytes detach from the vascular endothelial cells, forming leaky vessels, which leads to thrombosis and eventually necrosis. Necrosis is a hallmark signature of GBM, as oxygen and nutrient supply runs low which can be observed through contrast imaging. Cancer cells go through a phenotypic change by upregulating stemness genes and glycolytic metabolism. Cells migrate away from hypoxic and nutrient deprived regions forming pseudopalisading cells which are an indication of cells becoming more invasive and malignant. Mitochondrial protein trafficking is a tightly regulated mechanism which selectively allows specific peptides carrying a mitochondrial targeting sequence (MTS) to be transported through the TOM40 and TIM23 complexes. Magmas, a TIM23 subunit, negatively regulates DNAJC19 by inhibiting its stimulatory activity on Hsp70 in the mitochondrial matrix. The regulation of the ATPase activity on Hsp70 is critical for processing pre-cursor proteins through the TIM23 complex into the mitochondrial matrix. Our laboratory has uncovered a novel role of Magmas activity in GBM cells under serum starved conditions in vitro. Magmas is downregulated in serum starved cells which allows for an increase of mitochondrial matrix proteins, which include key subunits important for forming electron transport chain complexes. This influx of ETC proteins can explain how cells are able to reduce aerobic glycolysis and increase oxidative phosphorylation (OXPHOS), a mechanism that can be exploited for potential therapeutic treatment in patients with GBM.
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41

Ramesh, Ajay, Valentina Peleh, Sonia Martinez-Caballero, Florian Wollweber, Frederik Sommer, Martin van der Laan, Michael Schroda, R. Todd Alexander, María Luisa Campo, and Johannes M. Herrmann. "A disulfide bond in the TIM23 complex is crucial for voltage gating and mitochondrial protein import." Journal of Cell Biology 214, no. 4 (August 8, 2016): 417–31. http://dx.doi.org/10.1083/jcb.201602074.

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Tim17 is a central, membrane-embedded subunit of the mitochondrial protein import machinery. In this study, we show that Tim17 contains a pair of highly conserved cysteine residues that form a structural disulfide bond exposed to the intermembrane space (IMS). This disulfide bond is critical for efficient protein translocation through the TIM23 complex and for dynamic gating of its preprotein-conducting channel. The disulfide bond in Tim17 is formed during insertion of the protein into the inner membrane. Whereas the import of Tim17 depends on the binding to the IMS protein Mia40, the oxidoreductase activity of Mia40 is surprisingly dispensable for Tim17 oxidation. Our observations suggest that Tim17 can be directly oxidized by the sulfhydryl oxidase Erv1. Thus, import and oxidation of Tim17 are mediated by the mitochondrial disulfide relay, though the mechanism by which the disulfide bond in Tim17 is formed differs considerably from that of soluble IMS proteins.
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Martinez-Caballero, Sonia, Sergey M. Grigoriev, Johannes M. Herrmann, María Luisa Campo, and Kathleen W. Kinnally. "Tim17p Regulates the Twin Pore Structure and Voltage Gating of the Mitochondrial Protein Import Complex TIM23." Journal of Biological Chemistry 282, no. 6 (February 2007): 3584–93. http://dx.doi.org/10.1074/jbc.m607551200.

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43

Reinhold, R., V. Kruger, M. Meinecke, C. Schulz, B. Schmidt, S. D. Grunau, B. Guiard, et al. "The Channel-Forming Sym1 Protein Is Transported by the TIM23 Complex in a Presequence-Independent Manner." Molecular and Cellular Biology 32, no. 24 (October 8, 2012): 5009–21. http://dx.doi.org/10.1128/mcb.00843-12.

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44

Barchiesi, Arianna, Veronica Bazzani, Vanessa Tolotto, Praveenraj Elancheliyan, Michał Wasilewski, Agnieszka Chacinska, and Carlo Vascotto. "Mitochondrial Oxidative Stress Induces Rapid Intermembrane Space/Matrix Translocation of Apurinic/Apyrimidinic Endonuclease 1 Protein through TIM23 Complex." Journal of Molecular Biology 432, no. 24 (December 2020): 166713. http://dx.doi.org/10.1016/j.jmb.2020.11.012.

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45

Malhotra, Ketan, Murugappan Sathappa, Judith S. Landin, Arthur E. Johnson, and Nathan N. Alder. "The Mitochondrial Tim23 Protein Transport Complex Undergoes Conformational Dynamics Coupled to the Energized State of the Inner Membrane." Biophysical Journal 106, no. 2 (January 2014): 370a—371a. http://dx.doi.org/10.1016/j.bpj.2013.11.2098.

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46

Saleem, Ayesha, Sobia Iqbal, Yuan Zhang, and David A. Hood. "Effect of p53 on mitochondrial morphology, import, and assembly in skeletal muscle." American Journal of Physiology-Cell Physiology 308, no. 4 (February 15, 2015): C319—C329. http://dx.doi.org/10.1152/ajpcell.00253.2014.

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The purpose of this study was to investigate whether p53 regulates mitochondrial function via changes in mitochondrial protein import, complex IV (COX) assembly, or the expression of key proteins involved in mitochondrial dynamics and degradation. Mitochondria from p53 KO mice displayed ultra-structural alterations and were more punctate in appearance. This was accompanied by protein-specific alterations in fission, fusion, and mitophagy-related proteins. However, matrix-destined protein import into subsarcolemmal or intermyofibrillar mitochondria was unaffected in the absence of p53, despite mitochondrial subfraction-specific reductions in Tom20, Tim23, mtHsp70, and mtHsp60 in the knockout (KO) mitochondria. Complex IV activity in isolated mitochondria was also unchanged in KO mice, but two-dimensional blue native-PAGE revealed a reduction in the assembly of complex IV within the IMF fractions from KO mice in tandem with lower levels of the assembly protein Surf1. This observed defect in complex IV assembly may facilitate the previously documented impairment in mitochondrial function in p53 KO mice. We suspect that these morphological and functional impairments in mitochondria drive a decreased reliance on mitochondrial respiration as a means of energy production in skeletal muscle in the absence of p53.
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47

Yamamoto, Hayashi, Masatoshi Esaki, Takashi Kanamori, Yasushi Tamura, Shuh-ichi Nishikawa, and Toshiya Endo. "Tim50 Is a Subunit of the TIM23 Complex that Links Protein Translocation across the Outer and Inner Mitochondrial Membranes." Cell 111, no. 4 (November 2002): 519–28. http://dx.doi.org/10.1016/s0092-8674(02)01053-x.

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48

Tatsuta, Takashi, Kirstin Model, and Thomas Langer. "Formation of Membrane-bound Ring Complexes by Prohibitins in Mitochondria." Molecular Biology of the Cell 16, no. 1 (January 2005): 248–59. http://dx.doi.org/10.1091/mbc.e04-09-0807.

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Prohibitins comprise a remarkably conserved protein family in eukaryotic cells with proposed functions in cell cycle progression, senescence, apoptosis, and the regulation of mitochondrial activities. Two prohibitin homologues, Phb1 and Phb2, assemble into a high molecular weight complex of ∼1.2 MDa in the mitochondrial inner membrane, but a nuclear localization of Phb1 and Phb2 also has been reported. Here, we have analyzed the biogenesis and structure of the prohibitin complex in Saccharomyces cerevisiae. Both Phb1 and Phb2 subunits are targeted to mitochondria by unconventional noncleavable targeting sequences at their amino terminal end. Membrane insertion involves binding of newly imported Phb1 to Tim8/13 complexes in the intermembrane space and is mediated by the TIM23-translocase. Assembly occurs via intermediate-sized complexes of ∼120 kDa containing both Phb1 and Phb2. Conserved carboxy-terminal coiled-coil regions in both subunits mediate the formation of large assemblies in the inner membrane. Single particle electron microscopy of purified prohibitin complexes identifies diverse ring-shaped structures with outer dimensions of ∼270 × 200 Å. Implications of these findings for proposed cellular activities of prohibitins are discussed.
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Lee, Seoeun, Hunsang Lee, Suji Yoo, Raffaele Ieva, Martin Laan, Gunnar Heijne, and Hyun Kim. "The Mgr2 subunit of the TIM23 complex regulates membrane insertion of marginal stop‐transfer signals in the mitochondrial inner membrane." FEBS Letters 594, no. 6 (March 2020): 1081–87. http://dx.doi.org/10.1002/1873-3468.13692.

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50

Wang, Yan, Chris Carrie, Estelle Giraud, Dina Elhafez, Reena Narsai, Owen Duncan, James Whelan, and Monika W. Murcha. "Dual Location of the Mitochondrial Preprotein Transporters B14.7 and Tim23-2 in Complex I and the TIM17:23 Complex in Arabidopsis Links Mitochondrial Activity and Biogenesis." Plant Cell 24, no. 6 (June 2012): 2675–95. http://dx.doi.org/10.1105/tpc.112.098731.

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