Journal articles: 'Tim22'

1

Muñoz-Gómez, Sergio A., Shannon N. Snyder, Samantha J. Montoya, and Jeremy G. Wideman. "Independent accretion of TIM22 complex subunits in the animal and fungal lineages." F1000Research 9 (August 28, 2020): 1060. http://dx.doi.org/10.12688/f1000research.25904.1.

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Background: The mitochondrial protein import complexes arose early in eukaryogenesis. Most of the components of the protein import pathways predate the last eukaryotic common ancestor. For example, the carrier-insertase TIM22 complex comprises the widely conserved Tim22 channel core. However, the auxiliary components of fungal and animal TIM22 complexes are exceptions to this ancient conservation. Methods: Using comparative genomics and phylogenetic approaches, we identified precisely when each TIM22 accretion occurred. Results: In animals, we demonstrate that Tim29 and Tim10b arose early in the holozoan lineage. Tim29 predates the metazoan lineage being present in the animal sister lineages, choanoflagellate and filastereans, whereas the erroneously named Tim10b arose from a duplication of Tim9 at the base of metazoans. In fungi, we show that Tim54 has representatives present in every holomycotan lineage including microsporidians and fonticulids, whereas Tim18 and Tim12 appeared much later in fungal evolution. Specifically, Tim18 and Tim12 arose from duplications of Sdh3 and Tim10, respectively, early in the Saccharomycotina. Surprisingly, we show that Tim54 is distantly related to AGK suggesting that AGK and Tim54 are extremely divergent orthologues and the origin of AGK/Tim54 interaction with Tim22 predates the divergence of animals and fungi. Conclusions: We argue that the evolutionary history of the TIM22 complex is best understood as the neutral structural divergence of an otherwise strongly functionally conserved protein complex. This view suggests that many of the differences in structure/subunit composition of multi-protein complexes are non-adaptive. Instead, most of the phylogenetic variation of functionally conserved molecular machines, which have been under stable selective pressures for vast phylogenetic spans, such as the TIM22 complex, is most likely the outcome of the interplay of random genetic drift and mutation pressure.

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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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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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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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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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6

Kumar, Abhishek, Srujan Kumar Matta, and Patrick D'Silva. "Conserved regions of budding yeast Tim22 have a role in structural organization of the carrier translocase." Journal of Cell Science 133, no. 14 (June 26, 2020): jcs244632. http://dx.doi.org/10.1242/jcs.244632.

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ABSTRACTMitochondrial biogenesis requires efficient sorting of various proteins into different mitochondrial sub-compartments, mediated by dedicated protein machinery present in the outer and inner membrane. Among them, the TIM22 complex enables the integration of complex membrane proteins with internal targeting signals into the inner membrane. Although the Tim22 protein forms the core of the complex, the dynamic recruitment of subunits to the channel is still enigmatic. In this study, we highlight that the intermembrane space (IMS) and transmembrane 4 (TM4) regions of Tim22 are critically required for interactions with the membrane-embedded subunits, including Tim54, Tim18, and Sdh3, and thereby maintain the functional architecture of the TIM22 translocase. Furthermore, we find that the TM1 and TM2 regions of Tim22 are important for association with Tim18, whereas TM3 is exclusively required for the interaction with Sdh3. Moreover, impairment of TIM22 complex assembly influences its translocase activity, the mitochondrial network, and the viability of cells lacking mitochondrial DNA. Overall, our findings provide compelling evidence highlighting the significance of conserved regions of Tim22 that are important for the maintenance of the TIM22 complex and mitochondrial integrity.

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Wrobel, Lidia, Agata Trojanowska, Malgorzata E. Sztolsztener, and Agnieszka Chacinska. "Mitochondrial protein import: Mia40 facilitates Tim22 translocation into the inner membrane of mitochondria." Molecular Biology of the Cell 24, no. 5 (March 2013): 543–54. http://dx.doi.org/10.1091/mbc.e12-09-0649.

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The mitochondrial intermembrane space assembly (MIA) pathway is generally considered to be dedicated to the redox-dependent import and biogenesis of proteins localized to the intermembrane space of mitochondria. The oxidoreductase Mia40 is a central component of the pathway responsible for the transfer of disulfide bonds to intermembrane space precursor proteins, causing their oxidative folding. Here we present the first evidence that the function of Mia40 is not restricted to the transport and oxidative folding of intermembrane space proteins. We identify Tim22, a multispanning membrane protein and core component of the TIM22 translocase of inner membrane, as a protein with cysteine residues undergoing oxidation during Tim22 biogenesis. We show that Mia40 is involved in the biogenesis and complex assembly of Tim22. Tim22 forms a disulfide-bonded intermediate with Mia40 upon import into mitochondria. Of interest, Mia40 binds the Tim22 precursor also via noncovalent interactions. We propose that Mia40 not only is responsible for disulfide bond formation, but also assists the Tim22 protein in its integration into the inner membrane of mitochondria.

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8

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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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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10

Horten, Patrick, Lilia Colina-Tenorio, and Heike Rampelt. "Biogenesis of Mitochondrial Metabolite Carriers." Biomolecules 10, no. 7 (July 7, 2020): 1008. http://dx.doi.org/10.3390/biom10071008.

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Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize the majority of the cellular ATP. Like almost all mitochondrial proteins, carriers have to be imported into mitochondria from the cytosol. Carrier precursors utilize a specialized translocation pathway dedicated to the biogenesis of carriers and related proteins, the carrier translocase of the inner membrane (TIM22) pathway. After recognition and import through the mitochondrial outer membrane via the translocase of the outer membrane (TOM) complex, carrier precursors are ushered through the intermembrane space by hexameric TIM chaperones and ultimately integrated into the inner membrane by the TIM22 carrier translocase. Recent advances have shed light on the mechanisms of TOM translocase and TIM chaperone function, uncovered an unexpected versatility of the machineries, and revealed novel components and functional crosstalk of the human TIM22 translocase.

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11

Okamoto, Hiroaki, Akiko Miyagawa, Takuya Shiota, Yasushi Tamura, and Toshiya Endo. "Intramolecular Disulfide Bond of Tim22 Protein Maintains Integrity of the TIM22 Complex in the Mitochondrial Inner Membrane." Journal of Biological Chemistry 289, no. 8 (January 2, 2014): 4827–38. http://dx.doi.org/10.1074/jbc.m113.543264.

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12

Jensen, Robert E., and Cory D. Dunn. "Protein import into and across the mitochondrial inner membrane: role of the TIM23 and TIM22 translocons." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1592, no. 1 (September 2002): 25–34. http://dx.doi.org/10.1016/s0167-4889(02)00261-6.

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13

Murphy, Michael P., Danielle Leuenberger, Sean P. Curran, Wolfgang Oppliger, and Carla M. Koehler. "The Essential Function of the Small Tim Proteins in the TIM22 Import Pathway Does Not Depend on Formation of the Soluble 70-Kilodalton Complex." Molecular and Cellular Biology 21, no. 18 (September 15, 2001): 6132–38. http://dx.doi.org/10.1128/mcb.21.18.6132-6138.2001.

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ABSTRACT The TIM22 protein import pathway of the yeast mitochondrion contains several components, including a family of five proteins (Tim8p, -9p, -10p, -12p, and -13p [Tim, for translocase of inner membrane]) that are located in the intermembrane space and are 25% identical. Tim9p and Tim10p have dual roles in mediating the import of inner membrane proteins. Like the Tim8p-Tim13p complex, the Tim9p-Tim10p complex functions as a putative chaperone to guide hydrophobic precursors across the intermembrane space. Like membrane-associated Tim12p, they are members of the Tim18p-Tim22p-Tim54p membrane complex that mediates precursor insertion into the membrane. To understand the role of this family in protein import, we have used a genetic approach to manipulate the complement of the small Tim proteins. A strain has been constructed that lacks the 70-kDa soluble Tim8p-Tim13p and Tim9p-Tim10p complexes in the intermembrane space. Instead, a functional version of Tim9p (Tim9S67Cp), identified as a second-site suppressor of a conditional tim10 mutant, maintains viability. Characterization of this strain revealed that Tim9S67Cp and Tim10p were tightly associated with the inner membrane, the soluble 70-kDa Tim8p-Tim13p and Tim9p-Tim10p complexes were not detectable, and the rate of protein import into isolated mitochondria proceeded at a slower rate. An arrested translocation intermediate bound to Tim9S67Cp was located in the intermembrane space, associated with the inner membrane. We suggest that the 70-kDa complexes facilitate import, similar to the outer membrane receptors of the TOM (hetero-oligomeric translocase of the outer membrane) complex, and the essential role of Tim9p and Tim10p may be to mediate protein insertion in the inner membrane with the TIM22 complex.

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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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Chaudhuri, Minu, Chauncey Darden, Fidel Soto Gonzalez, Ujjal K. Singha, Linda Quinones, and Anuj Tripathi. "Tim17 Updates: A Comprehensive Review of an Ancient Mitochondrial Protein Translocator." Biomolecules 10, no. 12 (December 7, 2020): 1643. http://dx.doi.org/10.3390/biom10121643.

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The translocases of the mitochondrial outer and inner membranes, the TOM and TIMs, import hundreds of nucleus-encoded proteins into mitochondria. TOM and TIMs are multi-subunit protein complexes that work in cooperation with other complexes to import proteins in different sub-mitochondrial destinations. The overall architecture of these protein complexes is conserved among yeast/fungi, animals, and plants. Recent studies have revealed unique characteristics of this machinery, particularly in the eukaryotic supergroup Excavata. Despite multiple differences, homologues of Tim17, an essential component of one of the TIM complexes and a member of the Tim17/Tim22/Tim23 family, have been found in all eukaryotes. Here, we review the structure and function of Tim17 and Tim17-containing protein complexes in different eukaryotes, and then compare them to the single homologue of this protein found in Trypanosoma brucei, a unicellular parasitic protozoan.

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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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17

Callegari, Sylvie, Tobias Müller, Christian Schulz, Christof Lenz, Daniel C. Jans, Mirjam Wissel, Felipe Opazo, et al. "A MICOS–TIM22 Association Promotes Carrier Import into Human Mitochondria." Journal of Molecular Biology 431, no. 15 (July 2019): 2835–51. http://dx.doi.org/10.1016/j.jmb.2019.05.015.

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18

Wagner, Karina, Natalia Gebert, Bernard Guiard, Katrin Brandner, Kaye N. Truscott, Nils Wiedemann, Nikolaus Pfanner, and Peter Rehling. "The Assembly Pathway of the Mitochondrial Carrier Translocase Involves Four Preprotein Translocases." Molecular and Cellular Biology 28, no. 13 (May 5, 2008): 4251–60. http://dx.doi.org/10.1128/mcb.02216-07.

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ABSTRACT The mitochondrial inner membrane contains preprotein translocases that mediate insertion of hydrophobic proteins. Little is known about how the individual components of these inner membrane preprotein translocases combine to form multisubunit complexes. We have analyzed the assembly pathway of the three membrane-integral subunits Tim18, Tim22, and Tim54 of the twin-pore carrier translocase. Tim54 displayed the most complex pathway involving four preprotein translocases. The precursor is translocated across the intermembrane space in a supercomplex of outer and inner membrane translocases. The TIM10 complex, which translocates the precursor of Tim22 through the intermembrane space, functions in a new posttranslocational manner: in case of Tim54, it is required for the integration of Tim54 into the carrier translocase. Tim18, the function of which has been unknown so far, stimulates integration of Tim54 into the carrier translocase. We show that the carrier translocase is built via a modular process and that each subunit follows a different assembly route. Membrane insertion and assembly into the oligomeric complex are uncoupled for each precursor protein. We propose that the mitochondrial assembly machinery has adapted to the needs of each membrane-integral subunit and that the uncoupling of translocation and oligomerization is an important principle to ensure continuous import and assembly of protein complexes in a highly active membrane.

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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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20

Sirrenberg, Christian, Matthias F. Bauer, Bernard Guiard, Walter Neupert, and Michael Brunner. "Import of carrier proteins into the mitochondrial inner membrane mediated by Tim22." Nature 384, no. 6609 (December 1996): 582–85. http://dx.doi.org/10.1038/384582a0.

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Leuenberger, Danielle, Sean P. Curran, David Wong, and Carla M. Koehler. "The Role of Tim9p in the Assembly of the TIM22 Import Complexes." Traffic 4, no. 3 (March 2003): 144–52. http://dx.doi.org/10.1034/j.1600-0854.2003.00095.x.

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Bauer, Matthias F., Uli Rothbauer, Nicole Mühlenbein, Richard J. H. Smith, Klaus-Dieter Gerbitz, Walter Neupert, Michael Brunner, and Sabine Hofmann. "The mitochondrial TIM22 preprotein translocase is highly conserved throughout the eukaryotic kingdom." FEBS Letters 464, no. 1-2 (December 20, 1999): 41–47. http://dx.doi.org/10.1016/s0014-5793(99)01665-8.

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Yamano, Koji, Daigo Ishikawa, Masatoshi Esaki, and Toshiya Endo. "The Phosphate Carrier Has an Ability to be Sorted to either the TIM22 Pathway or the TIM23 Pathway for Its Import into Yeast Mitochondria." Journal of Biological Chemistry 280, no. 11 (January 11, 2005): 10011–17. http://dx.doi.org/10.1074/jbc.m413264200.

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Curran, Sean P., Danielle Leuenberger, Edward P. Leverich, David K. Hwang, Kristen N. Beverly, and Carla M. Koehler. "The Role of Hot13p and Redox Chemistry in the Mitochondrial TIM22 Import Pathway." Journal of Biological Chemistry 279, no. 42 (August 4, 2004): 43744–51. http://dx.doi.org/10.1074/jbc.m404878200.

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Cárdenas-Rodríguez, Mauricio, Martina Semenzato, and Luca Scorrano. "OPA1 processing regulates mitochondrial outer-inner membranes contacts and the TIM22 protein import complex." Biochimica et Biophysica Acta (BBA) - Bioenergetics 1863 (September 2022): 148798. http://dx.doi.org/10.1016/j.bbabio.2022.148798.

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Peixoto, Pablo M. V., Fernando Graña, Teresa J. Roy, Cory D. Dunn, Montaña Flores, Robert E. Jensen, and María Luisa Campo. "Awaking TIM22, a Dynamic Ligand-gated Channel for Protein Insertion in the Mitochondrial Inner Membrane." Journal of Biological Chemistry 282, no. 26 (April 26, 2007): 18694–701. http://dx.doi.org/10.1074/jbc.m700775200.

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Peixoto, Pablo, Lauro González-Fernández, Patricia Rojo, Jorge Bermejo, and María Luisa Campo. "Molecular dynamics of the mitochondrial protein translocase TIM22: Structure–function correlations of the channel's partakers." Biochimica et Biophysica Acta (BBA) - Bioenergetics 1797 (July 2010): 133–34. http://dx.doi.org/10.1016/j.bbabio.2010.04.397.

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Gomkale, Ridhima, Luis Daniel Cruz-Zaragoza, Ida Suppanz, Bernard Guiard, Julio Montoya, Sylvie Callegari, David Pacheu-Grau, Bettina Warscheid, and Peter Rehling. "Defining the Substrate Spectrum of the TIM22 Complex Identifies Pyruvate Carrier Subunits as Unconventional Cargos." Current Biology 30, no. 6 (March 2020): 1119–27. http://dx.doi.org/10.1016/j.cub.2020.01.024.

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29

Hasson, S. A., R. Damoiseaux, J. D. Glavin, D. V. Dabir, S. S. Walker, and C. M. Koehler. "Substrate specificity of the TIM22 mitochondrial import pathway revealed with small molecule inhibitor of protein translocation." Proceedings of the National Academy of Sciences 107, no. 21 (May 10, 2010): 9578–83. http://dx.doi.org/10.1073/pnas.0914387107.

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Chiusolo, Valentina, Guillaume Jacquemin, Esen Yonca Bassoy, Laurent Vinet, Lavinia Liguori, Michael Walch, Vera Kozjak-Pavlovic, and Denis Martinvalet. "Granzyme B enters the mitochondria in a Sam50-, Tim22- and mtHsp70-dependent manner to induce apoptosis." Cell Death & Differentiation 24, no. 4 (March 24, 2017): 747–58. http://dx.doi.org/10.1038/cdd.2017.3.

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Vukotic, Milena, Hendrik Nolte, Tim König, Shotaro Saita, Maria Ananjew, Marcus Krüger, Takashi Tatsuta, and Thomas Langer. "Acylglycerol Kinase Mutated in Sengers Syndrome Is a Subunit of the TIM22 Protein Translocase in Mitochondria." Molecular Cell 67, no. 3 (August 2017): 471–83. http://dx.doi.org/10.1016/j.molcel.2017.06.013.

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Kang, Yilin, David A. Stroud, Michael J. Baker, David P. De Souza, Ann E. Frazier, Michael Liem, Dedreia Tull, et al. "Sengers Syndrome-Associated Mitochondrial Acylglycerol Kinase Is a Subunit of the Human TIM22 Protein Import Complex." Molecular Cell 67, no. 3 (August 2017): 457–70. http://dx.doi.org/10.1016/j.molcel.2017.06.014.

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Jackson, Thomas D., Daniella H. Hock, Kenji M. Fujihara, Catherine S. Palmer, Ann E. Frazier, Yau C. Low, Yilin Kang, et al. "The TIM22 complex mediates the import of sideroflexins and is required for efficient mitochondrial one-carbon metabolism." Molecular Biology of the Cell 32, no. 6 (March 15, 2021): 475–91. http://dx.doi.org/10.1091/mbc.e20-06-0390.

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Proteomic profiling of Sengers patient fibroblasts and AGK knockout models identifies remodeling of the mitochondrial proteome, including mitochondrial one-carbon metabolism enzymes, inner membrane serine transporters, sideroflexins, and Complex I subunits and assembly factors.

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Gebert, Natalia, Michael Gebert, Silke Oeljeklaus, Karina von der Malsburg, David A. Stroud, Bogusz Kulawiak, Christophe Wirth, et al. "Dual Function of Sdh3 in the Respiratory Chain and TIM22 Protein Translocase of the Mitochondrial Inner Membrane." Molecular Cell 44, no. 5 (December 2011): 811–18. http://dx.doi.org/10.1016/j.molcel.2011.09.025.

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Chacinska, Agnieszka, Martin van der Laan, Carola S. Mehnert, Bernard Guiard, David U. Mick, Dana P. Hutu, Kaye N. Truscott, et al. "Distinct Forms of Mitochondrial TOM-TIM Supercomplexes Define Signal-Dependent States of Preprotein Sorting." Molecular and Cellular Biology 30, no. 1 (November 2, 2009): 307–18. http://dx.doi.org/10.1128/mcb.00749-09.

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ABSTRACT 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 presequence translocase-associated motor (PAM; TIM23-PAM) and a sorting form containing Tim21 (TIM23SORT). 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-TIM23SORT and TOM-TIM23-PAM. These 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.

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Dunn, Cory D., and Robert E. Jensen. "Suppression of a Defect in Mitochondrial Protein Import Identifies Cytosolic Proteins Required for Viability of Yeast Cells Lacking Mitochondrial DNA." Genetics 165, no. 1 (September 1, 2003): 35–45. http://dx.doi.org/10.1093/genetics/165.1.35.

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Abstract The TIM22 complex, required for the insertion of imported polytopic proteins into the mitochondrial inner membrane, contains the nonessential Tim18p subunit. To learn more about the function of Tim18p, we screened for high-copy suppressors of the inability of tim18Δ mutants to live without mitochondrial DNA (mtDNA). We identified several genes encoding cytosolic proteins, including CCT6, SSB1, ICY1, TIP41, and PBP1, which, when overproduced, rescue the mtDNA dependence of tim18Δ cells. Furthermore, these same plasmids rescue the petite-negative phenotype of cells lacking other components of the mitochondrial protein import machinery. Strikingly, disruption of the genes identified by the different suppressors produces cells that are unable to grow without mtDNA. We speculate that loss of mtDNA leads to a lowered inner membrane potential, and subtle changes in import efficiency can no longer be tolerated. Our results suggest that increased amounts of Cct6p, Ssb1p, Icy1p, Tip41p, and Pbp1p help overcome the problems resulting from a defect in protein import.

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Kovermann, Peter, Kaye N. Truscott, Bernard Guiard, Peter Rehling, Naresh B. Sepuri, Hanne Müller, Robert E. Jensen, Richard Wagner, and Nikolaus Pfanner. "Tim22, the Essential Core of the Mitochondrial Protein Insertion Complex, Forms a Voltage-Activated and Signal-Gated Channel." Molecular Cell 9, no. 2 (February 2002): 363–73. http://dx.doi.org/10.1016/s1097-2765(02)00446-x.

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Grevel, Alexander, and Thomas Becker. "Porins as helpers in mitochondrial protein translocation." Biological Chemistry 401, no. 6-7 (May 26, 2020): 699–708. http://dx.doi.org/10.1515/hsz-2019-0438.

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AbstractMitochondria import the vast majority of their proteins via dedicated protein machineries. The translocase of the outer membrane (TOM complex) forms the main entry site for precursor proteins that are produced on cytosolic ribosomes. Subsequently, different protein sorting machineries transfer the incoming preproteins to the mitochondrial outer and inner membranes, the intermembrane space, and the matrix. In this review, we highlight the recently discovered role of porin, also termed voltage-dependent anion channel (VDAC), in mitochondrial protein biogenesis. Porin forms the major channel for metabolites and ions in the outer membrane of mitochondria. Two different functions of porin in protein translocation have been reported. First, it controls the formation of the TOM complex by modulating the integration of the central receptor Tom22 into the mature translocase. Second, porin promotes the transport of carrier proteins toward the carrier translocase (TIM22 complex), which inserts these preproteins into the inner membrane. Therefore, porin acts as a coupling factor to spatially coordinate outer and inner membrane transport steps. Thus, porin links metabolite transport to protein import, which are both essential for mitochondrial function and biogenesis.

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Davis, Alison J., Nathan N. Alder, Robert E. Jensen, and Arthur E. Johnson. "The Tim9p/10p and Tim8p/13p Complexes Bind to Specific Sites on Tim23p during Mitochondrial Protein Import." Molecular Biology of the Cell 18, no. 2 (February 2007): 475–86. http://dx.doi.org/10.1091/mbc.e06-06-0546.

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The import of polytopic membrane proteins into the mitochondrial inner membrane (IM) is facilitated by Tim9p/Tim10p and Tim8p/Tim13p protein complexes in the intermembrane space (IMS). These complexes are proposed to act as chaperones by transporting the hydrophobic IM proteins through the aqueous IMS and preventing their aggregation. To examine the nature of this interaction, Tim23p molecules containing a single photoreactive cross-linking probe were imported into mitochondria in the absence of an IM potential where they associated with small Tim complexes in the IMS. On photolysis and immunoprecipitation, a probe located at a particular Tim23p site (27 different locations were examined) was found to react covalently with, in most cases, only one of the small Tim proteins. Tim8p, Tim9p, Tim10p, and Tim13p were therefore positioned adjacent to specific sites in the Tim23p substrate before its integration into the IM. This specificity of binding to Tim23p strongly suggests that small Tim proteins do not function solely as general chaperones by minimizing the exposure of nonpolar Tim23p surfaces to the aqueous medium, but may also align a folded Tim23p substrate in the proper orientation for delivery and integration into the IM at the TIM22 translocon.

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Reinbothe, Steffen, Claudia Rossig, John Gray, Sachin Rustgi, Diter von Wettstein, Christiane Reinbothe, and Joachim Rassow. "tRNA-Dependent Import of a Transit Sequence-Less Aminoacyl-tRNA Synthetase (LeuRS2) into the Mitochondria of Arabidopsis." International Journal of Molecular Sciences 22, no. 8 (April 7, 2021): 3808. http://dx.doi.org/10.3390/ijms22083808.

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Aminoacyl-tRNA synthetases (AaRS) charge tRNAs with amino acids for protein translation. In plants, cytoplasmic, mitochondrial, and chloroplast AaRS exist that are all coded for by nuclear genes and must be imported from the cytosol. In addition, only a few of the mitochondrial tRNAs needed for translation are encoded in mitochondrial DNA. Despite considerable progress made over the last few years, still little is known how the bulk of cytosolic AaRS and respective tRNAs are transported into mitochondria. Here, we report the identification of a protein complex that ties AaRS and tRNA import into the mitochondria of Arabidopsis thaliana. Using leucyl-tRNA synthetase 2 (LeuRS2) as a model for a mitochondrial signal peptide (MSP)-less precursor, a ≈30 kDa protein was identified that interacts with LeuRS2 during import. The protein identified is identical with a previously characterized mitochondrial protein designated HP30-2 (encoded by At3g49560) that contains a sterile alpha motif (SAM) similar to that found in RNA binding proteins. HP30-2 is part of a larger protein complex that contains with TIM22, TIM8, TIM9 and TIM10 four previously identified components of the translocase for MSP-less precursors. Lack of HP30-2 perturbed mitochondrial biogenesis and function and caused seedling lethality during greening, suggesting an essential role of HP30-2 in planta.

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Vasiljev, Andreja, Uwe Ahting, Frank E. Nargang, Nancy E. Go, Shukry J. Habib, Christian Kozany, Valérie Panneels, et al. "Reconstituted TOM Core Complex and Tim9/Tim10 Complex of Mitochondria Are Sufficient for Translocation of the ADP/ATP Carrier across Membranes." Molecular Biology of the Cell 15, no. 3 (March 2004): 1445–58. http://dx.doi.org/10.1091/mbc.e03-05-0272.

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Precursor proteins of the solute carrier family and of channel forming Tim components are imported into mitochondria in two main steps. First, they are translocated through the TOM complex in the outer membrane, a process assisted by the Tim9/Tim10 complex. They are passed on to the TIM22 complex, which facilitates their insertion into the inner membrane. In the present study, we have analyzed the function of the Tim9/Tim10 complex in the translocation of substrates across the outer membrane of mitochondria. The purified TOM core complex was reconstituted into lipid vesicles in which purified Tim9/Tim10 complex was entrapped. The precursor of the ADP/ATP carrier (AAC) was found to be translocated across the membrane of such lipid vesicles. Thus, these components are sufficient for translocation of AAC precursor across the outer membrane. Peptide libraries covering various substrate proteins were used to identify segments that are bound by Tim9/Tim10 complex upon translocation through the TOM complex. The patterns of binding sites on the substrate proteins suggest a mechanism by which portions of membrane-spanning segments together with flanking hydrophilic segments are recognized and bound by the Tim9/Tim10 complex as they emerge from the TOM complex into the intermembrane space.

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Barbosa-Gouveia, Sofia, Maria E. Vázquez-Mosquera, Emiliano Gonzalez-Vioque, Álvaro Hermida-Ameijeiras, Laura L. Valverde, Judith Armstrong-Moron, Maria del Carmen Fons-Estupiña, et al. "Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome." International Journal of Molecular Sciences 22, no. 24 (December 15, 2021): 13484. http://dx.doi.org/10.3390/ijms222413484.

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Mitochondrial functional integrity depends on protein and lipid homeostasis in the mitochondrial membranes and disturbances in their accumulation can cause disease. AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex in the inner mitochondrial membrane, which mediates the import of a subset of membrane proteins. AGK mutations can alter both phospholipid metabolism and mitochondrial protein biogenesis, contributing to the pathogenesis of Sengers syndrome. We describe the case of an infant carrying a novel homozygous AGK variant, c.518+1G>A, who was born with congenital cataracts, pielic ectasia, critical congenital dilated myocardiopathy, and hyperlactacidemia and died 20 h after birth. Using the patient’s DNA, we performed targeted sequencing of 314 nuclear genes encoding respiratory chain complex subunits and proteins implicated in mitochondrial oxidative phosphorylation (OXPHOS). A decrease of 96-bp in the length of the AGK cDNA sequence was detected. Decreases in the oxygen consumption rate (OCR) and the OCR:ECAR (extracellular acidification rate) ratio in the patient’s fibroblasts indicated reduced electron flow through the respiratory chain, and spectrophotometry revealed decreased activity of OXPHOS complexes I and V. We demonstrate a clear defect in mitochondrial function in the patient’s fibroblasts and describe the possible molecular mechanism underlying the pathogenicity of this novel AGK variant. Experimental validation using in vitro analysis allowed an accurate characterization of the disease-causing variant.

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Martinvalet, Denis. "Mitochondrial Entry of Cytotoxic Proteases: A New Insight into the Granzyme B Cell Death Pathway." Oxidative Medicine and Cellular Longevity 2019 (May 21, 2019): 1–13. http://dx.doi.org/10.1155/2019/9165214.

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The mitochondria represent an integration and amplification hub for various death pathways including that mediated by granzyme B (GB), a granule enzyme expressed by cytotoxic lymphocytes. GB activates the proapoptotic B cell CLL/lymphoma 2 (Bcl-2) family member BH3-interacting domain death agonist (BID) to switch on the intrinsic mitochondrial death pathway, leading to Bcl-2-associated X protein (Bax)/Bcl-2 homologous antagonist/killer- (Bak-) dependent mitochondrial outer membrane permeabilization (MOMP), the dissipation of mitochondrial transmembrane potential (ΔΨm), and the production of reactive oxygen species (ROS). GB can also induce mitochondrial damage in the absence of BID, Bax, and Bak, critical for MOMP, indicating that GB targets the mitochondria in other ways. Interestingly, granzyme A (GA), GB, and caspase 3 can all directly target the mitochondrial respiratory chain complex I for ROS-dependent cell death. Studies of ROS biogenesis have revealed that GB must enter the mitochondria for ROS production, making the mitochondrial entry of cytotoxic proteases (MECP) an unexpected critical step in the granzyme death pathway. MECP requires an intact ΔΨm and is mediated though Sam50 and Tim22 channels in a mtHSP70-dependent manner. Preventing MECP severely compromises GB cytotoxicity. In this review, we provide a brief overview of the canonical mitochondrial death pathway in order to put into perspective this new insight into the GB action on the mitochondria to trigger ROS-dependent cell death.

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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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Endo, Toshiya, and Haruka Sakaue. "Multifaceted roles of porin in mitochondrial protein and lipid transport." Biochemical Society Transactions 47, no. 5 (October 31, 2019): 1269–77. http://dx.doi.org/10.1042/bst20190153.

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Abstract Mitochondria are essential eukaryotic organelles responsible for primary cellular energy production. Biogenesis, maintenance, and functions of mitochondria require correct assembly of resident proteins and lipids, which require their transport into and within mitochondria. Mitochondrial normal functions also require an exchange of small metabolites between the cytosol and mitochondria, which is primarily mediated by a metabolite channel of the outer membrane (OM) called porin or voltage-dependent anion channel. Here, we describe recently revealed novel roles of porin in the mitochondrial protein and lipid transport. First, porin regulates the formation of the mitochondrial protein import gate in the OM, the translocase of the outer membrane (TOM) complex, and its dynamic exchange between the major form of a trimer and the minor form of a dimer. The TOM complex dimer lacks a core subunit Tom22 and mediates the import of a subset of mitochondrial proteins while the TOM complex trimer facilitates the import of most other mitochondrial proteins. Second, porin interacts with both a translocating inner membrane (IM) protein like a carrier protein accumulated at the small TIM chaperones in the intermembrane space and the TIM22 complex, a downstream translocator in the IM for the carrier protein import. Porin thereby facilitates the efficient transfer of carrier proteins to the IM during their import. Third, porin facilitates the transfer of lipids between the OM and IM and promotes a back-up pathway for the cardiolipin synthesis in mitochondria. Thus, porin has roles more than the metabolite transport in the protein and lipid transport into and within mitochondria, which is likely conserved from yeast to human.

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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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Britton, Rachel, Tristan Wasley, Reema Harish, Charles Holz, John Hall, Dennis C. Yee, Jody Melton Witt, et al. "Noncanonical Activity of Tissue Inhibitor of Metalloproteinases 2 (TIMP2) Improves Cognition and Synapse Density in Aging." eneuro 10, no. 6 (June 2023): ENEURO.0031–23.2023. http://dx.doi.org/10.1523/eneuro.0031-23.2023.

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AbstractPeripheral administration of tissue inhibitor of metalloproteinases 2 (TIMP2), a protein inhibitor of matrix metalloproteinases (MMPs), has previously been shown to have beneficial effects on cognition and neurons in aged mice. Here, to better understand the potential of recombinant TIMP2 proteins, an IgG4Fc fusion protein (TIMP2-hIgG4) was developed to extend the plasma half-life of TIMP2. Following one month of administration of TIMP2 or TIMP2-hIgG4 via intraperitoneal injections, 23-month-old male C57BL/6J mice showed improved hippocampal-dependent memory in a Y-maze, increased hippocampalcfosgene expression, and increased excitatory synapse density in the CA1 and dentate gyrus (DG) of the hippocampus. Thus, fusion to hIgG4 extended the half-life of TIMP2 while retaining the beneficial cognitive and neuronal effects. Moreover, it retained its ability to cross the blood-brain barrier. To deepen the mechanistic understanding of the beneficial function of TIMP2 on neuronal activity and cognition, a TIMP2 construct lacking MMP inhibitory activity, Ala-TIMP2, was generated, which provides steric hindrance that prevents inhibition of MMPs by the TIMP2 protein while still allowing MMP binding. A comprehensive assessment of the MMP inhibitory and binding capacity of these engineered proteins is outlined. Surprisingly, MMP inhibition by TIMP2 was not essential for its beneficial effects on cognition and neuronal function. These findings both confirm previously published research, expand on the potential mechanism for the beneficial effects of TIMP2, and provide important details for a therapeutic path forward for TIMP2 recombinant proteins in aging-related cognitive decline.

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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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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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Johnson, Ali C. M., and Richard A. Zager. "Mechanisms Underlying Increased TIMP2 and IGFBP7 Urinary Excretion in Experimental AKI." Journal of the American Society of Nephrology 29, no. 8 (July 6, 2018): 2157–67. http://dx.doi.org/10.1681/asn.2018030265.

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BackgroundRecent clinical data support the utility/superiority of a new AKI biomarker (“NephroCheck”), the arithmetic product of urinary TIMP × IGFBP7 concentrations. However, the pathophysiologic basis for its utility remains ill defined.MethodsTo clarify this issue, CD-1 mice were subjected to either nephrotoxic (glycerol, maleate) or ischemic AKI. Urinary TIMP2/IGFBP7 concentrations were determined at 4 and 18 hours postinjury and compared with urinary albumin levels. Gene transcription was assessed by measuring renal cortical and/or medullary TIMP2/IGFBP7 mRNAs (4 and 18 hours after AKI induction). For comparison, the mRNAs of three renal “stress” biomarkers (NGAL, heme oxygenase 1, and p21) were assessed. Renal cortical TIMP2/IGFBP7 protein was gauged by ELISA. Proximal tubule–specific TIMP2/IGFBP7 was assessed by immunohistochemistry.ResultsEach AKI model induced prompt (4 hours) and marked urinary TIMP2/IGFBP7 increases without an increase in renal cortical concentrations. Furthermore, TIMP2/IGFBP7 mRNAs remained at normal levels. Endotoxemia also failed to increase TIMP2/IGFBP7 mRNAs. In contrast, each AKI model provoked massive NGAL, HO-1, and p21 mRNA increases, confirming that a renal “stress response” had occurred. Urinary albumin rose up to 100-fold and strongly correlated (r=0.87–0.91) with urinary TIMP2/IGFBP7 concentrations. Immunohistochemistry showed progressive TIMP2/IGFBP7 losses from injured proximal tubule cells. Competitive inhibition of endocytic protein reabsorption in normal mice tripled urinary TIMP2/IGFBP7 levels, confirming this pathway’s role in determining urinary excretion.ConclusionsAKI-induced urinary TIMP2/IGFBP7 elevations are not due to stress-induced gene transcription. Rather, increased filtration, decreased tubule reabsorption, and proximal tubule cell TIMP2/IGFBP7 urinary leakage seem to be the most likely mechanisms.

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Journal articles on the topic 'Tim22'

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