Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter March 13, 2020

How to get to the other side of the mitochondrial inner membrane – the protein import motor

  • Dejana Mokranjac ORCID logo EMAIL logo
From the journal Biological Chemistry

Abstract

Biogenesis 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.

Award Identifier / Grant number: MO1944/1-2

Award Identifier / Grant number: MO1944/2-1

Funding statement: I would like to thank Umut Günsel for the help in preparing Figure 3 and the present and past members of my group and of the Mito Club for many stimulating discussions on mitochondrial biology. I am indebted to Dr. Andreas Bracher for his continuous help with and discussions on Hsp70 chaperones. The work in my laboratory is generously supported by Deutsche Forschungsgemeinschaft (Funder Id: http://dx.doi.org/10.13039/501100001659, grants MO1944/1-2 and MO1944/2-1), which I gratefully acknowledge.

References

Araiso, Y., Tsutsumi, A., Qiu, J., Imai, K., Shiota, T., Song, J., Lindau, C., Wenz, L.S., Sakaue, H., Yunoki, K., et al. (2019). Structure of the mitochondrial import gate reveals distinct preprotein paths. Nature 575, 395–401.10.1038/s41586-019-1680-7Search in Google Scholar

Backes, S., Hess, S., Boos, F., Woellhaf, M.W., Godel, S., Jung, M., Muhlhaus, T., and Herrmann, J.M. (2018). Tom70 enhances mitochondrial preprotein import efficiency by binding to internal targeting sequences. J. Cell Biol. 217, 1369–1382.10.1083/jcb.201708044Search in Google Scholar

Banerjee, R., Gladkova, C., Mapa, K., Witte, G., and Mokranjac, D. (2015). Protein translocation channel of mitochondrial inner membrane and matrix-exposed import motor communicate via two-domain coupling protein. eLife 4, e11897.10.7554/eLife.11897Search in Google Scholar

Berthold, J., Bauer, M.F., Schneider, H.C., Klaus, C., Dietmeier, K., Neupert, W., and Brunner, M. (1995). The MIM complex mediates preprotein translocation across the mitochondrial inner membrane and couples it to the mt-Hsp70/ATP driving system. Cell 81, 1085–1093.10.1016/S0092-8674(05)80013-3Search in Google Scholar

Blamowska, M., Sichting, M., Mapa, K., Mokranjac, D., Neupert, W., and Hell, K. (2010). ATPase domain and interdomain linker play a key role in aggregation of mitochondrial Hsp70 chaperone Ssc1. J. Biol. Chem. 285, 4423–4431.10.1074/jbc.M109.061697Search in Google Scholar PubMed PubMed Central

Blamowska, M., Neupert, W., and Hell, K. (2012). Biogenesis of the mitochondrial Hsp70 chaperone. J. Cell Biol. 199, 125–135.10.1083/jcb.201205012Search in Google Scholar PubMed PubMed Central

Chacinska, A., Lind, M., Frazier, A.E., Dudek, J., Meisinger, C., Geissler, A., Sickmann, A., Meyer, H.E., Truscott, K.N., Guiard, B., et al. (2005). Mitochondrial presequence translocase: switching between TOM tethering and motor recruitment involves Tim21 and Tim17. Cell 120, 817–829.10.1016/j.cell.2005.01.011Search in Google Scholar PubMed

Craig, E.A., Kramer, J., and Kosic-Smithers, J. (1987). SSC1, a member of the 70kDa heat shock protein multigene family of Saccharomyces cerevisiae, is essential for growth. Proc. Natl. Acad. Sci. USA 84, 4156–4160.10.1073/pnas.84.12.4156Search in Google Scholar PubMed PubMed Central

D’Silva, P.D., Schilke, B., Walter, W., Andrew, A., and Craig, E.A. (2003). J protein cochaperone of the mitochondrial inner membrane required for protein import into the mitochondrial matrix. Proc. Natl. Acad. Sci. USA 100, 13839–13844.10.1073/pnas.1936150100Search in Google Scholar PubMed PubMed Central

D’Silva, P., Liu, Q., Walter, W., and Craig, E.A. (2004). Regulated interactions of mtHsp70 with Tim44 at the translocon in the mitochondrial inner membrane. Nat. Struct. Mol. Biol. 11, 1084–1091.10.1038/nsmb846Search in Google Scholar PubMed

D’Silva, P.R., Schilke, B., Walter, W., and Craig, E.A. (2005). Role of Pam16’s degenerate J domain in protein import across the mitochondrial inner membrane. Proc. Natl. Acad. Sci. USA 102, 12419–12424.10.1073/pnas.0505969102Search in Google Scholar

D’Silva, P.R., Schilke, B., Hayashi, M., and Craig, E.A. (2008). Interaction of the j-protein heterodimer pam18/pam16 of the mitochondrial import motor with the translocon of the inner membrane. Mol. Biol. Cell 19, 424–432.10.1091/mbc.e07-08-0748Search in Google Scholar

De Los Rios, P., Ben-Zvi, A., Slutsky, O., Azem, A., and Goloubinoff, P. (2006). Hsp70 chaperones accelerate protein translocation and the unfolding of stable protein aggregates by entropic pulling. Proc. Natl. Acad. Sci. USA 103, 6166–6171.10.1073/pnas.0510496103Search in Google Scholar

Deloche, O., Kelley, W.L., and Georgopoulos, C. (1997). Structure-function analyses of the Ssc1p, Mdj1p, and Mge1p Saccharomyces cerevisiae mitochondrial proteins in Escherichia coli. J. Bacteriol. 179, 6066–6075.10.1128/jb.179.19.6066-6075.1997Search in Google Scholar

Demishtein-Zohary, K. and Azem, A. (2017). The TIM23 mitochondrial protein import complex: function and dysfunction. Cell. Tissue. Res. 367, 33–41.10.1007/s00441-016-2486-7Search in Google Scholar

Demishtein-Zohary, K., Gunsel, U., Marom, M., Banerjee, R., Neupert, W., Azem, A., and Mokranjac, D. (2017). Role of Tim17 in coupling the import motor to the translocation channel of the mitochondrial presequence translocase. eLife 6, e22696.10.7554/eLife.22696Search in Google Scholar

Frazier, A.E., Dudek, J., Guiard, B., Voos, W., Li, Y., Lind, M., Meisinger, C., Geissler, A., Sickmann, A., Meyer, H.E., et al. (2004). Pam16 has an essential role in the mitochondrial protein import motor. Nat. Struct. Mol. Biol. 11, 226–233.10.1038/nsmb735Search in Google Scholar

Glick, B.S. (1995). Can Hsp70 proteins act as force-generating motors? Cell 80, 11–14.10.1016/0092-8674(95)90444-1Search in Google Scholar

Goloubinoff, P. and De Los Rios, P. (2007). The mechanism of Hsp70 chaperones: (entropic) pulling the models together. Trends Biochem. Sci. 32, 372–380.10.1016/j.tibs.2007.06.008Search in Google Scholar PubMed

Günsel, U. and Mokranjac, D. (2019). A journely along the TIM23 complex, the major protein translocase of the mitochodnrial inner membrane. Biol. Serb. 41, 27–35.Search in Google Scholar

Handa, N., Kishishita, S., Morita, S., Akasaka, R., Jin, Z., Chrzas, J., Chen, L., Liu, Z.J., Wang, B.C., Sugano, S., et al. (2007). Structure of the human Tim44 C-terminal domain in complex with pentaethylene glycol: ligand-bound form. Acta Crystallogr. D Biol Crystallogr. 63, 1225–1234.10.1107/S0907444907051463Search in Google Scholar PubMed

Harrison, C.J., Hayer-Hartl, M., Di Liberto, M., Hartl, F., and Kuriyan, J. (1997). Crystal structure of the nucleotide exchange factor GrpE bound to the ATPase domain of the molecular chaperone DnaK. Science 276, 431–435.10.1126/science.276.5311.431Search in Google Scholar

Hayashi, M., Schilke, B., Marszalek, J., Williams, B., and Craig, E.A. (2011). Ancient gene duplication provided a key molecular step for anaerobic growth of Baker’s yeast. Mol. Biol. Evol. 28, 2005–2017.10.1093/molbev/msr019Search in Google Scholar

Horst, M., Jeno, P., Kronidou, N.G., Bolliger, L., Oppliger, W., Scherer, P., Manning-Krieg, U., Jascur, T., and Schatz, G. (1993). Protein import into yeast mitochondria: the inner membrane import site protein ISP45 is the MPI1 gene product. EMBO J. 12, 3035–3041.10.1002/j.1460-2075.1993.tb05972.xSearch in Google Scholar

Horst, M., Oppliger, W., Feifel, B., Schatz, G., and Glick, B.S. (1996). The mitochondrial protein import motor: dissociation of mitochondrial Hsp70 from its membrane anchor requires ATP binding rather than ATP hydrolysis. Protein Sci. 5, 759–767.10.1002/pro.5560050421Search in Google Scholar

Horst, M., Oppliger, W., Rospert, S., Schonfeld, H.J., Schatz, G., and Azem, A. (1997). Sequential action of two Hsp70 complexes during protein import into mitochondria. EMBO J. 16, 1842–1849.10.1093/emboj/16.8.1842Search in Google Scholar

Hoshino, A., Wang, W-J., Wada, S., McDermott-Roe, C., Evans, C., Gosis, B., Morley, M.P., Rathi, K.S., Li, J., Li, K., et al. (2019). The ADP/ATP translocase drives mitophagy independent of nucleotide exchange. Nature 575, 375–379.10.1038/s41586-019-1667-4Search in Google Scholar

Huang, S., Ratliff, K.S., and Matouschek, A. (2002). Protein unfolding by the mitochodnrial membrane potential. Nat. Struct. Biol. 9, 301–307.10.1038/nsb772Search in Google Scholar

Hurt, E. and Schatz, G. (1987). A cytosolic protein contains a cryptic mitochondrial targeting signal. Nature 325, 499–503.10.1038/325499a0Search in Google Scholar

Ikeda, E., Yoshida, S., Mitsuzawa, H., Uno, I., and Toh-e, A. (1994). YGE1 is a yeast homologue of Escherichia coli grpE and is required for maintenance of mitochondrial functions [published erratum appears in FEBS Lett. 343 (1994), p. 181]. FEBS Lett. 339, 265–268.10.1016/0014-5793(94)80428-1Search in Google Scholar

Iosefson, O., Levy, R., Marom, M., Slutsky-Leiderman, O., and Azem, A. (2007). The Pam18/Tim14–Pam16/Tim16 complex of the mitochondrial translocation motor: the formation of a stable complex from marginally stable proteins. Protein Sci. 16, 316–322.10.1110/ps.062459607Search in Google Scholar PubMed PubMed Central

Josyula, R., Jin, Z., Fu, Z., and Sha, B. (2006). Crystal structure of yeast mitochondrial peripheral membrane protein Tim44p C-terminal domain. J. Mol. Biol. 359, 798–804.10.1016/j.jmb.2006.04.020Search in Google Scholar PubMed

Kampinga, H.H. and Craig, E.A. (2010). The Hsp70 chaperone machinery: J proteins as drivers of functional specificity. Nat. Rev. Mol. Cell. Biol. 11, 579–592.10.1038/nrm2941Search in Google Scholar PubMed PubMed Central

Kanamori, T., Nishikawa, S., Shin, I., Schultz, P.G., and Endo, T. (1997). Probing the environment along the protein import pathways in yeast mitochondria by site-specific photocrosslinking. Proc. Natl. Acad. Sci. USA 94, 485–490.10.1073/pnas.94.2.485Search in Google Scholar PubMed PubMed Central

Kang, P.J., Ostermann, J., Shilling, J., Neupert, W., Craig, E.A., and Pfanner, N. (1990). Requirement for Hsp70 in the mitochondrial matrix for translocation and folding of precursor proteins. Nature 348, 137–143.10.1038/348137a0Search in Google Scholar PubMed

Kang, Y., Fielden, L.F., and Stojanovski, D. (2018). Mitochondrial protein transport in health and disease. Semin. Cell. Dev. Biol. 76, 142–153.10.1016/j.semcdb.2017.07.028Search in Google Scholar PubMed

Kityk, R., Kopp, J., and Mayer, M.P. (2018). Molecular mechanism of J-domain–triggered ATP hydrolysis by Hsp70 chaperones. Mol. Cell 69, 227–237 e224.10.1016/j.molcel.2017.12.003Search in Google Scholar PubMed

Kozany, C., Mokranjac, D., Sichting, M., Neupert, W., and Hell, K. (2004). The J domain-related cochaperone Tim16 is a constituent of the mitochondrial TIM23 preprotein translocase. Nat. Struct. Mol. Biol. 11, 234–241.10.1038/nsmb734Search in Google Scholar PubMed

Kronidou, N.G., Oppliger, W., Bolliger, L., Hannavy, K., Glick, B.S., Schatz, G., and Horst, M. (1994). Dynamic interaction between Isp45 and mitochondrial Hsp70 in the protein import system of the yeast mitochondrial inner membrane. Proc. Natl. Acad. Sci. USA 91, 12818–12822.10.1073/pnas.91.26.12818Search in Google Scholar PubMed PubMed Central

Laloraya, S., Gambill, B.D., and Craig, E.A. (1994). A role for a eukaryotic GrpE-related protein, Mge1p, in protein translocation. Proc. Natl. Acad. Sci. USA 91, 6481–6485.10.1073/pnas.91.14.6481Search in Google Scholar PubMed PubMed Central

Laloraya, S., Dekker, P.J., Voos, W., Craig, E.A., and Pfanner, N. (1995). Mitochondrial GrpE modulates the function of matrix Hsp70 in translocation and maturation of preproteins. Mol. Cell. Biol. 15, 7098–7105.10.1128/MCB.15.12.7098Search in Google Scholar PubMed PubMed Central

Li, Y., Dudek, J., Guiard, B., Pfanner, N., Rehling, P., and Voos, W. (2004). The presequence translocase-associated protein import motor of mitochondria. Pam16 functions in an antagonistic manner to Pam18. J. Biol. Chem. 279, 38047–38054.10.1240/sav_gbm_2004_h_000793Search in Google Scholar

Maarse, A.C., Blom, J., Grivell, L.A., and Meijer, M. (1992). MPI1, an essential gene encoding a mitochondrial membrane protein, is possibly involved in protein import into yeast mitochondria. EMBO J. 11, 3619–3628.10.1002/j.1460-2075.1992.tb05446.xSearch in Google Scholar

Mapa, K., Sikor, M., Kudryavtsev, V., Waegemann, K., Kalinin, S., Seidel, C.A., Neupert, W., Lamb, D.C., and Mokranjac, D. (2010). The conformational dynamics of the mitochondrial Hsp70 chaperone. Mol. Cell 38, 89–100.10.1016/j.molcel.2010.03.010Search in Google Scholar

Marada, A., Allu, P.K., Murari, A., PullaReddy, B., Tammineni, P., Thiriveedi, V.R., Danduprolu, J., and Sepuri, N.B. (2013). Mge1, a nucleotide exchange factor of Hsp70, acts as an oxidative sensor to regulate mitochondrial Hsp70 function. Mol. Biol. Cell 24, 692–703.10.1091/mbc.e12-10-0719Search in Google Scholar

Marom, M., Safonov, R., Amram, S., Avneon, Y., Nachliel, E., Gutman, M., Zohary, K., Azem, A., and Tsfadia, Y. (2009). Interaction of the Tim44 C-terminal domain with negatively charged phospholipids. Biochemistry 48, 11185–11195.10.1021/bi900998vSearch in Google Scholar

Matlack, K.E., Misselwitz, B., Plath, K., and Rapoport, T.A. (1999). BiP acts as a molecular ratchet during posttranslational transport of prepro-alpha factor across the ER membrane. Cell 97, 553–564.10.1016/S0092-8674(00)80767-9Search in Google Scholar

Matouschek, A., Azem, A., Ratliff, K., Glick, B.S., Schmid, K., and Schatz, G. (1997). Active unfolding of precursor proteins during mitochondrial protein import. EMBO J. 16, 6727–6736.10.1093/emboj/16.22.6727Search in Google Scholar PubMed PubMed Central

Miyata, N., Tang, Z., Conti, M.A., Johnson, M.E., Douglas, C.J., Hasson, S.A., Damoiseaux, R., Chang, C.A., and Koehler, C.M. (2017). Adaptation of a genetic screen reveals an inhibitor for mitochondrial protein import component Tim44. J. Biol. Chem. 292, 5429–5442.10.1074/jbc.M116.770131Search in Google Scholar PubMed PubMed Central

Mokranjac, D., Sichting, M., Neupert, W., and Hell, K. (2003). Tim14, a novel key component of the import motor of the TIM23 protein translocase of mitochondria. EMBO J. 22, 4945–4956.10.1093/emboj/cdg485Search in Google Scholar PubMed PubMed Central

Mokranjac, D., Sichting, M., Popov-Celeketic, D., Berg, A., Hell, K., and Neupert, W. (2005). The import motor of the yeast mitochondrial TIM23 preprotein translocase contains two different J proteins, Tim14 and Mdj2. J. Biol. Chem. 280, 31608–31614.10.1074/jbc.M502397200Search in Google Scholar PubMed

Mokranjac, D., Bourenkov, G., Hell, K., Neupert, W., and Groll, M. (2006). Structure and function of Tim14 and Tim16, the J and J-like components of the mitochondrial protein import motor. EMBO J. 25, 4675–4685.10.1038/sj.emboj.7601334Search in Google Scholar PubMed PubMed Central

Mokranjac, D., Berg, A., Adam, A., Neupert, W., and Hell, K. (2007). Association of the Tim14.Tim16 subcomplex with the TIM23 translocase is crucial for function of the mitochondrial protein import motor. J. Biol. Chem. 282, 18037–18045.10.1074/jbc.M701895200Search in Google Scholar PubMed

Momose, T., Ohshima, C., Maeda, M., and Endo, T. (2007). Structural basis of functional cooperation of Tim15/Zim17 with yeast mitochondrial Hsp70. EMBO Rep. 8, 664–670.10.1038/sj.embor.7400990Search in Google Scholar PubMed PubMed Central

Moro, F. and Muga, A. (2006). Thermal adaptation of the yeast mitochondrial Hsp70 system is regulated by the reversible unfolding of its nucleotide exchange factor. J. Mol. Biol. 358, 1367–1377.10.1016/j.jmb.2006.03.027Search in Google Scholar PubMed

Moro, F., Sirrenberg, C., Schneider, H.C., Neupert, W., and Brunner, M. (1999). The TIM17.23 preprotein translocase of mitochondria: composition and function in protein transport into the matrix. EMBO J. 18, 3667–3675.10.1093/emboj/18.13.3667Search in Google Scholar PubMed PubMed Central

Neupert, W. (2015). A perspective on transport of proteins into mitochondria: a myriad of open questions. J. Mol. Biol. 427, 1135–1158.10.1016/j.jmb.2015.02.001Search in Google Scholar PubMed

Neupert, W. and Brunner, M. (2002). The protein import motor of mitochondria. Nat. Rev. Mol. Cell. Biol. 3, 555–565.10.1038/nrm878Search in Google Scholar PubMed

Nunnari, J. and Suomalainen, A. (2012). Mitochondria: in sickness and in health. Cell 148, 1145–1159.10.1016/j.cell.2012.02.035Search in Google Scholar PubMed PubMed Central

Okamoto, K., Brinker, A., Paschen, S.A., Moarefi, I., Hayer-Hartl, M., Neupert, W., and Brunner, M. (2002). The protein import motor of mitochondria: a targeted molecular ratchet driving unfolding and translocation. EMBO J. 21, 3659–3671.10.1093/emboj/cdf358Search in Google Scholar PubMed PubMed Central

Pais, J.E., Schilke, B., and Craig, E.A. (2011). Reevaluation of the role of the Pam18:Pam16 interaction in translocation of proteins by the mitochondrial Hsp70-based import motor. Mol. Biol. Cell 22, 4740–4749.10.1091/mbc.e11-08-0715Search in Google Scholar

Pavlov, P.F. and Glaser, E. (2002). Probing the membrane topology of a subunit of the mitochondrial protein translocase, Tim44, with biotin maleimide. Biochem. Biophys. Res. Commun. 293, 321–326.10.1016/S0006-291X(02)00221-8Search in Google Scholar

Popov-Celeketic, D., Waegemann, K., Mapa, K., Neupert, W., and Mokranjac, D. (2011). Role of the import motor in insertion of transmembrane segments by the mitochondrial TIM23 complex. EMBO Rep. 12, 542–548.10.1038/embor.2011.72Search in Google Scholar

Rassow, J., Maarse, A.C., Krainer, E., Kubrich, M., Muller, H., Meijer, M., Craig, E.A., and Pfanner, N. (1994). Mitochondrial protein import: biochemical and genetic evidence for interaction of matrix Hsp70 and the inner membrane protein MIM44. J. Cell Biol. 127, 1547–1556.10.1083/jcb.127.6.1547Search in Google Scholar

Rosenzweig, R., Nillegoda, N.B., Mayer, M.P., and Bukau, B. (2019). The Hsp70 chaperone network. Nat. Rev. Mol. Cell. Biol. 20, 665–680.10.1038/s41580-019-0133-3Search in Google Scholar

Rowley, N., Prip-Buus, C., Westermann, B., Brown, C., Schwarz, E., Barrell, B., and Neupert, W. (1994). Mdj1p, a novel chaperone of the DnaJ family, is involved in mitochondrial biogenesis and protein folding. Cell 77, 249–259.10.1016/0092-8674(94)90317-4Search in Google Scholar

Sanjuan Szklarz, L.K., Guiard, B., Rissler, M., Wiedemann, N., Kozjak, V., van der Laan, M., Lohaus, C., Marcus, K., Meyer, H.E., Chacinska, A., et al. (2005). Inactivation of the mitochondrial heat shock protein zim17 leads to aggregation of matrix Hsp70s followed by pleiotropic effects on morphology and protein biogenesis. J. Mol. Biol. 351, 206–218.10.1016/j.jmb.2005.05.068Search in Google Scholar PubMed

Sato, T.K., Kawano, S., and Endo, T. (2019). Role of the membrane potential in mitochondrial protein unfolding and import. Sci. Rep. 9, 7637.10.1038/s41598-019-44152-zSearch in Google Scholar PubMed PubMed Central

Schendzielorz, A.B., Schulz, C., Lytovchenko, O., Clancy, A., Guiard, B., Ieva, R., van der Lann, M., and Rehling, P. (2017). Two distinct membrane potential-dependent steps drive mitochondrial matrix protein translocation. J. Cell Biol. 216, 83–92.10.1083/jcb.201607066Search in Google Scholar PubMed PubMed Central

Schendzielorz, A.B., Bragoszewski, P., Naumenko, N., Gomkale, R., Schulz, C., Guiard, B., Chacinska, A., and Rehling, P. (2018). Motor recruitment to the TIM23 channel’s lateral gate restricts polypeptide release into the inner membrane. Nat. Commun. 9, 4028.10.1038/s41467-018-06492-8Search in Google Scholar PubMed PubMed Central

Scherer, P.E., Manning-Krieg, U.C., Jeno, P., Schatz, G., and Horst, M. (1992). Identification of a 45-kDa protein at the protein import site of the yeast mitochondrial inner membrane. Proc. Natl. Acad. Sci. USA 89, 11930–11934.10.1073/pnas.89.24.11930Search in Google Scholar PubMed PubMed Central

Schilke, B.A., Hayashi, M., and Craig, E.A. (2012). Genetic analysis of complex interactions among components of the mitochondrial import motor and translocon in Saccharomyces cerevisiae. Genetics 190, 1341–1353.10.1534/genetics.112.138743Search in Google Scholar PubMed PubMed Central

Schiller, D., Cheng, Y.C., Liu, Q., Walter, W., and Craig, E.A. (2008). Residues of Tim44 involved in both association with the translocon of the inner mitochondrial membrane and regulation of mtHsp70 tethering. Mol. Cell. Biol. 28, 4424–4433.10.1128/MCB.00007-08Search in Google Scholar PubMed PubMed Central

Schneider, H.C., Berthold, J., Bauer, M.F., Dietmeier, K., Guiard, B., Brunner, M., and Neupert, W. (1994). Mitochondrial Hsp70/MIM44 complex facilitates protein import. Nature 371, 768–774.10.1038/371768a0Search in Google Scholar PubMed

Schneider, H.C., Westermann, B., Neupert, W., and Brunner, M. (1996). The nucleotide exchange factor MGE exerts a key function in the ATP-dependent cycle of mt-Hsp70–Tim44 interaction driving mitochondrial protein import. EMBO J. 15, 5796–5803.10.1002/j.1460-2075.1996.tb00966.xSearch in Google Scholar

Schulz, C. and Rehling, P. (2014). Remodelling of the active presequence transloase drives motor-dependent mitochondrial protein translocation. Nat. Commun. 5, 4349.10.1038/ncomms5349Search in Google Scholar PubMed

Schulz, C., Schendzielorz, A., and Rehling, P. (2015). Unlocking the presequence import pathway. Trends Cell. Biol. 25, 265–275.10.1016/j.tcb.2014.12.001Search in Google Scholar PubMed

Sichting, M., Mokranjac, D., Azem, A., Neupert, W., and Hell, K. (2005). Maintenance of structure and function of mitochondrial Hsp70 chaperones requires the chaperone Hep1. EMBO J. 24, 1046–1056.10.1038/sj.emboj.7600580Search in Google Scholar PubMed PubMed Central

Sikor, M., Mapa, K., von Voithenberg, L.V., Mokranjac, D., and Lamb, D.C. (2013). Real-time observation of the conformational dynamics of mitochondrial Hsp70 by spFRET. EMBO J. 32, 1639–1649.10.1038/emboj.2013.89Search in Google Scholar PubMed PubMed Central

Slutsky-Leiderman, O., Marom, M., Iosefson, O., Levy, R., Maoz, S., and Azem, A. (2007). The interplay between components of the mitochondrial protein translocation motor studied using purified components. J. Biol. Chem. 282, 33935–33942.10.1074/jbc.M704435200Search in Google Scholar PubMed

Ting, S.Y., Schilke, B.A., Hayashi, M., and Craig, E.A. (2014). Architecture of the TIM23 inner mitochondrial translocon and interactions with the matrix import motor. J. Biol. Chem. 289, 28689–28696.10.1074/jbc.M114.588152Search in Google Scholar PubMed PubMed Central

Ting, S.Y., Yan, N.L., Schilke, B.A., and Craig, E.A. (2017). Dual interaction of scaffold protein Tim44 of mitochondrial import motor with channel-forming translocase subunit Tim23. eLife 6, e23609.10.7554/eLife.23609.019Search in Google Scholar

Truscott, K.N., Voos, W., Frazier, A.E., Lind, M., Li, Y., Geissler, A., Dudek, J., Muller, H., Sickmann, A., Meyer, H.E., et al. (2003). A J-protein is an essential subunit of the presequence translocase-associated protein import motor of mitochondria. J. Cell Biol. 163, 707–713.10.1083/jcb.200308004Search in Google Scholar

Tucker, K. and Park, E. (2019). Cryo-EM structure of the mitochondrial protein–import channel TOM complex at near-atomic resolution. Nat. Struct. Mol. Biol. 26, 1158–1166.10.1038/s41594-019-0339-2Search in Google Scholar

Vogtle, F.N., Wortelkamp, S., Zahedi, R.P., Becker, D., Leidhold, C., Gevaert, K., Kellermann, J., Voos, W., Sickmann, A., Pfanner, N., et al. (2009). Global analysis of the mitochondrial N-proteome identifies a processing peptidase critical for protein stability. Cell 139, 428–439.10.1016/j.cell.2009.07.045Search in Google Scholar

Voisine, C., Craig, E.A., Zufall, N., von Ahsen, O., Pfanner, N., and Voos, W. (1999). The protein import motor of mitochondria: unfolding and trapping of preproteins are distinct and separable functions of matrix Hsp70. Cell 97, 565–574.10.1016/S0092-8674(00)80768-0Search in Google Scholar

von Ahsen, O., Voos, W., Henninger, H., and Pfanner, N. (1995). The mitochondrial protein import machinery. Role of ATP in dissociation of the Hsp70.Mim44 complex. J. Biol. Chem. 270, 29848–29853.10.1074/jbc.270.50.29848Search in Google Scholar PubMed

Westermann, B. and Neupert, W. (1997). Mdj2p, a novel DnaJ homolog in the mitochondrial inner membrane of the yeast Saccharomyces cerevisiae. J. Mol. Biol. 272, 477–483.10.1006/jmbi.1997.1267Search in Google Scholar PubMed

Westermann, B., Prip-Buus, C., Neupert, W., and Schwarz, E. (1995). The role of the GrpE homologue, Mge1p, in mediating protein import and protein folding in mitochondria. EMBO J. 14, 3452–3460.10.1002/j.1460-2075.1995.tb07351.xSearch in Google Scholar PubMed PubMed Central

Wiedemann, N. and Pfanner, N. (2017). Mitochondrial machineries for protein import and assembly. Annu. Rev. Biochem. 86, 685–714.10.1146/annurev-biochem-060815-014352Search in Google Scholar PubMed

Yamano, K., Kuroyanagi-Hasegawa, M., Esaki, M., Yokota, M., and Endo, T. (2008). Step-size analyses of the mitochondrial Hsp70 import motor reveal the Brownian ratchet in operation. J. Biol. Chem. 283, 27325–27332.10.1074/jbc.M805249200Search in Google Scholar PubMed

Received: 2020-01-07
Accepted: 2020-02-25
Published Online: 2020-03-13
Published in Print: 2020-05-26

©2020 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 27.2.2024 from https://www.degruyter.com/document/doi/10.1515/hsz-2020-0106/html
Scroll to top button