Roles of Tom70 in Import of Presequence-containing Mitochondrial Proteins
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Mitochondrial protein traffic requires precise recognition of the mitochondrial targeting signals by the import receptors on the mitochondrial surface including a general import receptor Tom20 and a receptor for presequence-less proteins, Tom70. Here we took a proteome-wide approach of mitochondrial protein import in vitro to find a set of presequence-containing precursor proteins for recognition by Tom70. The presequences of the Tom70-dependent precursor proteins were recognized by Tom20, whereas their mature parts exhibited Tom70-dependent import when attached to the presequence of Tom70-independent precursor proteins. The mature parts of the Tom70-dependent precursor proteins have the propensity to aggregate, and the presence of the receptor domain of Tom70 prevents their aggregate formation. Therefore Tom70 plays the role of a docking site for not only cytosolic chaperones but also aggregate-prone substrates to maintain their solubility for efficient transfer to downstream components of the mitochondrial import machineries.
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Mature protein substrates of Tom70 were observed to be aggregate-prone in the absence of Tom70.
“Indeed, mature protein substrates of Tom70 were observed to be aggregate-prone in the absence of Tom70, suggesting a crucial role of Tom70 in preventing aggregation (69).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [69]
Tom70 has a crucial role in preventing aggregation.
“Indeed, mature protein substrates of Tom70 were observed to be aggregate-prone in the absence of Tom70, suggesting a crucial role of Tom70 in preventing aggregation (69).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [69]
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Dynamic organization of the mitochondrial protein import machinery
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Cooperation of protein machineries in mitochondrial protein sorting.
Wenz, L.-S., Opaliński, Ł., Wiedemann, N., & Becker, T. (2015) · Biochimica et Biophysica Acta · doi:10.1016/j.bbamcr.2015.01.012 · Cited by 32 · see citing works
Giri, J., Srivastav, S., Basu, M., Palit, S., Gupta, P., & Ukil, A. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.672873 · Cited by 31
“Because TOM70 is important for mitochondrial translocation of proteins (40), we next examined the involvement of TOM70 in the mitochondrial import of MCL-1.”
BackgroundThe protein chaperone Ssa1 affects mRNA localization to the mitochondria
Eliyahu, E., Lesnik, C., & Arava, Y. (2012) · FEBS Letters · doi:10.1016/j.febslet.2011.11.025 · Cited by 31
Role of the Mitochondrial Protein Import Machinery and Protein Processing in Heart Disease
Zhao, F., & Zou, M.-H. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.749756 · Cited by 28 · see citing works
Boos, F., Mühlhaus, T., & Herrmann, J. M. (2018) · Bio-protocol · doi:10.21769/bioprotoc.2474 · Cited by 28 · see citing works
“Obviously, mature parts of proteins are critical for the translocation efficiency in vivo (Yamamoto et al., 2009; Chatzi et al., 2017; Backes et al., 2018).”
BackgroundLiu, Q., Fong, B., Yoo, S., Unruh, J., Guo, F.-L., Yu, Z.-L., Chen, J.-J., Si, K., Li, R., & Zhou, C. (2023) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2300475120 · Cited by 23 · see citing works
“Indeed, ∆tom70 also only partially blocks the mitochondrial import of its substrates (34, 35).”
BackgroundMethodInfluentialThe selectivity filter of the mitochondrial protein import machinery
Kreimendahl, S., Schwichtenberg, J., Günnewig, K., Brandherm, L., & Rassow, J. (2020) · BMC Biology · doi:10.1186/s12915-020-00888-z · Cited by 22
iMLP, a predictor for internal matrix targeting-like sequences in mitochondrial proteins
Schneider, K., Zimmer, D., Nielsen, H., Herrmann, J. M., & Mühlhaus, T. (2021) · Biological chemistry · doi:10.1515/hsz-2021-0185 · Cited by 19 · see citing works
“…Tom70 is particularly relevant for aggregation-prone or hydrophobic proteins and cooperative binding of several Tom70 receptors to one precursor might support the unfolding and import of precursor proteins (Backes et al. 2020; Backes and Herrmann 2017; Brix et al. 1999, 2000; Yamamoto et al. 2009).”
BackgroundNargang, F., Adames, K., Rüb, C., Cheung, S., Easton, N., Nargang, C., & Chae, M. S. (2012) · G3: Genes, Genomes, Genetics · doi:10.1534/g3.112.004218 · Cited by 19 · see citing works
“However, the mature portions of these precursor proteins were prone to aggregation, which could be prevented by association with Tom70 (Yamamoto et al. 2009).”
Protein Quality Control at the Mitochondrial Surface
den Brave, F., Gupta, A., & Becker, T. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.795685 · Cited by 18 · see citing works
“Tom70 was previously thought to function as a receptor for integral membrane proteins, but several studies demonstrated that this receptor is also involved in the import of several presequence-containing proteins that contain internal mitochondrial targeting sequences (Hines et al., 1990; Brix et al., 1997; Young et a…”
BackgroundThe structure of the TOM core complex in the mitochondrial outer membrane
Bausewein, T., Naveed, H., Liang, J., & Nussberger, S. (2020) · Biological chemistry · doi:10.1515/hsz-2020-0104 · Cited by 17 · see citing works
Porins as helpers in mitochondrial protein translocation
Grevel, A., & Becker, T. (2019) · Biological chemistry · doi:10.1515/hsz-2019-0438 · Cited by 17 · see citing works
Rödl, S., Hoffman, Y., Jung, F., Egeler, A., Nutz, A., Šimončík, O., Jung, M., Räschle, M., Muller, P., Storchová, Z., et al. (2025) · PLoS Biology · doi:10.1371/journal.pbio.3003298 · Cited by 16 · see citing works
“It was shown that longer presequences can contain segments that facilitate the binding to TOM receptors to increase the import efficiency [35,62,67,69,70].”
Crosstalk between Mitochondrial Protein Import and Lipids
Hoffmann, J. J., & Becker, T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095274 · Cited by 16 · see citing works
The structural plasticity of Tom71 for mitochondrial precursor translocations.
Li, J.-Z., Cui, W., & Sha, B. (2010) · Acta Crystallographica. Section F : Structural Biology and Crystallization Communications · doi:10.1107/s1744309110025522 · Cited by 15
“Firstly, Tom70/Tom71 has various precursor substrates and is involved in the translocation of all precursors with internal mitochondrial targeting signals and N-terminal pre-sequences (Yamamoto et al., 2009; Brix et al., 2000).”
BackgroundFidelity of organellar protein targeting.
Song, J., & Becker, T. (2022) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2022.02.005 · Cited by 14
Human mitochondrial import receptor Tom70 functions as a monomer.
Fan, A., Gava, L., Ramos, C. H., & Young, J. (2010) · Biochemical Journal · doi:10.1042/bj20091855 · Cited by 14 · see citing works
Wilson, B., Cruz-Díaz, N., Su, Y.-X., Rose, J., Gwathmey, T., & Chappell, M. (2017) · AJP - Renal Physiology · doi:10.1152/ajprenal.00246.2016 · Cited by 13 · see citing works
Failure to Guard: Mitochondrial Protein Quality Control in Cancer
Friedlander, J. E., Shen, N., Zeng, A., Korm, S., & Feng, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158306 · Cited by 11 · see citing works
Reed, A. L., Mitchell, W., Alexandrescu, A. T., & Alder, N. N. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1263420 · Cited by 13 · see citing works
“…Tom70, and Tom22 all have receptor domains containing tetratricopeptide repeat (TPR) motifs that mediate protein interactions (Zeytuni and Zarivach, 2012) and appear to have general protein chaperone function in addition to acting as precursor receptors (Yano et al., 2004; Yamamoto et al., 2009).”
Role of Hsp70 in Post-Translational Protein Targeting: Tail-Anchored Membrane Proteins and Beyond
Shan, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021170 · Cited by 9 · see citing works
MitoStores: stress-induced aggregation of mitochondrial proteins
Kaushik, P., Herrmann, J. M., & Hansen, K. G. (2025) · Biological chemistry · doi:10.1515/hsz-2024-0148 · Cited by 8 · see citing works
“In a cooperative activity, Hsp70, Hsp90 and Tom70 thereby promote the localunfoldingofprecursorsonthesurfaceinordertopromote their translocation through the protein-conducting channel of the TOM complex (Brix et al. 2000; Faou and Hoogenraad 2012; Yamamoto et al. 2009).”
Quality control of un-imported mitochondrial proteins at a glance.
Balzarini, M., Kim, J., & Weidberg, H. (2025) · Journal of Cell Science · doi:10.1242/jcs.263757 · Cited by 7 · see citing works
Insight into the Interactome of Intramitochondrial PKA Using Biotinylation-Proximity Labeling
Amer, Y. O., & Hébert-Chatelain, É. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218283 · Cited by 9 · see citing works
“As shown in Figure 1F, the OMM protein MFN2 and the IMM protein ATP5a were dose-dependently released in the supernatant after treatment with digitonin.”
BackgroundInfluentialEscorted by chaperones: Sti1 helps to usher precursor proteins from the ribosome to mitochondria
Hansen, K. G., Schlagowski, A. M., & Herrmann, J. M. (2016) · The FEBS Journal · doi:10.1111/febs.13821 · Cited by 7
Mitochondrial biogenesis: sorting mechanisms cooperate in ABC transporter assembly.
Webb, C., & Lithgow, T. (2010) · Current Biology · doi:10.1016/j.cub.2010.05.024 · Cited by 7
Biogenesis of Lipids and Proteins within Mitochondrial Membranes
Alder, N. N. (2011) · CRC Press eBooks · doi:10.1201/b11018-15 · Cited by 4 · see citing works
Mitochondrial presequences are more than just address labels
Heller, E. M., Lenhard, S., Rapaport, D., & Herrmann, J. (2026) · Protein Science · doi:10.1002/pro.70491 · Cited by 5 · see citing works
“…TOMM34/Cns1) presumably directs precursors to Tom70 on the mitochondrial surface to promote their unfolding and efficient translocation into mitochondria (Backes et al., 2018; Backes et al., 2021; Koch et al., 2024; Komiya et al., 1997; Rödl et al., 2025; Yamamoto et al., 2009; Young et al., 2003).”
Molecular Insights into Mitochondrial Protein Translocation and Human Disease
Ruiz-Pesini, E., Montoya, J., & Pacheu-Grau, D. (2021) · Genes · doi:10.3390/genes12071031 · Cited by 5 · see citing works
The mitochondrial surface receptor Tom70 protects the cytosol against mitoprotein-induced stress
Backes, S., Bykov, Y., Räschle, M., Zhou, J., Lenhard, S., Krämer, L., Mühlhaus, T., Chen, B.-B., Jann, C., Smith, J. D., et al. (2020) · bioRxiv · doi:10.1101/2020.09.14.296194 · Cited by 5
Akram, S., Zittlau, K. I., Sharma, K., Fitzgerald, J. C., Rafiq, N., Maček, B., & Jansen, R.-P. (2025) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5c00905 · Cited by 4 · see citing works
Akram, S., Zittlau, K. I., Maček, B., & Jansen, R.-P. (2024) · bioRxiv · doi:10.1101/2024.10.25.620316 · Cited by 4 · see citing works
“TOMM20 and TOMM70 recognize the targeting signals but differ in their substrate specificity, although overlap can be observed 2,3 .”
BackgroundResultA quantitative fluorescence‐based approach to study mitochondrial protein import
Jain, N., Gomkale, R., Bernhard, O., Rehling, P., & Cruz-Zaragoza, L. D. (2022) · bioRxiv · doi:10.15252/embr.202255760 · Cited by 4
“…alpha helices, which are recognized by receptors in the TOM and TIM23 complex (Roise et al , 1986; Brix et al , 1997; Geissler et al , 2002; Neupert & Herrmann, 2007; Yamano et al , 2008; Chacinska et al , 2009; Vo¨gtle et al , 2009; Yamamoto et al , 2009; Schulz et al , 2011; Araiso et al , 2022).”
BackgroundMpf1 affects the dual distribution of tail-anchored proteins between mitochondria and peroxisomes
Aravindan, N., Vitali, D. G., Breuer, J., Oberst, J., Zalckvar, E., Schuldiner, M., & Rapaport, D. (2025) · EMBO Reports · doi:10.1038/s44319-025-00440-6 · Cited by 3 · see citing works
“EV2), which is not surprising considering the functions of Tom70 as an important mitochondrial import receptor and a docking site for cytosolic chaperones (Backes et al, 2021; Kreimendahl and Rassow, 2020; Yamamoto et al, 2009; Young et al, 2003).”
The role of mitochondrial RNA association for mitochondrial homeostasis in neurons
Segura, I., & Harbauer, A. (2024) · Biochemical Journal · doi:10.1042/bcj20230110 · Cited by 3 · see citing works
Accessory signals in protein translocation
Hansen, K. G., Boos, F., & Herrmann, J. M. (2018) · Aging · doi:10.18632/aging.101435 · Cited by 2
Lapointe, C. P., Stefely, J. A., Jochem, A., Hutchins, P. D., Wilson, G., Kwiecien, N. W., Coon, J., Wickens, M., & Pagliarini, D. (2017) · bioRxiv · doi:10.1101/146985 · Cited by 2
A dynamic displacement mechanism drives protein import into mitochondria
Sučec, I., Guillerm, U., Schneider, J., Ganesan, I., Webling, N., Kapitonova, A., Steiert, C., Schmelter, F., Feignier, A., Singh, R., et al. (2026) · bioRxiv · doi:10.64898/2026.01.14.699430 · Cited by 1
Rödl, S., Hoffman, Y., Jung, F., Nutz, A., Egeler, A., Räschle, M., Storchová, Z., Mühlhaus, T., & Herrmann, J. M. (2024) · bioRxiv · doi:10.1101/2024.06.27.600981 · Cited by 1
“It was shown that longer presequences can contain segments that facilitate the binding to TOM receptors to increase the import efficiency (34, 57, 59-61).”
BackgroundAravindan, N., Vitali, D. G., Oberst, J., Zalckvar, E., Schuldiner, M., & Rapaport, D. (2024) · bioRxiv · doi:10.1101/2024.04.30.591829 · Cited by 1
“…mitochondrial morphology in tom70∆ cells (Figure S2), which is not surprising considering the functions of Tom70 as an important mitochondrial import receptor and a docking site for cytosolic chaperones (Backes et al., 2021; Kreimendahl & Rassow, 2020; Yamamoto et al., 2009; Young et al., 2003).”
BackgroundMitochondrial Origin of Cytosolic Protein AggregationPreprint
Liu, Q., Fong, B., Unruh, J., Guo, F.-L., Si, K., Li, R., & Zhou, C. (2021) · Social Science Research Network · doi:10.2139/ssrn.3808300 · Cited by 1 · see citing works
Tachezy, J., & Doležal, P. (2011) · Springer eBooks · doi:10.1007/978-3-7091-0198-8_11 · Cited by 1 · see citing works
Ribosome-Associated GTPase Drg1 Links Cytosolic Translation to Mitochondrial HomeostasisPreprint
Saha, S., Bhattacharya, A., & Jin, H. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.23.707305 · Cited by 1 · see citing works
“Such spatial coupling could reduce the exposure of aggregation-prone precursors in the cytosol and coordinate protein synthesis with mitochondrial import capacity (den Brave et al., 2021; Yamamoto et al., 2009).”
Regulation of cellular proteostasis via mitochondrial protein import
Nguyen, N. G. T., & Li, J. (2026) · Philosophical transactions of the Royal Society of London. Series B, Biological sciences · doi:10.1098/rstb.2025.0271
“Consistent with this, Tom70 also facilitates the transport of presequence-containing proteins recognized by Tom20 but containing aggregation-prone mature domains [30 ].”
Presequences of non-imported mitochondrial proteins serve as quality control elements in the cytosol
Lenhard, S., Nutz, A., Göktas, G., Bykov, Y., Räschle, M., & Herrmann, J. M. (2026) · bioRxiv · doi:10.64898/2026.08.13.744608
“…sequences can contain binding sites for cytosolic cochaperones of the Hsp90 system and for Tom70 to support the local unfolding of precursor proteins on the TOM pore (Backes et al., 2021, Faou & Hoogenraad, 2012, Rödl et al., 2025, Stan et al., 2000, Yamamoto et al., 2009, Young et al., 2003).”
- Authors
- Yamamoto, H., Fukui, K., Takahashi, H., Kitamura, S., Shiota, T., Terao, K., Uchida, M., Esaki, M., Nishikawa, S.-I., Yoshihisa, T., Yamano, K., & Endo, T.
- Affiliations
- Japan Science and Technology Agency (JP)
- Corresponding author
- Endo, Toshiya
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 284
- Issue
- 46
- Pages
- 31635-31646
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2797234
- OpenAlex
- W2050343565
- Cited by
- 119
- References
- 31
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 5 · 2023: 7 · 2022: 8 · 2021: 17 · 2020: 18 · 2019: 6 · 2018: 3 · 2017: 3 · 2016: 7 · 2015: 5 · 2013: 2 · 2012: 5
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Uehara Memorial Foundation
- Japan Society for the Promotion of Science (19058005)
- Japan Science and Technology Agency
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Tom70, Tom20, mitochondrial protein import, mitochondrial targeting signal, protein aggregation, cytosolic chaperones, precursor protein, mitochondrial import machinery
- MeSH terms
- Mitochondrial Precursor Protein Import Complex Proteins, Mitochondria, Protein Precursors, RNA, Fungal, Saccharomyces cerevisiae, Electrophoresis, Gel, Two-Dimensional, Molecular Chaperones, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Proteome, Mitochondrial Proteins, Saccharomyces cerevisiae Proteins, Mitochondrial Membrane Transport Proteins
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