Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Quality control of the mitochondrial proteome

Nature Reviews Molecular Cell Biology volume 22, pages 54–70 (2021)Cite this article

Subjects

Abstract

Mitochondria contain about 1,000–1,500 proteins that fulfil multiple functions. Mitochondrial proteins originate from two genomes: mitochondrial and nuclear. Hence, proper mitochondrial function requires synchronization of gene expression in the nucleus and in mitochondria and necessitates efficient import of mitochondrial proteins into the organelle from the cytosol. Furthermore, the mitochondrial proteome displays high plasticity to allow the adaptation of mitochondrial function to cellular requirements. Maintenance of this complex and adaptable mitochondrial proteome is challenging, but is of crucial importance to cell function. Defects in mitochondrial proteostasis lead to proteotoxic insults and eventually cell death. Different quality control systems monitor the mitochondrial proteome. The cytosolic ubiquitin–proteasome system controls protein transport across the mitochondrial outer membrane and removes damaged or mislocalized proteins. Concomitantly, a number of mitochondrial chaperones and proteases govern protein folding and degrade damaged proteins inside mitochondria. The quality control factors also regulate processing and turnover of native proteins to control protein import, mitochondrial metabolism, signalling cascades, mitochondrial dynamics and lipid biogenesis, further ensuring proper function of mitochondria. Thus, mitochondrial protein quality control mechanisms are of pivotal importance to integrate mitochondria into the cellular environment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Quality control mechanisms of mitochondrial protein biogenesis.
Fig. 2: Quality control at the protein entry gate of mitochondria.
Fig. 3: Stress response pathways on impaired mitochondrial protein import.
Fig. 4: Degradation of proteins at the OMM.
Fig. 5: Protein quality control in inner mitochondrial compartments.

Similar content being viewed by others

References

  1. Zimorski, V., Ku, C., Martin, W. F. & Gould, S. B. Endosymbiotic theory for organelle origins. Curr. Opin. Microbiol. 22, 38–48 (2014).

    CAS  PubMed  Google Scholar 

  2. Roger, A. J., Muñoz-Gómez, S. A. & Kamikawa, R. The origin and diversification of mitochondria. Curr. Biol. 27, R1177–R1192 (2017).

    CAS  PubMed  Google Scholar 

  3. Pagliarini, D. J. et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112–123 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Morgenstern, M. et al. Definition of a high-confidence mitochondrial proteome at quantitative scale. Cell Rep. 19, 2836–2852 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Pfanner, N., Warscheid, B. & Wiedemann, N. Mitochondrial proteins: from biogenesis to functional networks. Nat. Rev. Mol. Cell Biol. 20, 267–284 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Prinz, W. A., Toulmay, A. & Balla, T. The functional universe of contact sites. Nat. Rev. Mol. Cell Biol. 21, 7–24 (2020).

    CAS  PubMed  Google Scholar 

  7. Giacomello, M., Pyakurel, A., Glytsou, C. & Scorrano, L. The cell biology of mitochondrial membrane dynamics. Nat. Rev. Mol. Cell Biol. 21, 204–224 (2020).

    CAS  PubMed  Google Scholar 

  8. Endo, T., Yamano, K. & Kawano, S. Structural insight into the mitochondrial protein import system. Biochim. Biophys. Acta 1808, 955–970 (2011).

    CAS  PubMed  Google Scholar 

  9. Couvillion, M. T., Soto, I. C., Shipkovenska, G. & Churchman, L. S. Synchronized mitochondrial and cytosolic translation programs. Nature 533, 499–503 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Suhm, T. et al. Mitochondrial translation efficiency controls cytoplasmic protein homeostasis. Cell Metab. 27, 1309–1322 (2018).

    CAS  PubMed  Google Scholar 

  11. Herrmann, J. M., Woellhaf, M. W. & Bonnefoy, N. Control of protein synthesis in yeast mitochondria: the concept of translational activators. Biochim. Biophys. Acta 1833, 286–294 (2013).

    CAS  PubMed  Google Scholar 

  12. Ott, M., Amunts, A. & Brown, A. Organization and regulation of mitochondrial protein synthesis. Annu. Rev. Biochem. 85, 77–101 (2016).

    CAS  PubMed  Google Scholar 

  13. Priesnitz, C. & Becker, T. Pathways to balance mitochondrial translation and protein import. Genes Dev. 32, 1285–1296 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bragoszewski, P., Turek, M. & Chacinska, A. Control of mitochondrial biogenesis and function by the ubiquitin-proteasome system. Open Biol. 7, 170007 (2017).

    PubMed  PubMed Central  Google Scholar 

  15. Clague, M. J., Urbé, S. & Komander, D. Breaking the chains: deubiquitylating enzyme specificity begets function. Nat. Rev. Mol. Cell Biol. 20, 338–352 (2019).

    CAS  PubMed  Google Scholar 

  16. Pickles, S., Vigié, P. & Youle, R. J. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr. Biol. 28, 170–185 (2018).

    Google Scholar 

  17. Wang, X. & Chen, X. J. A cytosolic network suppressing mitochondria-mediated proteostatic stress and cell death. Nature 524, 481–484 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wrobel, L. et al. Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature 524, 485–488 (2015). Together with reference 17, this study shows that impaired protein import into mitochondria leads to increased activity of proteasomes and altered cytosolic protein biosynthesis.

    CAS  PubMed  Google Scholar 

  19. Araiso, Y. et al. Structure of the mitochondrial import gate reveals distinct preprotein paths. Nature 575, 395–401 (2019).

    CAS  PubMed  Google Scholar 

  20. Tucker, K. & Park, E. Cryo-EM structure of the mitochondrial protein-import channel TOM complex at near-atomic resolution. Nat. Struct. Mol. Biol. 26, 1158–1166 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Bausewein, T. et al. Cryo-EM structure of the TOM core complex from Neurospora crassa. Cell 170, 693–700 (2017). Together with references 19 and 20, this article reports the first high-resolution structures of the TOM complex.

    CAS  PubMed  Google Scholar 

  22. Vögtle, N. et al. Global analysis of the mitochondrial N-proteome identifies a processing peptidase critical for protein stability. Cell 139, 428–439 (2009).

    PubMed  Google Scholar 

  23. Westermann, B., Gaume, B., Herrmann, J. M., Neupert, W. & Schwarz, E. Role of the mitochondrial DnaJ homolog Mdj1p as a chaperone for mitochondrially synthesized and imported proteins. Mol. Cell. Biol. 16, 7063–7071 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Horst, M. et al. Sequential action of two hsp70 complexes during protein import into mitochondria. EMBO J. 16, 1842–1849 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Craig, E. A., Kramer, J. & Kosic-Smithers, J. SSC1, a member of the 70-kDa heat shock protein multigene family of Saccharomyces cerevisiae, is essential for growth. Proc. Natl Acad. Sci. USA 84, 4156–4160 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Ostermann, J., Horwich, A. L., Neupert, W. & Hartl, F. U. Protein folding in mitochondria requires complex formation with hsp60 and ATP hydrolysis. Nature 341, 125–130 (1989).

    CAS  PubMed  Google Scholar 

  27. Böttinger, L. et al. A complex of Cox4 and mitochondrial Hsp70 plays an important role in the assembly of the cytochrome c oxidase. Mol. Biol. Cell 24, 2609–2619 (2013).

    PubMed  PubMed Central  Google Scholar 

  28. Böttinger, L. et al. The mitochondrial heat shock protein 70 (Hsp70) and Hsp10 cooperate in the formation of Hsp60 complexes. J. Biol. Chem. 290, 11611–11622 (2015).

    Google Scholar 

  29. Schmitt, M., Neupert, W. & Langer, T. Hsp78, a Clp homologue within mitochondria, can substitute for chaperone functions of mt-Hsp70. EMBO J. 14, 3434–3444 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Moczko, M., Schönfisch, B., Voos, W., Pfanner, N. & Rassow, J. The mitochondrial ClpB homolog Hsp78 cooperates with matrix Hsp70 in maintenance of mitochondrial function. J. Mol. Biol. 254, 538–543 (1995).

    CAS  PubMed  Google Scholar 

  31. Röttgers, K., Zufall, N., Guiard, B. & Voos, W. The ClpB homolog Hsp78 is required for the efficient degradation of proteins in the mitochondrial matrix. J. Biol. Chem. 277, 45829–45837 (2002).

    PubMed  Google Scholar 

  32. Bateman, J. M., Iacovino, M., Perlman, P. S. & Butow, R. A. Mitochondrial DNA instability mutants of the bifunctional protein Ilv5p altered organization in mitochondria and are targeted for degradation by Hsp78 and the Pim1p protease. J. Biol. Chem. 277, 47946–47953 (2002).

    CAS  PubMed  Google Scholar 

  33. Becker, T., Song, J. & Pfanner, N. Versatility of preprotein transfer from the cytosol to mitochondria. Trends Cell Biol. 29, 534–548 (2019).

    CAS  PubMed  Google Scholar 

  34. Hansen, K. G. & Herrmann, J. M. Transport of proteins into mitochondria. Protein J. 38, 330–342 (2019).

    CAS  PubMed  Google Scholar 

  35. Williams, C. C., Jan, C. H. & Weissman, J. S. Targeting and plasticity of mitochondrial proteins revealed by proximity-specific ribosome profiling. Science 346, 748–751 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Lapointe, C. P. et al. Multi-omics reveal specific targets of the RNA-binding protein Puf3 and its orchestration of mitochondrial biogenesis. Cell Syst. 6, 125–135 (2018).

    CAS  PubMed  Google Scholar 

  37. Marc, P. et al. Genome-wide analysis of mRNAs targeted to yeast mitochondria. EMBO Rep. 3, 159–164 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Eliyahu, E. et al. Tom20 mediates localization of mRNAs to mitochondria in a translation-dependent manner. Mol. Cell Biol. 30, 284–294 (2010).

    CAS  PubMed  Google Scholar 

  39. Gold, V. A., Chroscicki, P., Bragoszewski, P. & Chacinska, A. Visualization of cytosolic ribosomes on the surface of mitochondria by electron cryo-tomography. EMBO Rep. 18, 1786–1800 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. George, R., Beddoe, T., Landl, K. & Lithgow, T. The yeast nascent polypeptide-associated complex initiates protein targeting to mitochondria in vivo. Proc. Natl Acad. Sci. USA 95, 2296–2301 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Fünfschilling, U. & Rospert, S. Nascent polypeptide-associated complex stimulates protein import into yeast mitochondria. Mol. Biol. Cell 10, 3289–3299 (1999).

    PubMed  PubMed Central  Google Scholar 

  42. Lesnik, C., Cohen, Y., Atir-Lande, A., Schuldiner, M. & Arava, Y. OM14 is a mitochondrial receptor for cytosolic ribosomes that supports co-translational import into mitochondria. Nat. Commun. 5, 5711 (2014).

    CAS  PubMed  Google Scholar 

  43. Ponce-Rojas, J. C. et al. αβ′-NAC cooperates with Sam37 to mediate early stages of mitochondrial protein import. FEBS J. 284, 814–830 (2017).

    PubMed  Google Scholar 

  44. Young, J. C., Hoogenrad, N. J. & Hartl, F. U. Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import receptor Tom70. Cell 112, 41–50 (2003).

    CAS  PubMed  Google Scholar 

  45. Opaliński, Ł. et al. Recruitment of cytosolic J-proteins by TOM receptors promotes mitochondrial protein biogenesis. Cell Rep. 25, 2026–2043 (2018).

    Google Scholar 

  46. Hoseini, H. et al. The cytosolic cochaperone Sti1 is relevant for mitochondrial biogenesis and morphology. FEBS J. 283, 3338–3352 (2016).

    CAS  PubMed  Google Scholar 

  47. Brandman, O. & Hegde, R. S. Ribosome-associated protein quality control. Nat. Struct. Mol. Biol. 23, 7–15 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Joazeiro, C. A. P. Mechanisms and functions of ribosome-associated protein quality control. Nat. Rev. Mol. Cell Biol. 20, 368–383 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Hipp, M. S., Kasturi, P. & Hartl, F. U. The proteostasis network and its decline in aging. Nat. Rev. Mol. Cell Biol. 20, 421–435 (2019).

    CAS  PubMed  Google Scholar 

  50. Sheffield, W. P., Shore, G. C. & Randall, S. K. Mitochondrial precursor protein. Effects of 70-kilodalton heat shock protein on polypeptide folding, aggregation, and import competence. J. Biol. Chem. 265, 11069–11076 (1990).

    CAS  PubMed  Google Scholar 

  51. Itakura, E. et al. Ubiquilins chaperone and triage mitochondrial membrane proteins for degradation. Mol. Cell 63, 21–33 (2016). This article reports that ubiquilins link targeting and quality control of mitochondrial outer membrane proteins.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Papić, D. et al. The role of Djp1 in import of the mitochondrial protein Mim1 demonstrates specificity between a cochaperone and its substrate protein. Mol. Cell Biol. 33, 4083–4094 (2013).

    PubMed  PubMed Central  Google Scholar 

  53. Hansen, K. G. et al. An ER surface retrieval pathway safeguards the import of mitochondrial membrane proteins in yeast. Science 361, 1118–1122 (2018). This study discovers that the surface of the ER forms a platform to bind precursors of mitochondrial membrane proteins to facilitate their transport to mitochondria.

    CAS  PubMed  Google Scholar 

  54. Whiteley, A. M. et al. Ubiquilin promotes antigen-receptor mediated proliferation by eliminating mislocalized mitochondrial proteins. eLife 6, e26435 (2017).

    PubMed  PubMed Central  Google Scholar 

  55. Ko, H. S., Uehara, T. & Nomura, Y. Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death. J. Biol. Chem. 277, 35386–35392 (2002).

    CAS  PubMed  Google Scholar 

  56. Liu, Y. et al. Ubiquilin-1 protects cells from oxidative stress and ischemic stroke caused tissue injury in mice. J. Neurosci. 34, 2813–2821 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Kowalski, L. et al. Determinants of the cytosolic turnover of mitochondrial intermembrane space proteins. BMC Biol. 16, 66 (2018).

    PubMed  PubMed Central  Google Scholar 

  58. Habich, M. et al. Vectorial import via a metastable disulfide-linked complex allows for a quality control step and import by the mitochondrial disulfide relay. Cell Rep. 26, 759–774 (2019).

    CAS  PubMed  Google Scholar 

  59. Boos, F. et al. Mitochondrial protein-induced stress triggers a global adaptive transcriptional programme. Nat. Cell Biol. 21, 442–451 (2019). This study shows that clogging of the mitochondrial protein translocon leads to a massive transcription remodelling.

    CAS  PubMed  Google Scholar 

  60. Mårtensson, C. U. et al. Mitochondrial protein translocation-associated degradation. Nature 569, 679–683 (2019). In this report, the mitoTAD pathway that clears stalled precursor proteins from the TOM complex is identified.

    PubMed  Google Scholar 

  61. Wang, C.-W. & Lee, S. C. The ubiquitin-like (UBX)-domain-containing protein Ubx2/Ubxd8 regulates lipid droplet homeostasis. J. Cell Sci. 125, 2930–2939 (2012).

    CAS  PubMed  Google Scholar 

  62. Metzger, M. B., Scales, J. L., Dunklebarger, M. F., Loncarek, J. & Weissman, A. M. A protein quality control pathway at the mitochondrial outer membrane. eLife 9, e51065 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Schuberth, C. & Buchberger, A. Membrane-bound Ubx2 recruits Cdc48 to ubiquitin ligases and their substrates to ensure efficient ER-associated protein degradation. Nat. Cell Biol. 7, 999–1006 (2005).

    CAS  PubMed  Google Scholar 

  64. Neuber, O., Jarosch, E., Volkwein, C., Walter, J. & Sommer, T. Ubx2 links the Cdc48 complex to ER-associated protein degradation. Nat. Cell Biol. 7, 993–998 (2005).

    CAS  PubMed  Google Scholar 

  65. Phu, L. et al. Dynamic regulation of mitochondrial import by the ubiquitin system. Mol. Cell 77, 1107–1123 (2020). This study reports that ubiquitylation and deubiquitylation control protein entry into mitochondria.

    CAS  PubMed  Google Scholar 

  66. Ordureau, A. et al. Global landscape and dynamics of Parkin and USP30-dependent ubiquitylomes in iNeurons during mitophagic signaling. Mol. Cell 77, 1124–1142 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Weidberg, H. & Amon, A. MitoCPR — a surveillance pathway that protects mitochondria in response to protein import stress. Science 360, eaan4146 (2018). This article identifies the mitoCPR pathway, which removes translocation-arrested precursor proteins from the TOM complex.

    PubMed  PubMed Central  Google Scholar 

  68. Basch, M. et al. Msp1 cooperates with the proteasome for extraction of arrested mitochondrial import intermediates. Mol. Biol. Cell 31, 753–767 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Izawa, T. et al. Roles of Dom34:Hbs1 in nonstop protein clearance from translocators for normal organelle protein influx. Cell Rep. 2, 447–452 (2012).

    CAS  PubMed  Google Scholar 

  70. Izawa, T., Park, S.-H., Zhao, L., Hartl, F. U. & Neupert, W. Cytosolic protein Vms1 links ribosome quality control to mitochondrial and cellular homeostasis. Cell 171, 890–903 (2017). In this article, the critical role of Vms1 in the ribosome-associated quality control during protein import into mitochondria is reported.

    CAS  PubMed  Google Scholar 

  71. Sitron, C. S. & Brandman, O. CAT tails drive degradation of stalled polypeptides on and off the ribosome. Nat. Struct. Mol. Biol. 26, 450–459 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Verma, R. et al. Vms1 and ANKZF1 peptidyl-tRNA hydrolases release nascent chains from stalled ribosomes. Nature 557, 446–451 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Zurita Rendón, O. et al. Vms1p is a release factor for the ribosome-associated quality control complex. Nat. Commun. 9, 2197 (2018).

    PubMed  PubMed Central  Google Scholar 

  74. Kuroha, K., Zinoviev, A., Hellen, C. U. T. & Pestova, T. V. Release of ubiquitinated and non-ubiquitinated nascent chains from stalled mammalian ribosomal complexes by ANKZF1 and Ptrh1. Mol. Cell 72, 286–302 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Su, T. et al. Structure and function of Vms1 and Arb1 in RQC and mitochondrial proteome homeostasis. Nature 570, 538–542 (2019).

    CAS  PubMed  Google Scholar 

  76. Heo, J. M. et al. A stress-responsive system for mitochondrial protein degradation. Mol. Cell 40, 465–480 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Boos, F., Labbadia, J. & Herrmann, J. M. How the mitoprotein-induced stress response safeguards the cytosol: a unified view. Trends Cell Biol. 30, 241–254 (2020).

    CAS  PubMed  Google Scholar 

  78. Shpilka, T. & Haynes, C. M. The mitochondrial UPR: mechanisms, physiological functions and implications in aging. Nat. Rev. Mol. Cell Biol. 19, 109–120 (2018).

    CAS  PubMed  Google Scholar 

  79. Nargund, A. M., Pellegrino, M. W., Fiorese, C. J., Baker, B. M. & Haynes, C. M. Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337, 587–590 (2012). This study identifies that impaired protein import into mitochondria in C. elegans leads to nuclear localization of ATFS-1, where it induces transcription of genes involved in the mitochondrial UPRmt.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Rolland, S. G. et al. Compromised mitochondrial protein import acts as a signal for UPRmt. Cell Rep. 28, 1659–1669 (2019).

    CAS  PubMed  Google Scholar 

  81. Nargund, A. M., Fiorese, C. J., Pellegrino, M. W., Deng, P. & Haynes, C. M. Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPRmt. Mol. Cell. 58, 123–133 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Fiorese, C. J. et al. The transcription factor ATF5 mediates a mammalian mitochondrial UPR. Curr. Biol. 26, 2037–2043 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Quirós, P. M. et al. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J. Cell. Biol. 216, 2027–2045 (2017).

    PubMed  PubMed Central  Google Scholar 

  84. Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374–1395 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Guo, X. et al. Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway. Nature 579, 427–432 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Fessler, E. et al. A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol. Nature 579, 433–437 (2020). Together with reference 85,this article reports the induction of the integrated stress response by OMA1-mediated cleavage of DELE1.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Jin, S. M. et al. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J. Cell Biol. 191, 933–942 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Yamano, K. & Youle, R. J. PINK1 is degraded through the N-end rule pathway. Autophagy 9, 1758–1769 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Lazarou, M., Jin, S. M., Kane, L. A. & Youle, R. J. Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin. Dev. Cell 22, 320–333 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Kane, L. A. et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J. Cell Biol. 205, 143–153 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Liang, J. R. et al. USP30 deubiquitylates mitochondrial parkin substrates and restricts apoptotic cell death. EMBO Rep. 16, 618–627 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Bingol, B. et al. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 510, 370–375 (2014).

    CAS  PubMed  Google Scholar 

  93. Pfeffer, S., Woellhaf, M. W., Herrmann, J. M. & Förster, F. Organization of the mitochondrial translation machinery studied in situ by cryoelectron tomography. Nat. Commun. 6, 6019 (2015).

    CAS  PubMed  Google Scholar 

  94. Möller-Hergt, B. V., Carlström, A., Stephan, K., Imhof, A. & Ott, M. The ribosome receptors Mrx15 and Mba1 jointly organize cotranslational insertion and protein biogenesis in mitochondria. Mol. Biol. Cell 29, 2386–2396 (2018).

    PubMed  PubMed Central  Google Scholar 

  95. Englmeier, R., Pfeffer, S. & Förster, F. Structure of the human mitochondrial ribosome studied in situ by cryoelectron tomography. Structure 25, 1574–1581 (2017).

    CAS  PubMed  Google Scholar 

  96. Szyrach, G., Ott, M., Bonnefoy, N., Neupert, W. & Herrmann, J. M. Ribosome binding of the Oxa1 complex facilitates co-translational protein insertion in mitochondria. EMBO J. 22, 6448–6457 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Jia, L. et al. Yeast Oxa1 interacts with mitochondrial ribosomes: the importance of the C-terminal region of Oxa1. EMBO J. 22, 6438–6447 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Stiburek, L. et al. YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphology, and cell proliferation. Mol. Biol. Cell 23, 1010–1023 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Richter, U., Lahtinen, T., Marttinen, P., Suomi, F. & Battersby, B. J. Quality control of mitochondrial protein synthesis is required for membrane integrity and cell fitness. J. Cell Biol. 211, 373–389 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Hornig-Do, H. T. et al. Nonsense mutations in the COX1 subunit impair the stability of respiratory chain complexes rather than their assembly. EMBO J. 31, 1293–1307 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Nakai, T., Yasuhara, T., Fujiki, Y. & Ohashi, A. Multiple genes, including a member of the AAA family, are essential for degradation of unassembled subunit 2 of cytochrome c oxidase in yeast mitochondria. Mol. Cell Biol. 15, 4441–4452 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Leonhard, K. et al. AAA proteases with catalytic sites on opposite membrane surfaces comprise a proteolytic system for the ATP-dependent degradation of inner membrane proteins in mitochondria. EMBO J. 15, 4218–4229 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. van Dyck, L., Neupert, W. & Langer, T. The ATP-dependent PIM1 protease is required for the expression of intron-containing genes in mitochondria. Genes Dev. 12, 1515–1524 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Khalimonchuk, O., Jeong, M. Y., Watts, T., Ferris, E. & Winge, D. R. Selective Oma1 protease-mediated proteolysis of Cox1 subunit of cytochrome oxidase in assembly mutants. J. Biol. Chem. 287, 7289–7300 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Kaser, M., Kambacheld, M., Kisters-Woike, B. & Langer, T. Oma1, a novel membrane-bound metallopeptidase in mitochondria with activities overlapping with the m-AAA protease. J. Biol. Chem. 278, 46414–46423 (2003).

    PubMed  Google Scholar 

  106. Cesnekova, J., Rodinova, M., Hansikova, H., Zeman, J. & Stiburek, L. Loss of mitochondrial AAA proteases AFG3L2 and YME1L impairs mitochondrial structure and respiratory chain biogenesis. Int. J. Mol. Sci. 17, E3930 (2018).

    Google Scholar 

  107. Zurita Rendón, O. & Shoubridge, E. A. LONP1 is required for maturation of a subset of mitochondrial proteins, and its loss elicits an integrated stress response. Mol. Cell. Biol. 38, e00412–e00417 (2018).

    PubMed  PubMed Central  Google Scholar 

  108. Poveda-Huertes, D. et al. An early mtUPR: redistribution of the nuclear transcription factor Rox1 to mitochondria protects against intramitochondrial proteotoxic aggregates. Mol. Cell 77, 180–188 (2020). This article shows that impaired processing of imported proteins leads to aggregation of precursor proteins and induction of a stress response that protects cells from damage.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Münch, C. & Harper, J. W. Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation. Nature 534, 710–713 (2016).

    PubMed  PubMed Central  Google Scholar 

  110. Rainbolt, T. K., Saunders, J. M. & Wiseman, R. L. YME1L degradation reduces mitochondrial proteolytic capacity during oxidative stress. EMBO Rep. 16, 97–106 (2015).

    CAS  PubMed  Google Scholar 

  111. MacVicar, T. et al. Lipid signalling drives proteolytic rewiring of mitochondria by YME1L. Nature 575, 361–365 (2019). This study reports the role of the protease YME1L for reshaping of the mitochondrial proteome during hypoxia.

    CAS  PubMed  Google Scholar 

  112. Bragoszewski, P. et al. Retro-translocation of mitochondrial intermembrane space proteins. Proc. Natl Acad. Sci. USA 112, 7713–7718 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Azzu, V. & Brand, M. D. Degradation of an intramitochondrial protein by the cytosolic proteasome. J. Cell Sci. 123, 578–585 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Mookerjee, S. A. & Brand, M. D. Characteristics of the turnover of uncoupling protein 3 by the ubiquitin proteasome system in isolated mitochondria. Biochim. Biophys. Acta 1807, 1474–1481 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Lavie, J. et al. Ubiquitin-dependent degradation of mitochondrial proteins regulates energy metabolism. Cell Rep. 23, 2852–2863 (2018).

    CAS  PubMed  Google Scholar 

  116. Chowdhury, A., Ogura, T. & Esaki, M. Two Cdc48 cofactors Ubp3 and Ubx2 regulate mitochondrial morphology and protein turnover. J. Biochem. 164, 349–358 (2018).

    CAS  PubMed  Google Scholar 

  117. Nahar, S., Chowdhury, A., Ogura, T. & Esaki, M. A AAA ATPase Cdc48 with a cofactor Ubx2 facilitates ubiquitylation of a mitochondrial fusion-promoting factor Fzo1 for proteasomal degradation. J. Biochem. 67, 279–286 (2020).

    Google Scholar 

  118. Wu, X., Li, L. & Jiang, H. Doa1 targets ubiquitinated substrates for mitochondria-associated degradation. J. Cell Biol. 213, 49–63 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Goodrum, J. M., Lever, A. R., Coody, T. K., Gottschling, D. E. & Hughes, A. L. Rsp5 and Mdm30 reshape the mitochondrial network in response to age-induced vacuole stress. Mol. Biol. Cell 30, 2141–2154 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Nielson, J. R. et al. Sterol oxidation mediates stress-responsive Vms1 translocation to mitochondria. Mol. Cell 68, 673–685 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Esaki, M. & Ogura, T. Cdc48p/p97-mediated regulation of mitochondrial morphology is Vms1p-independent. J. Struct. Biol. 179, 112–120 (2012).

    CAS  PubMed  Google Scholar 

  122. Anton, F., Dittmar, G., Langer, T. & Escobar-Henriques, M. Two deubiquitylases act on mitofusin and regulate mitochondrial function along independent pathways. Mol. Cell 49, 487–498 (2013).

    CAS  PubMed  Google Scholar 

  123. Yue, W. et al. A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30. Cell Res. 24, 482–496 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Escobar-Henriques, M., Westermann, B. & Langer, T. Regulation of mitochondrial fusion by the F-box protein Mdm30 involves proteasome-independent turnover of Fzo1. J. Cell. Biol. 173, 645–650 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Cohen, M. M. J., Leboucher, G. P., Livnat-Levanon, N., Glickman, M. H. & Weisman, A. M. Ubiquitin-proteasome-dependent degradation of a mitofusin, a critical regulator of mitochondrial fusion. Mol. Biol. Cell 19, 2457–2464 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Cavellini, L. et al. An ubiquitin-dependent balance between mitofusin turnover and fatty acids desaturation regulates mitochondrial fusion. Nat. Commun. 8, 15832 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Simões, T., Shuster, R., den Brave, F. & Escobar-Henriques, M. Cdc48 regulates a deubiquitylase cascade critical for mitochondrial fusion. eLife 7, e30015 (2018).

    PubMed  PubMed Central  Google Scholar 

  128. Nakamura, N., Kimura, Y., Tokuda, M., Honda, S. & Hirose, S. MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to change mitochondrial morphology. EMBO Rep. 7, 1019–1022 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Tanaka, A. et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J. Cell Biol. 191, 1367–1380 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Leboucher, G. P. et al. Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptosis. Mol. Cell 47, 547–557 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Sugiura, A. et al. MITOL regulates endoplasmic reticulum-mitochondria contacts via mitofusin 2. Mol. Cell 51, 20–34 (2013).

    CAS  PubMed  Google Scholar 

  132. Escobar-Henriques, M. & Joaquim, M. Mitofusins: disease gatekeepers and hubs in mitochondrial quality control by E3 ligases. Front. Physiol. 10, 517 (2019).

    PubMed  PubMed Central  Google Scholar 

  133. Saladi, S. et al. The NADH dehydrogenase Nde1 executes cell death after integrating signals from metabolism and proteostasis of the mitochondrial surface. Mol. Cell 77, 189–202 (2020).

    CAS  PubMed  Google Scholar 

  134. Xu, S., Peng, G., Wang, Y., Fang, S. & Karbowski, M. The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover. Mol. Biol. Cell 22, 291–300 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Inuzuka, H. et al. SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 471, 104–109 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Cakir, Z. et al. Parkin promotes proteasomal degradation of misregulated BAX. J. Cell Sci. 130, 2903–2913 (2017).

    CAS  PubMed  Google Scholar 

  137. Bernadini, J. P. et al. Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy. EMBO J. 38, e99916 (2019).

    Google Scholar 

  138. Schuldiner, M. et al. The GET complex mediates insertion of tail-anchored proteins into the ER membrane. Cell 134, 634–645 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Vitali, D. G. et al. The GET pathway can increase the risk of mitochondrial outer membrane proteins to be mistargeted to the ER. J. Cell Sci. 131, jcs11110 (2018).

    Google Scholar 

  140. Okreglak, V. & Walter, P. The conserved AAA-ATPase Msp1 confers organelle specificity to tail-anchored proteins. Proc. Natl Acad. Sci. USA 111, 8019–8024 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Chen, Y. C. et al. Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins. EMBO J. 33, 1548–1564 (2014). Together with reference 140, this article identifies the role of Msp1 in the removal of mislocalized proteins from the outer mitochondrial membrane.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Wohlever, M. L., Mateja, A., McGilvray, P. T., Day, K. J. & Keenan, R. J. Msp1 is a membrane protein dislocase for tail-anchored proteins. Mol. Cell 67, 194–202 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Wang, L., Myasnikov, A., Pan, X. & Walter, P. Structure of the AAA protein Msp1 reveals mechanism of mislocallized membrane protein extraction. eLife 9, e54031 (2020).

    PubMed  PubMed Central  Google Scholar 

  144. Li, L., Zheng, J., Wu, X., Jiang, H. & Mitochondrial, A. A. A. ATPase Msp1 detects mislocalized tail-anchored proteins through a dual-recognition mechanism. EMBO Rep. 20, e46989 (2019).

    PubMed  PubMed Central  Google Scholar 

  145. Matsumoto, S. et al. Msp1 clears mistargeted proteins by facilitating their transfer from mitochondria to the ER. Mol. Cell 76, 191–205 (2019).

    CAS  PubMed  Google Scholar 

  146. Dederer, V. et al. Cooperation of mitochondrial and ER factors in quality control of tail-anchored proteins. eLife 8, e45506 (2019). Together with reference 145, this article reports that components of the ER-associated degradation pathway cooperate with Msp1 in the removal of mislocalized proteins from the outer mitochondrial membrane.

    PubMed  PubMed Central  Google Scholar 

  147. Puchades, C. et al. Structure of the mitochondrial inner membrane AAA+ protease YME1 gives insight into substrate processing. Science 358, eaao0464 (2017).

    PubMed  PubMed Central  Google Scholar 

  148. Puchades, C. et al. Unique structural features of the mitochondrial AAA+ protease AFG3L2 reveal the molecular basis for activity in health and disease. Mol. Cell 75, 1073–1085 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Deshwal, S., Fiedler, K. U. & Langer, T. Mitochondrial proteases: multifaceted regulators of mitochondrial plasticity. Annu. Rev. Biochem. 89, 501–528 (2020).

    CAS  PubMed  Google Scholar 

  150. Oplalińska, M. & Jańska, H. AAA proteases: guardians of mitochondrial function and homeostasis. Cells 7, 163 (2018).

    Google Scholar 

  151. Baker, M. J. et al. Impaired folding of the mitochondrial small TIM chaperones induces clearance by the i-AAA protease. J. Mol. Biol. 424, 227–239 (2012).

    CAS  PubMed  Google Scholar 

  152. Wu, X., Li, L. & Jiang, H. Mitochondrial inner-membrane protease Yme1 degrades outer-membrane proteins Tom22 and Om45. J. Cell Biol. 217, 139–149 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Leonhard, K., Stiegler, A., Neupert, W. & Langer, T. Chaperone-like activity of the AAA domain of the yeast Yme1 AAA protease. Nature 398, 348–351 (1999).

    CAS  PubMed  Google Scholar 

  154. Schreiner, B. et al. Role of the AAA protease Yme1 in folding of proteins in the intermembrane space of mitochondria. Mol. Biol. Cell 23, 4335–4346 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Rainbolt, T. K., Atanassova, N., Genereux, J. C. & Wiseman, R. L. Stress-regulated translational attenuation adapts mitochondrial protein import through TIM17A. Cell Metab. 18, 908–919 (2013). This report shows that YME1L degrades the protein translocase subunit TIM17A to adjust protein import capacity under stress situations.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Connerth, M. et al. Intramitochondrial transport of phosphatidic acid in yeast by a lipid transfer protein. Science 338, 815–818 (2012).

    CAS  PubMed  Google Scholar 

  157. Watanabe, Y., Tamura, Y., Kawano, S. & Endo, T. Structural and mechanistic insights into phospholipid transfer by Ups1-Mdm35 in mitochondria. Nat. Commun. 6, 7922 (2015).

    CAS  PubMed  Google Scholar 

  158. Miyata, N., Watanabe, Y., Tamura, Y., Endo, T. & Kuge, O. Phosphatidylserine transport by Ups2-Mdm35 in respiration-active mitochondria. J. Cell Biol. 214, 77–88 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Aaltonen, M. J. et al. MICOS and phospholipid transfer by Ups2-Mdm35 organize lipid synthesis in mitochondria. J. Cell Biol. 213, 525–534 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Potting, C., Wilmes, C., Engmann, T., Osman, C. & Langer, T. Regulation of mitochondrial phospholipids by Ups1/PRELI-like proteins depends on proteolysis and Mdm35. EMBO J. 29, 2888–2898 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Saita, S. et al. PARL partitions the lipid transfer protein STARD7 between the cytosol and mitochondria. EMBO J. 37, e97909 (2018).

    PubMed  PubMed Central  Google Scholar 

  162. Anand, R. et al. The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J. Cell Biol. 204, 919–929 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Del Dotto, V. et al. OPA1 isoforms in the hierarchical organization of mitochondrial functions. Cell Rep. 19, 2557–2571 (2017).

    PubMed  Google Scholar 

  164. Ban, T. et al. Molecular basis of selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin. Nat. Cell Biol. 19, 856–863 (2017).

    CAS  PubMed  Google Scholar 

  165. Zhang, D. et al. Cryo-EM structures of s-OPA1 reveal its interactions with membrane and changes upon nucleotide binding. eLife 9, e50294 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Baker, M. J. et al. Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics. EMBO J. 33, 578–593 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Rainbolt, T. K., Lebeau, J., Puchades, C. & Wiseman, R. L. Reciprocal degradation of YME1L and OMA1 adapts mitochondrial proteolytic activity during stress. Cell Rep. 14, 2041–2049 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Wai, T. et al. Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science 350, aad0116 (2015).

    PubMed  Google Scholar 

  169. Sprenger, H. G. et al. Loss of the mitochondrial i-AAA protease YME1L leads to ocular dysfunction and spinal axonopathy. EMBO Mol. Med. 11, e9288 (2019).

    PubMed  Google Scholar 

  170. Herlan, M., Vogel, F., Bornhövd, C., Neupert, W. & Reichert, A. S. Processing of Mgm1 by the rhomboid-type protease Pcp1 is required for maintenance of mitochondrial morphology and of mitochondrial DNA. J. Biol. Chem. 278, 27781–27788 (2003).

    CAS  PubMed  Google Scholar 

  171. Vögtle, F. N. et al. Mitochondrial protein turnover: Role of the precursor intermediate peptidase Oct1 in protein stabilization. Mol. Biol. Cell 22, 2135–2143 (2011).

    PubMed  PubMed Central  Google Scholar 

  172. Falkevall, A. et al. Degradation of the amyloid β-protein by the novel mitochondrial peptidasome, PreP. J. Biol. Chem. 281, 29096–29104 (2006).

    CAS  PubMed  Google Scholar 

  173. Mossmann, D., Meisinger, C. & Vögtle, F. N. Processing of mitochondrial presequences. Biochim. Biophys. Acta 1819, 1098–106 (2012).

    CAS  PubMed  Google Scholar 

  174. Mossmann, D. et al. Amyloid-β peptide induces mitochondrial dysfunction by inhibition of preprotein maturation. Cell Metab. 20, 662–669 (2014).

    CAS  PubMed  Google Scholar 

  175. Wagner, I., Arlt, H., van Dyck, L., Langer, T. & Neupert, W. Molecular chaperones cooperate with PIM1 protease in the degradation of misfolded proteins in mitochondria. EMBO J. 13, 5135–5145 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Kang, S. G., Dimitrova, M. N., Ortega, J., Ginsburg, A. & Maurizi, M. R. Human mitochondrial ClpP is a stable heptamer that assembles into a tetradecamer in the presence of ClpX. J. Biol. Chem. 280, 35424–35432 (2005).

    CAS  PubMed  Google Scholar 

  177. Bender, T., Lewrenz, I., Franken, S., Baitzel, C. & Voos, W. Mitochondrial enzymes are protected from stress-induced aggregation by mitochondrial chaperones and the Pim1/LON protease. Mol. Biol. Cell 22, 541–554 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Fischer, F., Langer, J. D. & Osiewacz, H. D. Identification of potential mitochondrial CLPXP protease interactors and substrates suggests its central role in energy metabolism. Sci. Rep. 5, 18375 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Gatsogiannis, C., Balogh, C., Merino, F., Sieber, S. A. & Rausner, S. Cryo-EM structure of the ClpXP protein degradation machinery. Nat. Struct. Mol. Biol. 26, 946–954 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Szczepanowska, K. et al. CLPP coordinates mitoribosomal assembly through the regulation of ERAL1 levels. EMBO J. 35, 2566–2583 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Dennerlein, S., Rozanska, A., Wydro, M., Chrzanowska-Lightowlers, Z. M. & Lightowlers, R. N. Human ERAL1 is a mitochondrial RNA chaperone involved in the assembly of the 28S small mitochondrial ribosomal subunit. Biochem. J. 430, 551–558 (2010).

    CAS  PubMed  Google Scholar 

  182. Suzuki, C. K., Suda, K., Wang, N. & Schatz, G. Requirement for the yeast gene LON in intramitochondrial proteolysis and maintenance of respiration. Science 264, 273–276 (1994).

    CAS  PubMed  Google Scholar 

  183. van Dyck, L., Pearce, D. A. & Sherman, F. PIM1 encodes a mitochondrial ATP-dependent protease that is required for mitochondrial function in the yeast Saccharomyces cerevisiae. J. Biol. Chem. 269, 238–242 (1994).

    PubMed  Google Scholar 

  184. Matsushima, Y., Goto, Y. & Kaguni, L. S. Mitochondrial Lon protease regulates mitochondrial DNA copy number and transcription by selective degradation of mitochondrial transcription factor A (TFAM). Proc. Natl Acad. Sci. USA 107, 18410–18415 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Gustafsson, C. M., Falkenberg, M. & Larsson, N. G. Maintenance and expression of mammalian mitochondrial DNA. Annu. Rev. Biochem. 85, 133–160 (2016).

    CAS  PubMed  Google Scholar 

  186. Lu, B. et al. Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease. Mol. Cell 49, 121–132 (2013).

    CAS  PubMed  Google Scholar 

  187. Göke, A. et al. Mrx6 regulates mitochondrial DNA copy number in Saccharomyces cerevisiae by engaging the evolutionarily conserved Lon protease Pim1. Mol. Biol. Cell 31, 527–545 (2020).

    PubMed  PubMed Central  Google Scholar 

  188. Sepuri, N. B. V. et al. Mitochondrial LON protease-dependent degradation of cytochrome c oxidase subunits under hypoxia and myocardial ischemia. Biochim. Biophys. Acta Bioenerg. 1858, 519–528 (2017).

    CAS  PubMed  Google Scholar 

  189. Pryde, K. R., Taanman, J. W. & Schapira, A. H. A LON-ClpP proteolytic axis degrades complex I to extinguish ROS production in depolarized mitochondria. Cell Rep. 17, 2522–2531 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Szczepanowska, K. et al. A salvage pathway maintains highly functional respiratory complex I. Nat. Commun. 11, 1643 (2020).

    PubMed  PubMed Central  Google Scholar 

  191. Bota, A. D. & Davies, K. J. Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism. Nat. Cell Biol. 4, 674–680 (2002).

    CAS  PubMed  Google Scholar 

  192. Wallace, D. C. Mitochondrial genetic medicine. Nat. Genet. 50, 1642–1649 (2018).

    CAS  PubMed  Google Scholar 

  193. Luce, K. & Osiewacz, H. D. Increasing organismal health span by enhancing mitochondrial protein quality. Nat. Cell Biol. 11, 852–858 (2009).

    CAS  PubMed  Google Scholar 

  194. Lee, C. K., Klopp, R. G., Weindruch, R. & Prolla, T. A. Gene expression profile of aging and its retardation by caloric restriction. Science 285, 1390–1393 (1999).

    CAS  PubMed  Google Scholar 

  195. Bernstein, S. H. et al. The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivates. Blood 119, 3321–3329 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Quiros, P. M., Barcena, C. & Lopez-Otin, C. Lon protease: a key enzyme controlling mitochondrial bioenergetics in cancer. Mol. Cell. Oncol. 1, e968505 (2014).

    PubMed  PubMed Central  Google Scholar 

  197. Fukoda, R. et al. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129, 111–122 (2007).

    Google Scholar 

  198. Strauss, K. A. et al. CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease. Am. J. Hum. Genet. 96, 121–135 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Peter, B. et al. Defective mitochondrial protease LonP1 can cause classical mitochondrial disease. Hum. Mol. Genet. 27, 1743–1753 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Jenkinson, E. M. et al. Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am. J. Hum. Genet. 92, 605–613 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Brodie, E. J., Zhan, H., Saiyed, T., Truscott, K. N. & Dougan, D. A. Perrault syndrome type 3 caused by diverse molecular defects in CLPP. Sci. Rep. 8, 12862 (2018).

    PubMed  PubMed Central  Google Scholar 

  202. Hartmann, B. et al. Homozygous YME1L mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation. eLife 5, e16078 (2016).

    PubMed  PubMed Central  Google Scholar 

  203. Di Bella, D. et al. Mutations in the mitochondrial protease gene AGF3L2 cause dominant hereditary ataxia SCA28. Nat. Genet. 42, 313–321 (2010).

    PubMed  Google Scholar 

  204. Pierson, T. M. et al. Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS Genet. 7, e1002325 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Casari, G. et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin a nuclear-encoded mitochondrial metalloprotease. Cell 93, 973–983 (1998).

    CAS  PubMed  Google Scholar 

  206. Pfeffer, G. et al. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance. Brain 137, 1323–1336 (2014).

    PubMed  PubMed Central  Google Scholar 

  207. Selfridge, J. E., E, L., Lu, J. & Swerdlow, R. H. Role of mitochondrial homeostasis and dynamics in Alzheimer’s disease. Neurobiol. Dis. 51, 3–12 (2013).

    CAS  PubMed  Google Scholar 

  208. Devi, L., Prabhu, B. M., Galati, D. F., Avadhani, N. G. & Anandatheerthavarada, H. K. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J. Neurosci. 26, 9057–9068 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. An, Y. A. et al. Dysregulation of amyloid precursor protein impairs adipose tissue mitochondrial function and promotes obesity. Nat. Metab. 1, 1243–1257 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Cenini, G., Rüb, C., Bruderek, M. & Voos, W. Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process. Mol. Biol. Cell 27, 3257–3272 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Hansson Petersen, C. A. et al. The amyloid β-peptide is imported into mitochondrial via the TOM import machinery and localized to mitochondrial cristae. Proc. Natl Acad. Sci. USA 105, 13145–13150 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Sorrentino, V. et al. Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature 552, 187–193 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Schmidt, O. et al. Regulation of mitochondrial protein import by cytosolic kinases. Cell 144, 227–239 (2011).

    CAS  PubMed  Google Scholar 

  214. Gerbeth, C. et al. Glucose-induced regulation of protein import receptor Tom22 by cytosolic and mitochondria-bound kinases. Cell Metab. 18, 578–587 (2013).

    CAS  PubMed  Google Scholar 

  215. Harbauer, A. B. et al. Cell cycle-dependent regulation of mitochondrial preprotein translocase. Science 346, 1109–1113 (2014).

    CAS  PubMed  Google Scholar 

  216. Guerroué, F. L. et al. Autophagosomal content profiling reveals an LC3C-dependent piecemeal mitophagy pathway. Mol. Cell 68, 786–796 (2017).

    PubMed  Google Scholar 

  217. Burman, J. L. et al. Mitochondrial fission facilitates the selective mitophagy of protein aggregates. J. Cell Biol. 216, 3231–3247 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Sugiura, A., McLelland, G. L., Fon, E. A. & McBride, H. M. A new pathway for mitochondrial quality control: mitochondrial-derived vesicles. EMBO J. 33, 2142–2156 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Hughes, A., Hughes, C. E., Henderson, K. A., Yazvenko, N. & Gottschling, D. E. Selective sorting and destruction of mitochondrial membrane proteins in aged yeast. eLife 5, e13943 (2016).

    PubMed  PubMed Central  Google Scholar 

  220. Neuspiel, M. et al. Cargo-selected transport from the mitochondria to peroxisomes is mediated by vesicular carriers. Curr. Biol. 18, 102–108 (2008).

    CAS  PubMed  Google Scholar 

  221. Soubannier, V. et al. A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr. Biol. 22, 135–141 (2012).

    CAS  PubMed  Google Scholar 

  222. McLelland, G. L., Soubannier, V., Chen, C. X., McBride, H. M. & Fon, E. A. Parkin and PINK1 function in vesicular trafficking pathway regulating mitochondrial quality control. EMBO J. 33, 282–295 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Matheoud, D. et al. Parkinson’s disease-related proteins PINK1 and parkin repress mitochondrial antigen presentation. Cell 166, 314–327 (2016).

    CAS  PubMed  Google Scholar 

  224. McLelland, G. L., Lee, S. A., McBride, H. M. & Fon, E. A. Syntaxin-17 delivers PINK1/parkin-dependent mitochondrial vesicles to the endolysosomal system. J. Cell Biol. 214, 275–291 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank F. den Brave for critical reading of the manuscript. This work was supported by funds from the Deutsche Forschungsgemeinschaft (SFB 1218 project ID 269925409 and BE 4679/2-2 to T.B. and HE 2803/9-1 and DIP MitoBalance to J.M.H.).

Author information

Authors and Affiliations

  1. Institute of Biochemistry and Molecular Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Jiyao Song

  2. Cell Biology, University of Kaiserslautern, Kaiserslautern, Germany

    Johannes M. Herrmann

  3. Institute of Biochemistry and Molecular Biology, Faculty of Medicine, University of Bonn, Bonn, Germany

    Thomas Becker

Authors
  1. Jiyao Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Johannes M. Herrmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed to all aspects of the article.

Corresponding author

Correspondence to Thomas Becker.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Molecular Cell Biology thanks T. Langer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Alphaproteobacteria

A class of Proteobacteria, which is a major phylum of Gram-negative bacteria. Alphaproteobacteria are highly diverse, comprising intracellular pathogens and phototropic bacteria.

Iron–sulfur clusters

Cofactors of proteins involved in electron transport, enzymatic catalysis and regulatory mechanisms.

Membrane contact sites

Close contacts between membrane-bound cell organelles that tether two organelles and contain a subset of proteins to fulfil specific functions, such as lipid transport and Ca2+ trafficking.

Ubiquitin

A 76 amino acid polypeptide that is transferred onto proteins either to target them for proteasomal degradation or to regulate their activity.

E3 ubiquitin ligases

A large group of proteins that transfer activated ubiquitins to proteins.

ATPase associated with various cellular activities proteases

(AAA proteases). Multimeric proteases that contain a proteolytic chamber and an AAA ATPase domain.

Mitophagy

A selective autophagy pathway that involves the core machinery of autophagy to remove damaged mitochondria by lysosomal degradation.

SNARE proteins

A protein family that promotes fusion of vesicles with target membranes.

TOM complex

The translocase of the outer membrane. It forms the major entry gate for precursor proteins into mitochondria.

TIM23 complex

The presequence translocase of the inner mitochondrial membrane. It integrates precursor proteins with a cleavable presequence into the inner membrane or transports them into the matrix.

Mitochondrial processing peptidase

(MPP). Removes the cleavable presequence of precursor proteins that are imported via the TIM23 complex.

Nascent polypeptide-associated complex

(NAC). A heterodynamic complex that binds to translating ribosomes.

Ubiquilins

Cytosolic chaperones that bind hydrophobic regions of their substrates during protein targeting and deliver them for proteasomal degradation.

Tail-anchored proteins

Membrane proteins with a carboxy-terminal α-helical transmembrane anchor.

Cdc48

Like its human homologue p97 (also known as VCP), it is a multifunctional AAA protein in the cytosol that extracts proteins from cellular membranes and protein complexes for proteasomal degradation.

ER-associated degradation

A process that removes misfolded proteins from the endoplasmic reticulum (ER). Substrate proteins are ubiquitylated and subsequently extracted from the ER to deliver them for proteasomal degradation.

Msp1

An AAA ATPase that extracts proteins from the outer membrane for proteasomal degradation.

Integrated stress response

A general cellular stress response pathway that is induced by various different stress situations. It leads to reduced general protein biosynthesis, but increased production of some transcription factors.

OMA1

An inner membrane metalloproteinase which together with the i-AAA protease controls the proteolytic cleavage of mitochondrial dynamics regulator OPA1.

Retrotranslocation

Reverse protein transport from cell organelles into the cytosol.

Succinate dehydrogenase

Complex II of the respiratory chain, which oxidizes succinate to fumarate in the tricarboxylic acid cycle.

OPA1

GTPase that controls fusion of the inner membrane and modulates the formation of cristae.

Mitochondrial transcription factor A

(TFAM). Protein that binds to mitochondrial DNA to maintain its transcription and stability.

Aconitase

An iron–sulfur cluster-containing enzyme of the tricarboxylic acid cycle that converts citric acid to isocitric acid.

CODAS syndrome

A rare congenital disease that causes cerebral, ocular, dental, auricular and skeletal anomalies.

Perrault syndrome

A rare congenital syndrome with sensorineural deafness in males and females and associated ovarian dysgenesis in females.

Purkinje cells

Neurons in the cerebellum that produce the neurotransmitter γ-aminobutyric acid.

Ataxia

Perturbations of the nervous system that affect coordination of muscle movements.

Hereditary spastic paraplegia

Inherited diseases that are characterized by a progressive gait disorder.

Chronic ophthalmoplegia

Disease of the eye that is characterized by progressive impaired eye movement.

Amyloid precursor protein

A protein with unknown function that is proteolytically cleaved into amyloid-β peptides.

Amyloid-β peptide

Polypeptides that can aggregate into amyloid fibrils, which are a primary component of amyloid plaques in brains of people with Alzheimer disease.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, J., Herrmann, J.M. & Becker, T. Quality control of the mitochondrial proteome. Nat Rev Mol Cell Biol 22, 54–70 (2021). https://doi.org/10.1038/s41580-020-00300-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41580-020-00300-2

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing