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Mechanisms and regulation of protein synthesis in mitochondria

Abstract

Mitochondria are cellular organelles responsible for generation of chemical energy in the process called oxidative phosphorylation. They originate from a bacterial ancestor and maintain their own genome, which is expressed by designated, mitochondrial transcription and translation machineries that differ from those operating for nuclear gene expression. In particular, the mitochondrial protein synthesis machinery is structurally and functionally very different from that governing eukaryotic, cytosolic translation. Despite harbouring their own genetic information, mitochondria are far from being independent of the rest of the cell and, conversely, cellular fitness is closely linked to mitochondrial function. Mitochondria depend heavily on the import of nuclear-encoded proteins for gene expression and function, and hence engage in extensive inter-compartmental crosstalk to regulate their proteome. This connectivity allows mitochondria to adapt to changes in cellular conditions and also mediates responses to stress and mitochondrial dysfunction. With a focus on mammals and yeast, we review fundamental insights that have been made into the biogenesis, architecture and mechanisms of the mitochondrial translation apparatus in the past years owing to the emergence of numerous near-atomic structures and a considerable amount of biochemical work. Moreover, we discuss how cellular mitochondrial protein expression is regulated, including aspects of mRNA and tRNA maturation and stability, roles of auxiliary factors, such as translation regulators, that adapt mitochondrial translation rates, and the importance of inter-compartmental crosstalk with nuclear gene expression and cytosolic translation and how it enables integration of mitochondrial translation into the cellular context.

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Fig. 1: Biogenesis of the human mitochondrial ribosome.
Fig. 2: The human mitochondrial translation cycle.
Fig. 3: RNA maturation and turnover in human mitochondria.
Fig. 4: Regulation of translation of mitochondrially encoded OXPHOS components by auxiliary factors.

References

  1. 1.

    Martijn, J., Vosseberg, J., Guy, L., Offre, P. & Ettema, T. J. G. Deep mitochondrial origin outside the sampled alphaproteobacteria. Nature 557, 101–105 (2018).

    CAS  PubMed  Google Scholar 

  2. 2.

    Spinelli, J. B. & Haigis, M. C. The multifaceted contributions of mitochondria to cellular metabolism. Nat. Cell Biol. 20, 745–754 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Pearce, S., Nezich, C. L. & Spinazzola, A. Mitochondrial diseases: translation matters. Mol. Cell Neurosci. 55, 1–12 (2013).

    CAS  PubMed  Google Scholar 

  4. 4.

    Boczonadi, V. & Horvath, R. Mitochondria: impaired mitochondrial translation in human disease. Int. J. Biochem. Cell Biol. 48, 77–84 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Sun, N., Youle, R. J. & Finkel, T. The mitochondrial basis of aging. Mol. Cell 61, 654–666 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Greber, B. J. & Ban, N. Structure and function of the mitochondrial ribosome. Annu. Rev. Biochem. 85, 103–132 (2016).

    CAS  PubMed  Google Scholar 

  7. 7.

    Zhang, L. et al. Antibiotic susceptibility of mammalian mitochondrial translation. FEBS Lett. 579, 6423–6427 (2005).

    CAS  PubMed  Google Scholar 

  8. 8.

    Waltz, F. & Giege, P. Striking diversity of mitochondria-specific translation processes across eukaryotes. Trends Biochem. Sci. 45, 149–162 (2020).

    CAS  PubMed  Google Scholar 

  9. 9.

    Ojala, D., Montoya, J. & Attardi, G. tRNA punctuation model of RNA processing in human mitochondria. Nature 290, 470–474 (1981). This paper is the first description of the tRNA punctuation model of mitochondrial RNA processing.

    CAS  PubMed  Google Scholar 

  10. 10.

    Rackham, O. et al. Hierarchical RNA processing is required for mitochondrial ribosome assembly. Cell Rep. 16, 1874–1890 (2016).

    CAS  PubMed  Google Scholar 

  11. 11.

    Siira, S. J. et al. Concerted regulation of mitochondrial and nuclear non-coding RNAs by a dual-targeted RNase Z. EMBO Rep. https://doi.org/10.15252/embr.201846198 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Merten, S., Synenki, R. M., Locker, J., Christianson, T. & Rabinowitz, M. Processing of precursors of 21S ribosomal RNA from yeast mitochondria. Proc. Natl Acad. Sci. USA 77, 1417–1421 (1980).

    CAS  PubMed  Google Scholar 

  13. 13.

    Bogenhagen, D. F., Martin, D. W. & Koller, A. Initial steps in RNA processing and ribosome assembly occur at mitochondrial DNA nucleoids. Cell Metab. 19, 618–629 (2014).

    CAS  PubMed  Google Scholar 

  14. 14.

    Dalla Rosa, I. et al. MPV17L2 is required for ribosome assembly in mitochondria. Nucleic Acids Res. 42, 8500–8515 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Jourdain, A. A. et al. GRSF1 regulates RNA processing in mitochondrial RNA granules. Cell Metab. 17, 399–410 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Antonicka, H. & Shoubridge, E. A. Mitochondrial RNA granules are centers for posttranscriptional RNA processing and ribosome biogenesis. Cell Rep. 10, 920–932 (2015).

    CAS  PubMed  Google Scholar 

  17. 17.

    Tu, Y. T. & Barrientos, A. The human mitochondrial DEAD-box protein DDX28 resides in RNA granules and functions in mitoribosome assembly. Cell Rep. 10, 854–864 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Maiti, P., Kim, H. J., Tu, Y. T. & Barrientos, A. Human GTPBP10 is required for mitoribosome maturation. Nucleic Acids Res. 46, 11423–11437 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Sloan, K. E. et al. Tuning the ribosome: the influence of rRNA modification on eukaryotic ribosome biogenesis and function. RNA Biol. 14, 1138–1152 (2017).

    PubMed  Google Scholar 

  20. 20.

    Van Haute, L. et al. METTL15 introduces N4-methylcytidine into human mitochondrial 12S rRNA and is required for mitoribosome biogenesis. Nucleic Acids Res. 47, 10267–10281 (2019).

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    De Silva, D., Tu, Y. T., Amunts, A., Fontanesi, F. & Barrientos, A. Mitochondrial ribosome assembly in health and disease. Cell Cycle 14, 2226–2250 (2015).

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Brown, A. et al. Structures of the human mitochondrial ribosome in native states of assembly. Nat. Struct. Mol. Biol. 24, 866–869 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Itoh, Y., Naschberger, A., Mortezaei, N., Herrmann, J. M. & Amunts, A. Analysis of translating mitoribosome reveals functional characteristics of translation in mitochondria of fungi. Preprint at bioRxiv https://doi.org/10.1101/2020.01.31.929331 (2020).

    Article  Google Scholar 

  24. 24.

    Davis, J. H. & Williamson, J. R. Structure and dynamics of bacterial ribosome biogenesis. Philos. Trans. R Soc. Lond. B Biol. Sci. https://doi.org/10.1098/rstb.2016.0181 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Kargas, V. et al. Mechanism of completion of peptidyltransferase centre assembly in eukaryotes. eLife https://doi.org/10.7554/eLife.44904 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Ma, C. et al. Structural snapshot of cytoplasmic pre-60S ribosomal particles bound by Nmd3, Lsg1, Tif6 and Reh1. Nat. Struct. Mol. Biol. 24, 214–220 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Malyutin, A. G., Musalgaonkar, S., Patchett, S., Frank, J. & Johnson, A. W. Nmd3 is a structural mimic of eIF5A, and activates the cpGTPase Lsg1 during 60S ribosome biogenesis. EMBO J. 36, 854–868 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Jomaa, A. et al. Functional domains of the 50S subunit mature late in the assembly process. Nucleic Acids Res. 42, 3419–3435 (2014).

    CAS  PubMed  Google Scholar 

  29. 29.

    Davis, J. H. et al. Modular assembly of the bacterial large ribosomal subunit. Cell 167, 1610–1622.e15 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Klinge, S. & Woolford, J. L. Jr. Ribosome assembly coming into focus. Nat. Rev. Mol. Cell Biol. 20, 116–131 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Ramrath, D. J. F. et al. Evolutionary shift toward protein-based architecture in trypanosomal mitochondrial ribosomes. Science https://doi.org/10.1126/science.aau7735 (2018). This study is the first visualization of an extreme case of mitoribosomal diversification with a minimal rRNA core and a giant ribosomal protein shell.

    Article  PubMed  Google Scholar 

  32. 32.

    Saurer, M. et al. Mitoribosomal small subunit biogenesis in trypanosomes involves an extensive assembly machinery. Science 365, 1144–1149 (2019).

    CAS  PubMed  Google Scholar 

  33. 33.

    Jaskolowski, M. et al. Structural insights into the mechanism of mitoribosomal large subunit biogenesis. Mol. Cell 79, 629–644 (2020).

    CAS  PubMed  Google Scholar 

  34. 34.

    Soufari, H. et al. Structure of the mature kinetoplastids mitoribosome and insights into its large subunit biogenesis. Proc. Natl Acad. Sci. USA 117, 29851–29861 (2020).

    CAS  PubMed  Google Scholar 

  35. 35.

    Tobiasson, V. et al. Interconnected assembly factors regulate the biogenesis of mitoribosomal large subunit. Preprint at bioRxiv https://doi.org/10.1101/2020.06.28.176446 (2020).

    Article  Google Scholar 

  36. 36.

    Bogenhagen, D. F., Ostermeyer-Fay, A. G., Haley, J. D. & Garcia-Diaz, M. Kinetics and mechanism of mammalian mitochondrial ribosome assembly. Cell Rep. 22, 1935–1944 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Zeng, R., Smith, E. & Barrientos, A. Yeast mitoribosome large subunit assembly proceeds by hierarchical incorporation of protein clusters and modules on the inner membrane. Cell Metab. 27, 645–656.e7 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Kaur, J. & Stuart, R. A. Truncation of the Mrp20 protein reveals new ribosome-assembly subcomplex in mitochondria. EMBO Rep. 12, 950–955 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Chen, S. S., Sperling, E., Silverman, J. M., Davis, J. H. & Williamson, J. R. Measuring the dynamics of E. coli ribosome biogenesis using pulse-labeling and quantitative mass spectrometry. Mol. Biosyst. 8, 3325–3334 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    De Silva, D., Fontanesi, F. & Barrientos, A. The DEAD box protein Mrh4 functions in the assembly of the mitochondrial large ribosomal subunit. Cell Metab. 18, 712–725 (2013).

    PubMed  Google Scholar 

  41. 41.

    Rodnina, M. V. Translation in prokaryotes. Cold Spring Harb. Perspect Biol. https://doi.org/10.1101/cshperspect.a032664 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Weisser, M. & Ban, N. Extensions, extra factors, and extreme complexity: ribosomal structures provide insights into eukaryotic translation. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a032367 (2019).

    Article  PubMed  Google Scholar 

  43. 43.

    Spencer, A. C. & Spremulli, L. L. Interaction of mitochondrial initiation factor 2 with mitochondrial fMet-tRNA. Nucleic Acids Res. 32, 5464–5470 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Roll-Mecak, A., Shin, B. S., Dever, T. E. & Burley, S. K. Engaging the ribosome: universal IFs of translation. Trends Biochem. Sci. 26, 705–709 (2001).

    CAS  PubMed  Google Scholar 

  45. 45.

    Carter, A. P. et al. Crystal structure of an initiation factor bound to the 30S ribosomal subunit. Science 291, 498–501 (2001).

    CAS  PubMed  Google Scholar 

  46. 46.

    Lomakin, I. B. & Steitz, T. A. The initiation of mammalian protein synthesis and mRNA scanning mechanism. Nature 500, 307–311 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Hussain, T. et al. Structural changes enable start codon recognition by the eukaryotic translation initiation complex. Cell 159, 597–607 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Weisser, M., Voigts-Hoffmann, F., Rabl, J., Leibundgut, M. & Ban, N. The crystal structure of the eukaryotic 40S ribosomal subunit in complex with eIF1 and eIF1A. Nat. Struct. Mol. Biol. 20, 1015–1017 (2013).

    CAS  PubMed  Google Scholar 

  49. 49.

    Atkinson, G. C. et al. Evolutionary and genetic analyses of mitochondrial translation initiation factors identify the missing mitochondrial IF3 in S. cerevisiae. Nucleic Acids Res. 40, 6122–6134 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Gaur, R. et al. A single mammalian mitochondrial translation initiation factor functionally replaces two bacterial factors. Mol. Cell 29, 180–190 (2008). This paper is the first description that a mitochondria-specific insertion in an initiation factor compensates for the loss of bacterial IF1.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Yassin, A. S. et al. Insertion domain within mammalian mitochondrial translation initiation factor 2 serves the role of eubacterial initiation factor 1. Proc. Natl Acad. Sci. USA 108, 3918–3923 (2011).

    CAS  PubMed  Google Scholar 

  52. 52.

    Kummer, E. et al. Unique features of mammalian mitochondrial translation initiation revealed by cryo-EM. Nature 560, 263–267 (2018). This paper is the first structural report on a complete, reconstituted mitochondrial translation complex.

    CAS  PubMed  Google Scholar 

  53. 53.

    Kozak, M. Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell 44, 283–292 (1986).

    CAS  PubMed  Google Scholar 

  54. 54.

    Hinnebusch, A. G. The scanning mechanism of eukaryotic translation initiation. Annu. Rev. Biochem. 83, 779–812 (2014).

    CAS  PubMed  Google Scholar 

  55. 55.

    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 

  56. 56.

    Temperley, R. J., Wydro, M., Lightowlers, R. N. & Chrzanowska-Lightowlers, Z. M. Human mitochondrial mRNAs — like members of all families, similar but different. Biochim. Biophys. Acta 1797, 1081–1085 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Montoya, J., Ojala, D. & Attardi, G. Distinctive features of the 5′-terminal sequences of the human mitochondrial mRNAs. Nature 290, 465–470 (1981).

    CAS  PubMed  Google Scholar 

  58. 58.

    Greber, B. J. et al. Ribosome. The complete structure of the 55S mammalian mitochondrial ribosome. Science 348, 303–308 (2015).

    CAS  PubMed  Google Scholar 

  59. 59.

    Christian, B. E. & Spremulli, L. L. Preferential selection of the 5′-terminal start codon on leaderless mRNAs by mammalian mitochondrial ribosomes. J. Biol. Chem. 285, 28379–28386 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Ayyub, S. A. et al. Fidelity of translation in the presence of mammalian mitochondrial initiation factor 3. Mitochondrion 39, 1–8 (2018).

    CAS  PubMed  Google Scholar 

  61. 61.

    Bhargava, K. & Spremulli, L. L. Role of the N- and C-terminal extensions on the activity of mammalian mitochondrial translational initiation factor 3. Nucleic Acids Res. 33, 7011–7018 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Haque, M. E. & Spremulli, L. L. Roles of the N- and C-terminal domains of mammalian mitochondrial initiation factor 3 in protein biosynthesis. J. Mol. Biol. 384, 929–940 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Rudler, D. L. et al. Fidelity of translation initiation is required for coordinated respiratory complex assembly. Sci. Adv. 5, eaay2118 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Koripella, R. K. et al. Structure of human mitochondrial translation initiation factor 3 bound to the small ribosomal subunit. iScience 12, 76–86 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Khawaja, A. et al. Distinct pre-initiation steps in human mitochondrial translation. Nat. Commun. 11, 2932 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Bilbille, Y. et al. The human mitochondrial tRNAMet: structure/function relationship of a unique modification in the decoding of unconventional codons. J. Mol. Biol. 406, 257–274 (2011).

    CAS  PubMed  Google Scholar 

  67. 67.

    Nakano, S. et al. NSUN3 methylase initiates 5-formylcytidine biogenesis in human mitochondrial tRNA(Met). Nat. Chem. Biol. 12, 546–551 (2016).

    CAS  PubMed  Google Scholar 

  68. 68.

    Haag, S. et al. NSUN3 and ABH1 modify the wobble position of mt-tRNAMet to expand codon recognition in mitochondrial translation. EMBO J. 35, 2104–2119 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Van Haute, L. et al. Deficient methylation and formylation of mt-tRNAMet wobble cytosine in a patient carrying mutations in NSUN3. Nat. Commun. 7, 12039 (2016).

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Schwartzbach, C. J. & Spremulli, L. L. Bovine mitochondrial protein synthesis elongation factors. Identification and initial characterization of an elongation factor Tu-elongation factor Ts complex. J. Biol. Chem. 264, 19125–19131 (1989).

    CAS  PubMed  Google Scholar 

  71. 71.

    Woriax, V. L., Bullard, J. M., Ma, L., Yokogawa, T. & Spremulli, L. L. Mechanistic studies of the translational elongation cycle in mammalian mitochondria. Biochim. Biophys. Acta 1352, 91–101 (1997).

    CAS  PubMed  Google Scholar 

  72. 72.

    Cai, Y. C., Bullard, J. M., Thompson, N. L. & Spremulli, L. L. Interaction of mitochondrial elongation factor Tu with aminoacyl-tRNA and elongation factor Ts. J. Biol. Chem. 275, 20308–20314 (2000).

    CAS  PubMed  Google Scholar 

  73. 73.

    Jeppesen, M. G., Navratil, T., Spremulli, L. L. & Nyborg, J. Crystal structure of the bovine mitochondrial elongation factor Tu.Ts complex. J. Biol. Chem. 280, 5071–5081 (2005).

    CAS  PubMed  Google Scholar 

  74. 74.

    Hammarsund, M. et al. Identification and characterization of two novel human mitochondrial elongation factor genes, hEFG2 and hEFG1, phylogenetically conserved through evolution. Hum. Genet. 109, 542–550 (2001).

    CAS  PubMed  Google Scholar 

  75. 75.

    Tsuboi, M. et al. EF-G2mt is an exclusive recycling factor in mammalian mitochondrial protein synthesis. Mol. Cell 35, 502–510 (2009). This paper is the first description of mtEFG1 and mtEFG2 having divergent functions in the translation cycle.

    CAS  PubMed  Google Scholar 

  76. 76.

    Bhargava, K., Templeton, P. & Spremulli, L. L. Expression and characterization of isoform 1 of human mitochondrial elongation factor G. Protein Expr. Purif. 37, 368–376 (2004).

    CAS  PubMed  Google Scholar 

  77. 77.

    Chung, H. K. & Spremulli, L. L. Purification and characterization of elongation factor G from bovine liver mitochondria. J. Biol. Chem. 265, 21000–21004 (1990).

    CAS  PubMed  Google Scholar 

  78. 78.

    Eberly, S. L., Locklear, V. & Spremulli, L. L. Bovine mitochondrial ribosomes. Elongation factor specificity. J. Biol. Chem. 260, 8721–8725 (1985).

    CAS  PubMed  Google Scholar 

  79. 79.

    Koripella, R. K. et al. Structures of the human mitochondrial ribosome bound to EF-G1 reveal distinct features of mitochondrial translation elongation. Nat. Commun. 11, 3830 (2020).

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    Kummer, E. & Ban, N. Structural insights into mammalian mitochondrial translation elongation catalyzed by mtEFG1. EMBO J. https://doi.org/10.15252/embj.2020104820 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Zhou, J., Lancaster, L., Donohue, J. P. & Noller, H. F. Spontaneous ribosomal translocation of mRNA and tRNAs into a chimeric hybrid state. Proc. Natl Acad. Sci. USA 116, 7813–7818 (2019).

    CAS  PubMed  Google Scholar 

  82. 82.

    Peng, B. Z. et al. Active role of elongation factor G in maintaining the mRNA reading frame during translation. Sci. Adv. 5, eaax8030 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Bauerschmitt, H., Funes, S. & Herrmann, J. M. The membrane-bound GTPase Guf1 promotes mitochondrial protein synthesis under suboptimal conditions. J. Biol. Chem. 283, 17139–17146 (2008).

    CAS  PubMed  Google Scholar 

  84. 84.

    Yang, F. et al. Mitochondrial EF4 links respiratory dysfunction and cytoplasmic translation in Caenorhabditis elegans. Biochim. Biophys. Acta 1837, 1674–1683 (2014).

    CAS  PubMed  Google Scholar 

  85. 85.

    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 

  86. 86.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Ott, M. et al. Mba1, a membrane-associated ribosome receptor in mitochondria. EMBO J. 25, 1603–1610 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Haque, M. E. et al. Properties of the C-terminal tail of human mitochondrial inner membrane protein Oxa1L and its interactions with mammalian mitochondrial ribosomes. J. Biol. Chem. 285, 28353–28362 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Escobar-Alvarez, S. et al. Inhibition of human peptide deformylase disrupts mitochondrial function. Mol. Cell Biol. 30, 5099–5109 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Lee, M. D. et al. A new human peptide deformylase inhibitable by actinonin. Biochem. Biophys. Res. Commun. 312, 309–315 (2003).

    CAS  PubMed  Google Scholar 

  91. 91.

    Nguyen, K. T. et al. Characterization of a human peptide deformylase: implications for antibacterial drug design. Biochemistry 42, 9952–9958 (2003).

    CAS  PubMed  Google Scholar 

  92. 92.

    Serero, A., Giglione, C., Sardini, A., Martinez-Sanz, J. & Meinnel, T. An unusual peptide deformylase features in the human mitochondrial N-terminal methionine excision pathway. J. Biol. Chem. 278, 52953–52963 (2003).

    CAS  PubMed  Google Scholar 

  93. 93.

    Leszczyniecka, M. et al. MAP1D, a novel methionine aminopeptidase family member is overexpressed in colon cancer. Oncogene 25, 3471–3478 (2006).

    CAS  PubMed  Google Scholar 

  94. 94.

    Greber, B. J. et al. Architecture of the large subunit of the mammalian mitochondrial ribosome. Nature 505, 515–519 (2014).

    CAS  PubMed  Google Scholar 

  95. 95.

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

    CAS  PubMed  Google Scholar 

  96. 96.

    Englmeier, R., Pfeffer, S. & Forster, F. Structure of the human mitochondrial ribosome studied in situ by cryoelectron tomography. Structure 25, 1574–1581 e1572 (2017). Together with Pfeffer et al. (2015), this paper is the first visualization of mitochondrial ribosomes inside the mitochondrion.

    CAS  PubMed  Google Scholar 

  97. 97.

    Lee, R. G. et al. Cardiolipin is required for membrane docking of mitochondrial ribosomes and protein synthesis. J. Cell Sci. https://doi.org/10.1242/jcs.240374 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Barrell, B. G., Bankier, A. T. & Drouin, J. A different genetic code in human mitochondria. Nature 282, 189–194 (1979).

    CAS  PubMed  Google Scholar 

  99. 99.

    Anderson, S. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457–465 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Akabane, S., Ueda, T., Nierhaus, K. H. & Takeuchi, N. Ribosome rescue and translation termination at non-standard stop codons by ICT1 in mammalian mitochondria. PLoS Genet. 10, e1004616 (2014).

    PubMed  PubMed Central  Google Scholar 

  101. 101.

    Soleimanpour-Lichaei, H. R. et al. mtRF1a is a human mitochondrial translation release factor decoding the major termination codons UAA and UAG. Mol. Cell 27, 745–757 (2007). This study discovers that mtRF1a is the translation termination factor recognizing canonical stop codons.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Nozaki, Y., Matsunaga, N., Ishizawa, T., Ueda, T. & Takeuchi, N. HMRF1L is a human mitochondrial translation release factor involved in the decoding of the termination codons UAA and UAG. Genes Cell 13, 429–438 (2008).

    CAS  Google Scholar 

  103. 103.

    Richter, R. et al. A functional peptidyl-tRNA hydrolase, ICT1, has been recruited into the human mitochondrial ribosome. EMBO J. 29, 1116–1125 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Kogure, H. et al. Identification of residues required for stalled-ribosome rescue in the codon-independent release factor YaeJ. Nucleic Acids Res. 42, 3152–3163 (2014).

    CAS  PubMed  Google Scholar 

  105. 105.

    Wesolowska, M. T., Richter-Dennerlein, R., Lightowlers, R. N. & Chrzanowska-Lightowlers, Z. M. Overcoming stalled translation in human mitochondria. Front. Microbiol. 5, 374 (2014).

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Feaga, H. A., Quickel, M. D., Hankey-Giblin, P. A. & Keiler, K. C. Human cells require non-stop ribosome rescue activity in mitochondria. PLoS Genet. 12, e1005964 (2016).

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Lind, C., Sund, J. & Aqvist, J. Codon-reading specificities of mitochondrial release factors and translation termination at non-standard stop codons. Nat. Commun. 4, 2940 (2013).

    PubMed  Google Scholar 

  108. 108.

    Temperley, R., Richter, R., Dennerlein, S., Lightowlers, R. N. & Chrzanowska-Lightowlers, Z. M. Hungry codons promote frameshifting in human mitochondrial ribosomes. Science 327, 301 (2010).

    CAS  PubMed  Google Scholar 

  109. 109.

    Young, D. J. et al. Bioinformatic, structural, and functional analyses support release factor-like MTRF1 as a protein able to decode nonstandard stop codons beginning with adenine in vertebrate mitochondria. RNA 16, 1146–1155 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Desai, N. et al. Elongational stalling activates mitoribosome-associated quality control. Science 370, 1105–1110 (2020). This paper is the first description of a mitoribosomal rescue pathway that alleviates ribosome stalling.

    CAS  PubMed  Google Scholar 

  111. 111.

    Pearce, S. F. et al. Maturation of selected human mitochondrial tRNAs requires deadenylation. eLife https://doi.org/10.7554/eLife.27596 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Gopalakrishna, S. et al. C6orf203 is an RNA-binding protein involved in mitochondrial protein synthesis. Nucleic Acids Res. 47, 9386–9399 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Christian, B. E. & Spremulli, L. L. Evidence for an active role of IF3mt in the initiation of translation in mammalian mitochondria. Biochemistry 48, 3269–3278 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Lavdovskaia, E. et al. Dual function of GTPBP6 in biogenesis and recycling of human mitochondrial ribosomes. Nucleic Acids Res. 48, 12929–12942 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Zhang, Y. et al. HflX is a ribosome-splitting factor rescuing stalled ribosomes under stress conditions. Nat. Struct. Mol. Biol. 22, 906–913 (2015).

    CAS  PubMed  Google Scholar 

  116. 116.

    Chujo, T. et al. LRPPRC/SLIRP suppresses PNPase-mediated mRNA decay and promotes polyadenylation in human mitochondria. Nucleic Acids Res. 40, 8033–8047 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Nagao, A., Hino-Shigi, N. & Suzuki, T. Measuring mRNA decay in human mitochondria. Methods Enzymol. 447, 489–499 (2008).

    CAS  PubMed  Google Scholar 

  118. 118.

    Piechota, J. et al. Differential stability of mitochondrial mRNA in HeLa cells. Acta Biochim. Pol. 53, 157–168 (2006).

    CAS  PubMed  Google Scholar 

  119. 119.

    Jourdain, A. A. et al. The FASTK family of proteins: emerging regulators of mitochondrial RNA biology. Nucleic Acids Res. 45, 10941–10947 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Lagouge, M. et al. SLIRP regulates the rate of mitochondrial protein synthesis and protects LRPPRC from degradation. PLoS Genet. 11, e1005423 (2015).

    PubMed  PubMed Central  Google Scholar 

  121. 121.

    Ruzzenente, B. et al. LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs. EMBO J. 31, 443–456 (2012).

    CAS  PubMed  Google Scholar 

  122. 122.

    Kehrein, K. et al. Organization of mitochondrial gene expression in two distinct ribosome-containing assemblies. Cell Rep. 10, 843–853 (2015).

    CAS  PubMed  Google Scholar 

  123. 123.

    Aibara, S., Singh, V., Modelska, A. & Amunts, A. Structural basis of mitochondrial translation. eLife https://doi.org/10.7554/eLife.58362 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Popow, J. et al. FASTKD2 is an RNA-binding protein required for mitochondrial RNA processing and translation. RNA 21, 1873–1884 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Hillen, H. S., Temiakov, D. & Cramer, P. Structural basis of mitochondrial transcription. Nat. Struct. Mol. Biol. 25, 754–765 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Barchiesi, A. & Vascotto, C. Transcription, processing, and decay of mitochondrial RNA in health and disease. Int. J. Mol. Sci. https://doi.org/10.3390/ijms20092221 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  127. 127.

    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 

  128. 128.

    Holzmann, J. et al. RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme. Cell 135, 462–474 (2008). This paper identifies the unusual protein-only RNase P in mitochondria.

    CAS  PubMed  Google Scholar 

  129. 129.

    Brzezniak, L. K., Bijata, M., Szczesny, R. J. & Stepien, P. P. Involvement of human ELAC2 gene product in 3′ end processing of mitochondrial tRNAs. RNA Biol. 8, 616–626 (2011).

    CAS  PubMed  Google Scholar 

  130. 130.

    Rossmanith, W. Localization of human RNase Z isoforms: dual nuclear/mitochondrial targeting of the ELAC2 gene product by alternative translation initiation. PLoS ONE 6, e19152 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Sanchez, M. I. et al. RNA processing in human mitochondria. Cell Cycle 10, 2904–2916 (2011).

    CAS  PubMed  Google Scholar 

  132. 132.

    Nagaike, T. et al. Identification and characterization of mammalian mitochondrial tRNA nucleotidyltransferases. J. Biol. Chem. 276, 40041–40049 (2001).

    CAS  PubMed  Google Scholar 

  133. 133.

    Mercer, T. R. et al. The human mitochondrial transcriptome. Cell 146, 645–658 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Ali, A. T. et al. Nuclear genetic regulation of the human mitochondrial transcriptome. eLife https://doi.org/10.7554/eLife.41927 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Borowski, L. S., Dziembowski, A., Hejnowicz, M. S., Stepien, P. P. & Szczesny, R. J. Human mitochondrial RNA decay mediated by PNPase–hSuv3 complex takes place in distinct foci. Nucleic Acids Res. 41, 1223–1240 (2013).

    CAS  PubMed  Google Scholar 

  136. 136.

    Szczesny, R. J. et al. Human mitochondrial RNA turnover caught in flagranti: involvement of hSuv3p helicase in RNA surveillance. Nucleic Acids Res. 38, 279–298 (2010).

    CAS  PubMed  Google Scholar 

  137. 137.

    Nagaike, T., Suzuki, T., Katoh, T. & Ueda, T. Human mitochondrial mRNAs are stabilized with polyadenylation regulated by mitochondria-specific poly(A) polymerase and polynucleotide phosphorylase. J. Biol. Chem. 280, 19721–19727 (2005).

    CAS  PubMed  Google Scholar 

  138. 138.

    Wang, D. D. et al. Helicase SUV3, polynucleotide phosphorylase, and mitochondrial polyadenylation polymerase form a transient complex to modulate mitochondrial mRNA polyadenylated tail lengths in response to energetic changes. J. Biol. Chem. 289, 16727–16735 (2014).

    PubMed  PubMed Central  Google Scholar 

  139. 139.

    Jourdain, A. A. et al. A mitochondria-specific isoform of FASTK is present in mitochondrial RNA granules and regulates gene expression and function. Cell Rep. 10, 1110–1121 (2015).

    CAS  PubMed  Google Scholar 

  140. 140.

    Pietras, Z. et al. Dedicated surveillance mechanism controls G-quadruplex forming non-coding RNAs in human mitochondria. Nat. Commun. 9, 2558 (2018). This paper is the first description of the specific role of GRSF1 in removal of G quadruplex-containing light-strand transcripts to preserve the mitochondrial transcriptome.

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Wang, G. et al. PNPASE regulates RNA import into mitochondria. Cell 142, 456–467 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Silva, S., Camino, L. P. & Aguilera, A. Human mitochondrial degradosome prevents harmful mitochondrial R loops and mitochondrial genome instability. Proc. Natl Acad. Sci. USA 115, 11024–11029 (2018).

    CAS  PubMed  Google Scholar 

  143. 143.

    Dhir, A. et al. Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature 560, 238–242 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Siira, S. J. et al. LRPPRC-mediated folding of the mitochondrial transcriptome. Nat. Commun. 8, 1532 (2017).

    PubMed  PubMed Central  Google Scholar 

  145. 145.

    Sasarman, F. et al. LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria. Mol. Biol. Cell 21, 1315–1323 (2010). Together with Siira et al. (2017), this paper discovers LRPPRC–SLIRP as a general mitochondrial RNA chaperone.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Wilson, W. C. et al. A human mitochondrial poly(A) polymerase mutation reveals the complexities of post-transcriptional mitochondrial gene expression. Hum. Mol. Genet. 23, 6345–6355 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Wolf, A. R. & Mootha, V. K. Functional genomic analysis of human mitochondrial RNA processing. Cell Rep. 7, 918–931 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Boehm, E. et al. FASTKD1 and FASTKD4 have opposite effects on expression of specific mitochondrial RNAs, depending upon their endonuclease-like RAP domain. Nucleic Acids Res. 45, 6135–6146 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Boehm, E. et al. Role of FAST kinase domains 3 (FASTKD3) in post-transcriptional regulation of mitochondrial gene expression. J. Biol. Chem. 291, 25877–25887 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Antonicka, H., Sasarman, F., Nishimura, T., Paupe, V. & Shoubridge, E. A. The mitochondrial RNA-binding protein GRSF1 localizes to RNA granules and is required for posttranscriptional mitochondrial gene expression. Cell Metab. 17, 386–398 (2013). Together with Jourdain et al. (2013) and Antonicka and Shoubridge (2015), this paper is the first description of mitochondrial RNA granules.

    CAS  PubMed  Google Scholar 

  151. 151.

    Rackham, O. et al. Long noncoding RNAs are generated from the mitochondrial genome and regulated by nuclear-encoded proteins. RNA 17, 2085–2093 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Levy, S. & Schuster, G. Polyadenylation and degradation of RNA in the mitochondria. Biochem. Soc. Trans. 44, 1475–1482 (2016).

    CAS  PubMed  Google Scholar 

  153. 153.

    Slomovic, S., Portnoy, V., Liveanu, V. & Schuster, G. RNA polyadenylation in prokaryotes and organelles; different tails tell different tales. Crit. Rev. Plant. Sci. 25, 65–77 (2007).

    Google Scholar 

  154. 154.

    Hammani, K. & Giege, P. RNA metabolism in plant mitochondria. Trends Plant. Sci. 19, 380–389 (2014).

    CAS  PubMed  Google Scholar 

  155. 155.

    Tomecki, R., Dmochowska, A., Gewartowski, K., Dziembowski, A. & Stepien, P. P. Identification of a novel human nuclear-encoded mitochondrial poly(A) polymerase. Nucleic Acids Res. 32, 6001–6014 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Hirsch, M. & Penman, S. Post-transcriptional addition of polyadenylic acid to mitochondrial RNA by a cordycepin-insensitive process. J. Mol. Biol. 83, 131–142 (1974).

    CAS  PubMed  Google Scholar 

  157. 157.

    Fiedler, M., Rossmanith, W., Wahle, E. & Rammelt, C. Mitochondrial poly(A) polymerase is involved in tRNA repair. Nucleic Acids Res. 43, 9937–9949 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Bratic, A. et al. Mitochondrial polyadenylation is a one-step process required for mRNA integrity and tRNA maturation. PLoS Genet. 12, e1006028 (2016).

    PubMed  PubMed Central  Google Scholar 

  159. 159.

    Slomovic, S., Laufer, D., Geiger, D. & Schuster, G. Polyadenylation and degradation of human mitochondrial RNA: the prokaryotic past leaves its mark. Mol. Cell Biol. 25, 6427–6435 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160.

    Toompuu, M. et al. Polyadenylation and degradation of structurally abnormal mitochondrial tRNAs in human cells. Nucleic Acids Res. 46, 5209–5226 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Kuznetsova, I. et al. Simultaneous processing and degradation of mitochondrial RNAs revealed by circularized RNA sequencing. Nucleic Acids Res. 45, 5487–5500 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Temperley, R. J. et al. Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria. Hum. Mol. Genet. 12, 2341–2348 (2003).

    CAS  PubMed  Google Scholar 

  163. 163.

    Wydro, M., Bobrowicz, A., Temperley, R. J., Lightowlers, R. N. & Chrzanowska-Lightowlers, Z. M. Targeting of the cytosolic poly(A) binding protein PABPC1 to mitochondria causes mitochondrial translation inhibition. Nucleic Acids Res. 38, 3732–3742 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Slomovic, S. & Schuster, G. Stable PNPase RNAi silencing: its effect on the processing and adenylation of human mitochondrial RNA. RNA 14, 310–323 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Rorbach, J., Nicholls, T. J. & Minczuk, M. PDE12 removes mitochondrial RNA poly(A) tails and controls translation in human mitochondria. Nucleic Acids Res. 39, 7750–7763 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Poulsen, J. B. et al. Human 2′-phosphodiesterase localizes to the mitochondrial matrix with a putative function in mitochondrial RNA turnover. Nucleic Acids Res. 39, 3754–3770 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Couvillion, M. T., Soto, I. C., Shipkovenska, G. & Churchman, L. S. Synchronized mitochondrial and cytosolic translation programs. Nature 533, 499–503 (2016). This paper describes unidirectional coupling of cytosolic and mitochondrial translation in yeast.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Isaac, R. S., McShane, E. & Churchman, L. S. The multiple levels of mitonuclear coregulation. Annu. Rev. Genet. 52, 511–533 (2018).

    CAS  PubMed  Google Scholar 

  169. 169.

    Weraarpachai, W. et al. Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nat. Genet. 41, 833–837 (2009).

    CAS  PubMed  Google Scholar 

  170. 170.

    Richman, T. R. et al. Loss of the RNA-binding protein TACO1 causes late-onset mitochondrial dysfunction in mice. Nat. Commun. 7, 11884 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Richter-Dennerlein, R. et al. Mitochondrial protein synthesis adapts to influx of nuclear-encoded protein. Cell 167, 471–483.e10 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Wang, C. et al. MITRAC15/COA1 promotes mitochondrial translation in a ND2 ribosome–nascent chain complex. EMBO Rep. 21, e48833 (2020).

    CAS  PubMed  Google Scholar 

  173. 173.

    Mick, D. U. et al. MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation. Cell 151, 1528–1541 (2012). This paper is the first description of the role of OXPHOS assembly factors in feedback regulation of mitochondrial translation to the import of nuclear-encoded OXPHOS subunits in humans.

    CAS  PubMed  Google Scholar 

  174. 174.

    Weraarpachai, W. et al. Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis. Am. J. Hum. Genet. 90, 142–151 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Bogenhagen, D. F. & Haley, J. D. Pulse-chase SILAC-based analyses reveal selective oversynthesis and rapid turnover of mitochondrial protein components of respiratory complexes. J. Biol. Chem. 295, 2544–2554 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Quiros, P. M., Mottis, A. & Auwerx, J. Mitonuclear communication in homeostasis and stress. Nat. Rev. Mol. Cell Biol. 17, 213–226 (2016).

    CAS  PubMed  Google Scholar 

  177. 177.

    Michel, S., Canonne, M., Arnould, T. & Renard, P. Inhibition of mitochondrial genome expression triggers the activation of CHOP-10 by a cell signaling dependent on the integrated stress response but not the mitochondrial unfolded protein response. Mitochondrion 21, 58–68 (2015).

    CAS  PubMed  Google Scholar 

  178. 178.

    Houtkooper, R. H. et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497, 451–457 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179.

    Quiros, 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Ferreira, N. et al. Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation. EMBO J. 38, e102155 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    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 

  183. 183.

    Weidberg, H. & Amon, A. MitoCPR — a surveillance pathway that protects mitochondria in response to protein import stress. Science https://doi.org/10.1126/science.aan4146 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  184. 184.

    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 

  185. 185.

    Wrobel, L. et al. Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature 524, 485–488 (2015).

    CAS  PubMed  Google Scholar 

  186. 186.

    Boos, F. et al. Mitochondrial protein-induced stress triggers a global adaptive transcriptional programme. Nat. Cell Biol. 21, 442–451 (2019). This paper identifies the integration of mitochondrial precursor accumulation stress into the general heat shock response.

    CAS  PubMed  Google Scholar 

  187. 187.

    Suhm, T. et al. Mitochondrial translation efficiency controls cytoplasmic protein homeostasis. Cell Metab. 27, 1309–1322.e6 (2018).

    CAS  PubMed  Google Scholar 

  188. 188.

    Zhao, Q. et al. A mitochondrial specific stress response in mammalian cells. EMBO J. 21, 4411–4419 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Aldridge, J. E., Horibe, T. & Hoogenraad, N. J. Discovery of genes activated by the mitochondrial unfolded protein response (mtUPR) and cognate promoter elements. PLoS ONE 2, e874 (2007).

    PubMed  PubMed Central  Google Scholar 

  190. 190.

    Fakruddin, M. et al. Defective mitochondrial tRNA taurine modification activates global proteostress and leads to mitochondrial disease. Cell Rep. 22, 482–496 (2018).

    CAS  PubMed  Google Scholar 

  191. 191.

    Song, J., Herrmann, J. M. & Becker, T. Quality control of the mitochondrial proteome. Nat. Rev. Mol. Cell Biol. 22, 54–70 (2021).

    CAS  PubMed  Google Scholar 

  192. 192.

    Fessler, E. et al. A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol. Nature 579, 433–437 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193.

    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 

  194. 194.

    Khan, N. A. et al. mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression. Cell Metab. 26, 419–428.e5 (2017).

    CAS  PubMed  Google Scholar 

  195. 195.

    Morita, M. et al. mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metab. 18, 698–711 (2013).

    CAS  PubMed  Google Scholar 

  196. 196.

    Donnelly, N., Gorman, A. M., Gupta, S. & Samali, A. The eIF2α kinases: their structures and functions. Cell Mol. Life Sci. 70, 3493–3511 (2013).

    CAS  PubMed  Google Scholar 

  197. 197.

    Martinus, R. D. et al. Selective induction of mitochondrial chaperones in response to loss of the mitochondrial genome. Eur. J. Biochem. 240, 98–103 (1996).

    CAS  PubMed  Google Scholar 

  198. 198.

    Rainbolt, T. K., Atanassova, N., Genereux, J. C. & Wiseman, R. L. Stress-regulated translational attenuation adapts mitochondrial protein import through Tim17A degradation. Cell Metab. 18, 908–919 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199.

    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 

  200. 200.

    Cunningham, J. T. et al. mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex. Nature 450, 736–740 (2007).

    CAS  PubMed  Google Scholar 

  201. 201.

    Torrence, M. E. et al. The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals. Preprint bioRxiv https://doi.org/10.1101/2020.10.03.324186 (2020).

    Article  Google Scholar 

  202. 202.

    Ben-Sahra, I., Hoxhaj, G., Ricoult, S. J. H., Asara, J. M. & Manning, B. D. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 351, 728–733 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203.

    Park, Y., Reyna-Neyra, A., Philippe, L. & Thoreen, C. C. mTORC1 balances cellular amino acid supply with demand for protein synthesis through post-transcriptional control of ATF4. Cell Rep. 19, 1083–1090 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204.

    Molenaars, M. et al. A conserved mito-cytosolic translational balance links two longevity pathways. Cell Metab. 31, 549–563.e7 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205.

    Fernandez-Marcos, P. J. & Auwerx, J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am. J. Clin. Nutr. 93, 884S–890S (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206.

    Gleyzer, N., Vercauteren, K. & Scarpulla, R. C. Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol. Cell Biol. 25, 1354–1366 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 207.

    Virbasius, J. V. & Scarpulla, R. C. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc. Natl Acad. Sci. USA 91, 1309–1313 (1994).

    CAS  PubMed  Google Scholar 

  208. 208.

    Cam, H. et al. A common set of gene regulatory networks links metabolism and growth inhibition. Mol. Cell 16, 399–411 (2004).

    CAS  PubMed  Google Scholar 

  209. 209.

    Scarpulla, R. C. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol. Rev. 88, 611–638 (2008).

    CAS  PubMed  Google Scholar 

  210. 210.

    Lehtonen, J. M. et al. FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders. Neurology 87, 2290–2299 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211.

    Suomalainen, A. & Battersby, B. J. Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat. Rev. Mol. Cell Biol. 19, 77–92 (2018).

    CAS  PubMed  Google Scholar 

  212. 212.

    Hill, S. & Van Remmen, H. Mitochondrial stress signaling in longevity: a new role for mitochondrial function in aging. Redox Biol. 2, 936–944 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. 213.

    Ferrari, A., Del’Olio, S. & Barrientos, A. The diseased mitoribosome. FEBS Lett. https://doi.org/10.1002/1873-3468.14024 (2020).

    Article  PubMed  Google Scholar 

  214. 214.

    Levinger, L., Morl, M. & Florentz, C. Mitochondrial tRNA 3′ end metabolism and human disease. Nucleic Acids Res. 32, 5430–5441 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. 215.

    Di Nottia, M. et al. A homozygous MRPL24 mutation causes a complex movement disorder and affects the mitoribosome assembly. Neurobiol. Dis. 141, 104880 (2020).

    PubMed  Google Scholar 

  216. 216.

    Serre, V. et al. Mutations in mitochondrial ribosomal protein MRPL12 leads to growth retardation, neurological deterioration and mitochondrial translation deficiency. Biochim. Biophys. Acta 1832, 1304–1312 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. 217.

    Emdadul Haque, M., Grasso, D., Miller, C., Spremulli, L. L. & Saada, A. The effect of mutated mitochondrial ribosomal proteins S16 and S22 on the assembly of the small and large ribosomal subunits in human mitochondria. Mitochondrion 8, 254–261 (2008).

    CAS  PubMed  Google Scholar 

  218. 218.

    Lake, N. J. et al. Biallelic mutations in MRPS34 lead to instability of the small mitoribosomal subunit and Leigh syndrome. Am. J. Hum. Genet. 101, 239–254 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. 219.

    Richman, T. R. et al. Mutation in MRPS34 compromises protein synthesis and causes mitochondrial dysfunction. PLoS Genet. 11, e1005089 (2015).

    PubMed  PubMed Central  Google Scholar 

  220. 220.

    Menezes, M. J. et al. Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. Hum. Mol. Genet. 24, 2297–2307 (2015).

    CAS  PubMed  Google Scholar 

  221. 221.

    Jackson, C. B. et al. A variant in MRPS14 (uS14m) causes perinatal hypertrophic cardiomyopathy with neonatal lactic acidosis, growth retardation, dysmorphic features and neurological involvement. Hum. Mol. Genet. 28, 639–649 (2019).

    CAS  PubMed  Google Scholar 

  222. 222.

    Huang, G., Li, H. & Zhang, H. Abnormal expression of mitochondrial ribosomal proteins and their encoding genes with cell apoptosis and diseases. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21228879 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  223. 223.

    Greber, B. J. et al. The complete structure of the large subunit of the mammalian mitochondrial ribosome. Nature 515, 283–286 (2014).

    CAS  PubMed  Google Scholar 

  224. 224.

    Brown, A. et al. Structure of the large ribosomal subunit from human mitochondria. Science 346, 718–722 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. 225.

    Rorbach, J. et al. Human mitochondrial ribosomes can switch their structural RNA composition. Proc. Natl Acad. Sci. USA 113, 12198–12201 (2016).

    CAS  PubMed  Google Scholar 

  226. 226.

    Suzuki, T. et al. Proteomic analysis of the mammalian mitochondrial ribosome. Identification of protein components in the 28S small subunit. J. Biol. Chem. 276, 33181–33195 (2001).

    CAS  PubMed  Google Scholar 

  227. 227.

    Sharma, M. R. et al. Structure of the mammalian mitochondrial ribosome reveals an expanded functional role for its component proteins. Cell 115, 97–108 (2003).

    CAS  PubMed  Google Scholar 

  228. 228.

    Amunts, A., Brown, A., Toots, J., Scheres, S. H. W. & Ramakrishnan, V. Ribosome. The structure of the human mitochondrial ribosome. Science 348, 95–98 (2015). Together with Greber et al. (2015), this paper is the first near-atomic description of the architecture of the mammalian mitoribosome.

    CAS  PubMed  PubMed Central  Google Scholar 

  229. 229.

    Amunts, A. et al. Structure of the yeast mitochondrial large ribosomal subunit. Science 343, 1485–1489 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230.

    Desai, N., Brown, A., Amunts, A. & Ramakrishnan, V. The structure of the yeast mitochondrial ribosome. Science 355, 528–531 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. 231.

    Waltz, F., Soufari, H., Bochler, A., Giege, P. & Hashem, Y. Cryo-EM structure of the RNA-rich plant mitochondrial ribosome. Nat. Plants 6, 377–383 (2020).

    PubMed  Google Scholar 

  232. 232.

    Tobiasson, V. & Amunts, A. Ciliate mitoribosome illuminates evolutionary steps of mitochondrial translation. eLife https://doi.org/10.7554/eLife.59264 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  233. 233.

    Sloan, D. B. et al. Cytonuclear integration and co-evolution. Nat. Rev. Genet. 19, 635–648 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. 234.

    Petrov, A. S. et al. Structural patching fosters divergence of mitochondrial ribosomes. Mol. Biol. Evol. 36, 207–219 (2019).

    CAS  PubMed  Google Scholar 

  235. 235.

    Rodel, G. Two yeast nuclear genes, CBS1 and CBS2, are required for translation of mitochondrial transcripts bearing the 5′-untranslated COB leader. Curr. Genet. 11, 41–45 (1986).

    CAS  PubMed  Google Scholar 

  236. 236.

    Islas-Osuna, M. A., Ellis, T. P., Marnell, L. L., Mittelmeier, T. M. & Dieckmann, C. L. Cbp1 is required for translation of the mitochondrial cytochrome b mRNA of Saccharomyces cerevisiae. J. Biol. Chem. 277, 37987–37990 (2002).

    CAS  PubMed  Google Scholar 

  237. 237.

    Mittelmeier, T. M. & Dieckmann, C. L. In vivo analysis of sequences required for translation of cytochrome b transcripts in yeast mitochondria. Mol. Cell Biol. 15, 780–789 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. 238.

    Gruschke, S. et al. Cbp3–Cbp6 interacts with the yeast mitochondrial ribosomal tunnel exit and promotes cytochrome b synthesis and assembly. J. Cell Biol. 193, 1101–1114 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. 239.

    Salvatori, R. et al. Molecular wiring of a mitochondrial translational feedback loop. Mol. Cell 77, 887–900.e5 (2020).

    CAS  PubMed  Google Scholar 

  240. 240.

    Tucker, E. J. et al. Mutations in the UQCC1-interacting protein, UQCC2, cause human complex III deficiency associated with perturbed cytochrome b protein expression. PLoS Genet. 9, e1004034 (2013).

    PubMed  PubMed Central  Google Scholar 

  241. 241.

    Manthey, G. M. & McEwen, J. E. The product of the nuclear gene PET309 is required for translation of mature mRNA and stability or production of intron-containing RNAs derived from the mitochondrial COX1 locus of Saccharomyces cerevisiae. EMBO J. 14, 4031–4043 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. 242.

    Tavares-Carreon, F. et al. The pentatricopeptide repeats present in Pet309 are necessary for translation but not for stability of the mitochondrial COX1 mRNA in yeast. J. Biol. Chem. 283, 1472–1479 (2008).

    CAS  PubMed  Google Scholar 

  243. 243.

    Roloff, G. A. & Henry, M. F. Mam33 promotes cytochrome c oxidase subunit I translation in Saccharomyces cerevisiae mitochondria. Mol. Biol. Cell 26, 2885–2894 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. 244.

    Decoster, E., Simon, M., Hatat, D. & Faye, G. The MSS51 gene product is required for the translation of the COX1 mRNA in yeast mitochondria. Mol. Gen. Genet. 224, 111–118 (1990).

    CAS  PubMed  Google Scholar 

  245. 245.

    Poutre, C. G. & Fox, T. D. PET111, a Saccharomyces cerevisiae nuclear gene required for translation of the mitochondrial mRNA encoding cytochrome c oxidase subunit II. Genetics 115, 637–647 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. 246.

    Costanzo, M. C. & Fox, T. D. Specific translational activation by nuclear gene products occurs in the 5′ untranslated leader of a yeast mitochondrial mRNA. Proc. Natl Acad. Sci. USA 85, 2677–2681 (1988).

    CAS  PubMed  Google Scholar 

  247. 247.

    De Silva, D. et al. The DEAD-box helicase Mss116 plays distinct roles in mitochondrial ribogenesis and mRNA-specific translation. Nucleic Acids Res. 45, 6628–6643 (2017).

    PubMed  PubMed Central  Google Scholar 

  248. 248.

    Brown, N. G., Costanzo, M. C. & Fox, T. D. Interactions among three proteins that specifically activate translation of the mitochondrial COX3 mRNA in Saccharomyces cerevisiae. Mol. Cell Biol. 14, 1045–1053 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  249. 249.

    Green-Willms, N. S., Butler, C. A., Dunstan, H. M. & Fox, T. D. Pet111p, an inner membrane-bound translational activator that limits expression of the Saccharomyces cerevisiae mitochondrial gene COX2. J. Biol. Chem. 276, 6392–6397 (2001).

    CAS  PubMed  Google Scholar 

  250. 250.

    Manthey, G. M., Przybyla-Zawislak, B. D. & McEwen, J. E. The Saccharomyces cerevisiae Pet309 protein is embedded in the mitochondrial inner membrane. Eur. J. Biochem. 255, 156–161 (1998).

    CAS  PubMed  Google Scholar 

  251. 251.

    Naithani, S., Saracco, S. A., Butler, C. A. & Fox, T. D. Interactions among COX1, COX2, and COX3 mRNA-specific translational activator proteins on the inner surface of the mitochondrial inner membrane of Saccharomyces cerevisiae. Mol. Biol. Cell 14, 324–333 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  252. 252.

    Zamudio-Ochoa, A., Camacho-Villasana, Y., Garcia-Guerrero, A. E. & Perez-Martinez, X. The Pet309 pentatricopeptide repeat motifs mediate efficient binding to the mitochondrial COX1 transcript in yeast. RNA Biol. 11, 953–967 (2014).

    PubMed  PubMed Central  Google Scholar 

  253. 253.

    Siep, M., van Oosterum, K., Neufeglise, H., van der Spek, H. & Grivell, L. A. Mss51p, a putative translational activator of cytochrome c oxidase subunit-1 (COX1) mRNA, is required for synthesis of Cox1p in Saccharomyces cerevisiae. Curr. Genet. 37, 213–220 (2000).

    CAS  PubMed  Google Scholar 

  254. 254.

    Barrientos, A., Korr, D. & Tzagoloff, A. Shy1p is necessary for full expression of mitochondrial COX1 in the yeast model of Leigh’s syndrome. EMBO J. 21, 43–52 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  255. 255.

    Perez-Martinez, X., Broadley, S. A. & Fox, T. D. Mss51p promotes mitochondrial Cox1p synthesis and interacts with newly synthesized Cox1p. EMBO J. 22, 5951–5961 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. 256.

    Barrientos, A., Zambrano, A. & Tzagoloff, A. Mss51p and Cox14p jointly regulate mitochondrial Cox1p expression in Saccharomyces cerevisiae. EMBO J. 23, 3472–3482 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. 257.

    Mick, D. U. et al. Shy1 couples Cox1 translational regulation to cytochrome c oxidase assembly. EMBO J. 26, 4347–4358 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. 258.

    Mick, D. U. et al. Coa3 and Cox14 are essential for negative feedback regulation of COX1 translation in mitochondria. J. Cell Biol. 191, 141–154 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. 259.

    Zambrano, A. et al. Aberrant translation of cytochrome c oxidase subunit 1 mRNA species in the absence of Mss51p in the yeast Saccharomyces cerevisiae. Mol. Biol. Cell 18, 523–535 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. 260.

    Pierrel, F. et al. Coa1 links the Mss51 post-translational function to Cox1 cofactor insertion in cytochrome c oxidase assembly. EMBO J. 26, 4335–4346 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. 261.

    Fontanesi, F., Clemente, P. & Barrientos, A. Cox25 teams up with Mss51, Ssc1, and Cox14 to regulate mitochondrial cytochrome c oxidase subunit 1 expression and assembly in Saccharomyces cerevisiae. J. Biol. Chem. 286, 555–566 (2011).

    CAS  PubMed  Google Scholar 

  262. 262.

    Perez-Martinez, X., Butler, C. A., Shingu-Vazquez, M. & Fox, T. D. Dual functions of Mss51 couple synthesis of Cox1 to assembly of cytochrome c oxidase in Saccharomyces cerevisiae mitochondria. Mol. Biol. Cell 20, 4371–4380 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  263. 263.

    Helfenbein, K. G., Ellis, T. P., Dieckmann, C. L. & Tzagoloff, A. ATP22, a nuclear gene required for expression of the F0 sector of mitochondrial ATPase in Saccharomyces cerevisiae. J. Biol. Chem. 278, 19751–19756 (2003).

    CAS  PubMed  Google Scholar 

  264. 264.

    Rak, M. et al. Regulation of mitochondrial translation of the ATP8/ATP6 mRNA by Smt1p. Mol. Biol. Cell 27, 919–929 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. 265.

    Rak, M. & Tzagoloff, A. F1-dependent translation of mitochondrially encoded Atp6p and Atp8p subunits of yeast ATP synthase. Proc. Natl Acad. Sci. USA 106, 18509–18514 (2009).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank A. Filipovska, T. Lenarcic, M.Saurer and M. Jaskolowski for critical reading of the manuscript and helpful comments. They also thank all referees for helpful comments. The authors apologize to everyone whose work unfortunately could not be included in this review due to space restrictions. E.K. was supported by a European Molecular Biology Organization (EMBO) long-term fellowship (1196-2014). This work was supported by a Swiss National Science Foundation grant (310030B_163478) and via the National Centre of Excellence in RNA and Disease and project funding 138262 to N.B.

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E.K. conceptualized and wrote the manuscript and prepared the figures. N.B. edited the manuscript.

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Correspondence to Nenad Ban.

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Supplementary information

Glossary

Pseudouridylation

RNA modification whereby the nucleoside uridine is converted into an isomer, in which the nucleobase uracil is attached to the ribose via a carbon–carbon instead of a nitrogen–carbon bond.

Small nucleolar RNAs

Short RNA molecules that are usually found in complex with proteins and that target specific sites of ribosomal RNA (rRNA) to trigger modification of these rRNA sites by the associated protein component.

Peptidyl transferase centre

An active site of the large ribosomal subunit that catalyses peptide bond formation during protein synthesis.

Ribosomal P site

The peptidyl (P) site is one of three ribosomal tRNA binding sites and contains the tRNA carrying the nascent polypeptide chain.

Formylated methionine

(fMet-tRNAMet). A derivative of the amino acid methionine (Met-tRNAMet) that carries an additional formyl modification at its amino group.

Ribosomal A site

The aminoacyl (A) site is one of three ribosomal tRNA binding sites and contains the newly delivered, aminoacylated tRNA.

Ribosomal decoding centre

A site on the small ribosomal subunit at which the correct base pairing of the mRNA codon and the aminoacylated tRNA is probed.

Shine–Dalgarno sequence

A ribosomal binding site in bacterial mRNAs with the consensus sequence AGGAGG that is located upstream of the start codon and helps to align the ribosome with the start of the open reading frame.

Kozak sequence

A consensus sequence of the most frequent nucleobases surrounding the mRNA start codon in eukaryotes, which aids start codon recognition by the ribosome during translation initiation.

Pentatricopeptide repeat

(PPR). A conserved protein fold that usually occurs in tandem to mediate binding to RNAs or proteins.

Ribosomal GTPase-associated centre

A site on the large ribosomal subunit that contains multiple protein and RNA elements involved in binding and activation of translational GTPases.

Back-translocation

Backward movement of the tRNA–mRNA complex on the ribosome that may help to overcome ribosome stalling or that may reduce translation speed to facilitate co-translational protein folding.

–1 frameshifting

Movement of the ribosome on the mRNA in the 5′ direction by one nucleotide.

G-quadruplex structures

Guanosine-rich RNA or DNA sequences that fold into a stable secondary structure, in which four guanine nucleobases self-assemble via Hoogsteen hydrogen base pairing into a planar array.

Poly(A)-assisted RNA degradation

A 3′–5′ RNA decay pathway, in which a short poly(A) tail serves as a degron to initiate exonucleolytic RNA cleavage, for example in order to remove aberrant RNA fragments generated by endoribonucleases, and to control the abundance of regulatory non-coding RNAs.

Leigh syndrome

A severe neurological disorder driven by the degeneration of the central nervous system, which results, among others, in cognitive and movement disabilities.

OXPHOS assembly factors

Protein factors that aid the assembly but are not part of the oxidative phosphorylation (OXPHOS) complex. Assembly factors may, for example, stabilize assembly intermediates, modify OXPHOS subunits or mediate delivery of cofactors.

Mitochondrial membrane potential

The potential across the inner mitochondrial membrane due to an electrochemical proton gradient that is generated by oxidative phosphorylation.

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Kummer, E., Ban, N. Mechanisms and regulation of protein synthesis in mitochondria. Nat Rev Mol Cell Biol 22, 307–325 (2021). https://doi.org/10.1038/s41580-021-00332-2

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