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Inventory control: cytochrome c oxidase assembly regulates mitochondrial translation

Abstract

Mitochondria maintain genome and translation machinery to synthesize a small subset of subunits of the oxidative phosphorylation system. To build up functional enzymes, these organellar gene products must assemble with imported subunits that are encoded in the nucleus. New findings on the early steps of cytochrome c oxidase assembly reveal how the mitochondrial translation of its core component, cytochrome c oxidase subunit 1 (Cox1), is directly coupled to the assembly of this respiratory complex.

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Figure 1: Dual origin of cytochrome c oxidase subunits.
Figure 2: Mechanistic model for the translational regulation of Cox1.

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References

  1. Schmidt, O., Pfanner, N. & Meisinger, C. Mitochondrial protein import: from proteomics to functional mechanisms. Nature Rev. Mol. Cell Biol. 11, 655–667 (2010).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  3. Sickmann, A. et al. The proteome of Saccharomyces cerevisiae mitochondria. Proc. Natl Acad. Sci. USA 100, 13207–13212 (2003).

    Article  CAS  Google Scholar 

  4. Bonnefoy, N., Fiumera, H., Dujardin, G. & Fox, T. Roles of Oxa1-related inner-membrane translocases in assembly of respiratory chain complexes. Biochim. Biophys. Acta 1793, 60–70 (2009).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Jia, L., Kaur, J. & Stuart, R. A. Mapping of the Saccharomyces cerevisiae Oxa1-mitochondrial ribosome interface and identification of MrpL40, a ribosomal protein in close proximity to Oxa1 and critical for oxidative phosphorylation complex assembly. Eukaryotic Cell 8, 1792–1802 (2009).

    Article  CAS  Google Scholar 

  8. Kohler, R. et al. YidC and Oxa1 form dimeric insertion pores on the translating ribosome. Mol. Cell 34, 344–353 (2009).

    Article  CAS  Google Scholar 

  9. Hell, K., Neupert, W. & Stuart, R. Oxa1p acts as a general membrane insertion machinery for proteins encoded by mitochondrial DNA. EMBO J. 20, 1281–1288 (2001).

    Article  CAS  Google Scholar 

  10. Bohnert, M. et al. Cooperation of stop-transfer and conservative sorting mechanisms in mitochondrial protein transport. Curr. Biol. 20, 1227–1232 (2010).

    Article  CAS  Google Scholar 

  11. Barrientos, A. et al. Cytochrome oxidase in health and disease. Gene 286, 53–63 (2002).

    Article  CAS  Google Scholar 

  12. Tsukihara, T. et al. The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 Å. Science 272, 1136–1144 (1996).

    Article  CAS  Google Scholar 

  13. Mashkevich, G., Repetto, B., Glerum, D., Jin, C. & Tzagoloff, A. SHY1, the yeast homolog of the mammalian SURF-1 gene, encodes a mitochondrial protein required for respiration. J. Biol. Chem. 272, 14356–14364 (1997).

    Article  CAS  Google Scholar 

  14. Khalimonchuk, O., Bestwick, M., Meunier, B., Watts, T. C. & Winge, D. R. Formation of the redox cofactor centers during Cox1 maturation in yeast cytochrome oxidase. Mol. Cell Biol. 30, 1004–1017 (2010).

    Article  CAS  Google Scholar 

  15. Bundschuh, F., Hannappel, A., Anderka, O. & Ludwig, B. Surf1, associated with Leigh syndrome in humans, is a heme-binding protein in bacterial oxidase biogenesis. J. Biol. Chem. 284, 25735–25741 (2009).

    Article  CAS  Google Scholar 

  16. Pierrel, F., Khalimonchuk, O., Cobine, P. A., Bestwick, M. & Winge, D. R. Coa2 is an assembly factor for yeast cytochrome c oxidase biogenesis that facilitates the maturation of Cox1. Mol. Cell Biol. 28, 4927–4939 (2008).

    Article  CAS  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Bestwick, M., Jeong, M.-Y., Khalimonchuk, O., Kim, H. & Winge, D. R. Analysis of Leigh syndrome mutations in the yeast SURF1 homolog reveals a new member of the cytochrome oxidase assembly factor family. Mol. Cell Biol. 30, 4480–4491 (2010).

    Article  CAS  Google Scholar 

  20. Mick, D. U. et al. Coa3 and Cox14 are essential for negative feedback regulation of COX1 translation in mitochondria. J. Cell Biol. 191, 142–154 (2010).

    Article  Google Scholar 

  21. Bestwick, M., Khalimonchuk, O., Pierrel, F. & Winge, D. R. The role of Coa2 in hemylation of yeast Cox1 revealed by its genetic interaction with Cox10. Mol. Cell Biol. 30, 172–185 (2010).

    Article  CAS  Google Scholar 

  22. Frazier, A. et al. Mdm38 interacts with ribosomes and is a component of the mitochondrial protein export machinery. J. Cell Biol. 172, 553–564 (2006).

    Article  CAS  Google Scholar 

  23. Khalimonchuk, O., Ostermann, K. & Rödel, G. Evidence for the association of yeast mitochondrial ribosomes with Cox11p, a protein required for the CuB site formation of cytochrome c oxidase. Curr. Genet. 47, 223–233 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Bauerschmitt, H. et al. Ribosome-binding proteins Mdm38 and Mba1 display overlapping functions for regulation of mitochondrial translation. Mol. Biol. Cell 21, 1937–1944 (2010).

    Article  CAS  Google Scholar 

  26. Ostrander, D. B., Zhang, M., Mileykovskaya, E., Rho, M. & Dowhan, W. Lack of mitochondrial anionic phospholipids causes an inhibition of translation of protein components of the electron transport chain. A yeast genetic model system for the study of anionic phospholipid function in mitochondria. J. Biol. Chem. 276, 25262–25272 (2001).

    Article  CAS  Google Scholar 

  27. Towpik, J. Regulation of mitochondrial translation in yeast. Cell. Mol. Biol. Lett. 10, 571–594 (2005).

    CAS  PubMed  Google Scholar 

  28. Krause, K., Lopes de Souza, R., Roberts, D. G. W. & Dieckmann, C. L. The mitochondrial message-specific mRNA protectors Cbp1 and Pet309 are associated in a high-molecular weight complex. Mol. Biol. Cell 15, 2674–2683 (2004).

    Article  CAS  Google Scholar 

  29. 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).

    Article  CAS  Google Scholar 

  30. Sanchirico, M. E., Fox, T. D. & Mason, T. L. Accumulation of mitochondrially synthesized Saccharomyces cerevisiae Cox2p and Cox3p depends on targeting information in untranslated portions of their mRNAs. EMBO J. 17, 5796–5804 (1998).

    Article  CAS  Google Scholar 

  31. Tavares-Carreón, 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).

    Article  Google Scholar 

  32. Manthey, G. & McEwen, J. 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).

    Article  CAS  Google Scholar 

  33. Perez-Martinez, X., Butler, C., Shingu-Vazquez, M. & Fox, T. 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).

    Article  CAS  Google Scholar 

  34. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Khalimonchuk, O., Bird, A. & Winge, D. R. Evidence for a pro-oxidant intermediate in the assembly of cytochrome oxidase. J. Biol. Chem. 282, 17442–17449 (2007).

    Article  CAS  Google Scholar 

  38. Glerum, D., Koerner, T. & Tzagoloff, A. Cloning and characterization of COX14, whose product is required for assembly of yeast cytochrome oxidase. J. Biol. Chem. 270, 15585–15590 (1995).

    Article  CAS  Google Scholar 

  39. 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. 10 Nov 2010 (doi:10.1074/jbc.M110.188805).

    Article  Google Scholar 

  40. Arlt, H. et al. The formation of respiratory chain complexes in mitochondria is under the proteolytic control of the m-AAA protease. EMBO J. 17, 4837–4847 (1998).

    Article  CAS  Google Scholar 

  41. Guzelin, E., Rep., M. & Grivell, L. Afg3p, a mitochondrial ATP-dependent metalloprotease, is involved in degradation of mitochondrially-encoded Cox1, Cox3, Cob, Su6, Su8 and Su9 subunits of the inner membrane complexes, III, IV and, V. FEBS Lett. 381, 42–46 (1996).

    Article  CAS  Google Scholar 

  42. Fontanesi, F., Soto, I. C., Horn, D. & Barrientos, A. Mss51 and Ssc1 facilitate translational regulation of cytochrome c oxidase biogenesis. Mol. Cell Biol. 30, 245–259 (2010).

    Article  CAS  Google Scholar 

  43. Herrmann, J. M., Stuart, R. A., Craig, E. A. & Neupert, W. Mitochondrial heat shock protein 70, a molecular chaperone for proteins encoded by mitochondrial DNA. J. Cell Biol. 127, 893–902 (1994).

    Article  CAS  Google Scholar 

  44. Shingu-Vazquez, M. et al. The carboxyl-terminal end of Cox1 is required for feedback-assembly regulation of Cox1 synthesis in Saccharomyces cerevisiae mitochondria. J. Biol. Chem. 285, 34382–34389 (2010).

    Article  CAS  Google Scholar 

  45. Smith, D., Gray, J., Mitchell, L., Antholine, W. & Hosler, J. Assembly of cytochrome-c oxidase in the absence of assembly protein Surf1p leads to loss of the active site heme. J. Biol. Chem. 280, 17652–17656 (2005).

    Article  CAS  Google Scholar 

  46. 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).

    Article  CAS  Google Scholar 

  47. Fontanesi, F., Jin, C., Tzagoloff, A. & Barrientos, A. Transcriptional activators HAP/NF-Y rescue a cytochrome c oxidase defect in yeast and human cells. Hum. Mol. Genet. 17, 775–788 (2008).

    Article  CAS  Google Scholar 

  48. Horan, S., Bourges, I., Taanman, J. & Meunier, B. Analysis of COX2 mutants reveals cytochrome oxidase subassemblies in yeast. Biochem. J. 390, 703–708 (2005).

    Article  CAS  Google Scholar 

  49. Stiburek, L. et al. Tissue-specific cytochrome c oxidase assembly defects due to mutations in SCO2 and SURF1. Biochem. J. 392, 625–632 (2005).

    Article  CAS  Google Scholar 

  50. Wallace, D. C., Fan, W. & Procaccio, V. Mitochondrial energetics and therapeutics. Annu. Rev. Pathol. 5, 297–348 (2010).

    Article  CAS  Google Scholar 

  51. Leary, S. C. et al. The human cytochrome c oxidase assembly factors SCO1 and SCO2 have regulatory roles in the maintenance of cellular copper homeostasis. Cell. Metab. 5, 9–20 (2007).

    Article  CAS  Google Scholar 

  52. Leary, S. C., Sasarman, F., Nishimura, T. & Shoubridge, E. A. Human SCO2 is required for the synthesis of CO II and as a thiol-disulphide oxidoreductase for SCO1. Hum. Mol. Genet. 18, 2230–2240 (2009).

    Article  CAS  Google Scholar 

  53. Zhu, Z. et al. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nature Genet. 20, 337–343 (1998).

    Article  CAS  Google Scholar 

  54. Tiranti, V. et al. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am. J. Hum. Genet. 63, 1609–1621 (1998).

    Article  CAS  Google Scholar 

  55. Mootha, V. et al. Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc. Natl Acad. Sci. USA 100, 605–610 (2003).

    Article  CAS  Google Scholar 

  56. Sterky, F. H., Ruzzenente, B., Gustafsson, C. M., Samuelsson, T. & Larsson, N.-G. LRPPRC is a mitochondrial matrix protein that is conserved in metazoans. Biochem. Biophys. Res. Commun. 398, 759–764 (2010).

    Article  CAS  Google Scholar 

  57. Mili, S. & Piñol-Roma, S. LRP130, a pentatricopeptide motif protein with a noncanonical RNA-binding domain, is bound in vivo to mitochondrial and nuclear RNAs. Mol. Cell Biol. 23, 4972–4982 (2003).

    Article  CAS  Google Scholar 

  58. 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).

    Article  CAS  Google Scholar 

  59. 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. Nature Genet. 41, 833–837 (2009).

    Article  CAS  Google Scholar 

  60. 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).

    Article  CAS  Google Scholar 

  61. Choquet, Y. & Wollman, F.-A. Translational regulations as specific traits of chloroplast gene expression. FEBS Lett. 529, 39–42 (2002).

    Article  CAS  Google Scholar 

  62. Choquet, Y., Zito, F., Wostrikoff, K. & Wollman, F.-A. Cytochrome f translation in Chlamydomonas chloroplast is autoregulated by its carboxyl-terminal domain. Plant Cell 15, 1443–1454 (2003).

    Article  CAS  Google Scholar 

  63. Hell, K., Tzagoloff, A., Neupert, W. & Stuart, R. A. Identification of Cox20p, a novel protein involved in the maturation and assembly of cytochrome oxidase subunit 2. J. Biol. Chem. 275, 4571–4578 (2000).

    Article  CAS  Google Scholar 

  64. Tiranti, V. et al. A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome. Hum. Mol. Genet. 9, 2733–2742 (2000).

    Article  CAS  Google Scholar 

  65. Williams, S., Valnot, I., Rustin, P. & Taanman, J. Cytochrome c oxidase subassemblies in fibroblast cultures from patients carrying mutations in COX10, SCO1, or SURF1. J. Biol. Chem. 279, 7462–7469 (2004).

    Article  CAS  Google Scholar 

  66. Church, C., Goehring, B., Forsha, D., Wazny, P. & Poyton, R. O. A role for Pet100p in the assembly of yeast cytochrome c oxidase: interaction with a subassembly that accumulates in a pet100 mutant. J. Biol. Chem. 280, 1854–1863 (2005).

    Article  CAS  Google Scholar 

  67. Massa, V. et al. Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase. Am. J. Hum. Genet. 82, 1281–1289 (2008).

    Article  CAS  Google Scholar 

  68. Taanman, J. & Capaldi, R. Subunit VIa of yeast cytochrome c oxidase is not necessary for assembly of the enzyme complex but modulates the enzyme activity. Isolation and characterization of the nuclear-coded gene. J. Biol. Chem. 268, 18754–187761 (1993).

    CAS  PubMed  Google Scholar 

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Mick, D., Fox, T. & Rehling, P. Inventory control: cytochrome c oxidase assembly regulates mitochondrial translation. Nat Rev Mol Cell Biol 12, 14–20 (2011). https://doi.org/10.1038/nrm3029

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