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Coordination of Two Genomes by Mitochondrial Translational Plasticity

2016; Cell Press; Volume: 167; Issue: 2 Linguagem: Inglês

10.1016/j.cell.2016.09.042

1097-4172

Heike Rampelt, Nikolaus Pfanner,

RNA modifications and cancer

The dual genetic origin of mitochondrial respiratory chain complexes leads to the synthesis of subunits by mitochondrial and cytosolic ribosomes. Now, Richter-Dennerlein et al. report that membrane-integrated assembly factors associate with ribosome nascent chain complexes in human mitochondria to coordinate translational plasticity with the import of subunits from the cytosol. The dual genetic origin of mitochondrial respiratory chain complexes leads to the synthesis of subunits by mitochondrial and cytosolic ribosomes. Now, Richter-Dennerlein et al. report that membrane-integrated assembly factors associate with ribosome nascent chain complexes in human mitochondria to coordinate translational plasticity with the import of subunits from the cytosol. The oxidative phosphorylation (OXPHOS) machinery of the mitochondrial inner membrane generates the vast majority of cellular ATP. Defects of its biogenesis and function cause severe diseases (Fernández-Vizarra et al., 2009Fernández-Vizarra E. Tiranti V. Zeviani M. Biochim. Biophys. Acta. 2009; 1793: 200-211Crossref PubMed Scopus (166) Google Scholar). Most OXPHOS complexes, including the respiratory complexes I, III, and IV and the F1Fo-ATP synthase are of dual genetic origin. While several central membrane-integrated subunits of these complexes are encoded by the mitochondrial genome and synthesized on mitochondrial ribosomes, the majority of OXPHOS subunits are encoded by nuclear genes, synthesized on cytosolic ribosomes, and imported into mitochondria (Figure 1A). To avoid an imbalance of nuclear-encoded and mitochondrial-encoded subunits and to enable adaptive changes, the cells need to coordinate cytosolic and mitochondrial translation of the OXPHOS subunits. The balanced biogenesis of mitochondrial-encoded proteins in the model organism baker's yeast is governed at the level of translation (Herrmann et al., 2013Herrmann J.M. Woellhaf M.W. Bonnefoy N. Biochim. Biophys. Acta. 2013; 1833: 286-294Crossref PubMed Scopus (107) Google Scholar). In addition, a degradation of excess subunits contributes to proteostasis. The subunits encoded by yeast mtDNA possess specific translational activators that engage both the 5′ UTR of the mRNA and the protein in early assembly intermediates. If these intermediates fail to mature, the translational activators remain trapped and further translation is blocked. This system constitutes a feedback loop that couples mitochondrial translation to proper assembly of the OXPHOS complexes (Herrmann et al., 2013Herrmann J.M. Woellhaf M.W. Bonnefoy N. Biochim. Biophys. Acta. 2013; 1833: 286-294Crossref PubMed Scopus (107) Google Scholar). Little is known, however, about the coordination of cytosolic and mitochondrial translation in mammalian cells. Expression of mtDNA in mammals shows significant differences to that in yeast. In particular, mammalian mitochondrial mRNAs possess either no or only very short 5′ UTRs and thus lack typical binding sites for translational activators (Hällberg and Larsson, 2014Hällberg B.M. Larsson N.G. Cell Metab. 2014; 20: 226-240Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Classical translational activators and feedback loops have not been described so far. In this issue of Cell, Richter-Dennerlein et al., 2016Richter-Dennerlein R. Oeljeklaus S. Lorenzi I. Ronsör C. Bareth B. Schendzielorz A.B. Wang C. Warscheid B. Rehling P. Dennerlein S. Cell. 2016; 167 (this issue): 471-483Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar report the discovery of an intriguing new mechanism that imparts feedback regulation on translation and assembly of a mitochondrial-encoded OXPHOS subunit in human mitochondria, revealing a direct physical link between the translation machinery and assembly intermediates. Human complex IV or cytochrome c oxidase (COX) is composed of 3 mitochondrial-encoded subunits, COX1, COX2, and COX3, and 11 nuclear-encoded subunits. Its biogenesis is assisted by numerous assembly factors (Soto et al., 2012Soto I.C. Fontanesi F. Liu J. Barrientos A. Biochim. Biophys. Acta. 2012; 1817: 883-897Crossref PubMed Scopus (150) Google Scholar). COX assembly is initiated by translation of the central subunit COX1, which contains twelve transmembrane segments and is intensively chaperoned from its earliest beginning. Newly synthesized COX1 interacts with the proteins C12ORF62 (hCOX14) and MITRAC12 (hCOA3), forming the first of a series of intermediates that have been termed mitochondrial translation regulation assembly intermediate of cytochrome c oxidase (MITRAC) (Mick et al., 2012Mick D.U. Dennerlein S. Wiese H. Reinhold R. Pacheu-Grau D. Lorenzi I. Sasarman F. Weraarpachai W. Shoubridge E.A. Warscheid B. Rehling P. Cell. 2012; 151: 1528-1541Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). Now, Richter-Dennerlein et al., 2016Richter-Dennerlein R. Oeljeklaus S. Lorenzi I. Ronsör C. Bareth B. Schendzielorz A.B. Wang C. Warscheid B. Rehling P. Dennerlein S. Cell. 2016; 167 (this issue): 471-483Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar found that the assembly factor C12ORF62 is recruited to COX1 at an even earlier time point than anticipated. It interacts with mitochondrial ribosomes that are actively translating COX1 (Figure 1B). Defined COX1 fragments are co-purified with C12ORF62 upon releasing nascent chains from ribosomes by treatment with puromycin, demonstrating that the assembly factor associates with the ribosome nascent chain complex upon synthesis of four to six of the twelve COX1 transmembrane domains. These nascent chains are partially membrane integrated and represent productive on-pathway intermediates. Richter-Dennerlein et al., 2016Richter-Dennerlein R. Oeljeklaus S. Lorenzi I. Ronsör C. Bareth B. Schendzielorz A.B. Wang C. Warscheid B. Rehling P. Dennerlein S. Cell. 2016; 167 (this issue): 471-483Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar demonstrate that C12ORF62 is required for translation of COX1, pointing to an active licensing of COX1 translation by C12ORF62. Thus, a negative translational feedback loop prevents COX1 synthesis in the absence of its initial assembly chaperone. Is there a mechanism to balance COX1 biogenesis against the levels of nuclear-encoded COX subunits? Strikingly, the translational feedback regulation discovered by Richter-Dennerlein et al., 2016Richter-Dennerlein R. Oeljeklaus S. Lorenzi I. Ronsör C. Bareth B. Schendzielorz A.B. Wang C. Warscheid B. Rehling P. Dennerlein S. Cell. 2016; 167 (this issue): 471-483Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar extends to the incorporation of the first nuclear-encoded COX subunit, COX4. In the absence of COX4, COX1 translation is arrested. Only when sufficient amounts of COX4 are synthesized in the cytosol and imported into the mitochondrial inner membrane, the synthesis of COX1 is completed and COX4 stably assembles with it (Figure 1B). In this newly identified mechanism of mitochondrial translational regulation, the fidelity of every single step in the early assembly of COX1 is monitored, from co-translational chaperoning to post-translational assembly with nuclear-encoded subunits. Failure at any point results in the arrest of COX1-translating ribosomes. Thus, the biogenesis of the mitochondrial-encoded core subunit COX1 is intimately connected to the availability of the nuclear-encoded COX4. The interaction of translating ribosomes with early MITRAC complexes bypasses the requirement for a classical mRNA-binding translational activator. The exact molecular mechanisms of this translational plasticity with pausing and resumption of protein synthesis remain to be elucidated. C12ORF62 is a good candidate for a master chaperone since it is required for COX1 translation but is also present in arrested ribosome nascent chain complexes when downstream factors fail to engage. C12ORF62 may thus integrate signals about the folding and assembly status of COX1 and transmit them to the ribosome. MITRAC12 likely also contributes to the feedback regulation. Weraarpachai et al., 2009Weraarpachai W. Antonicka H. Sasarman F. Seeger J. Schrank B. Kolesar J.E. Lochmüller H. Chevrette M. Kaufman B.A. Horvath R. Shoubridge E.A. Nat. Genet. 2009; 41: 833-837Crossref PubMed Scopus (221) Google Scholar reported that the nuclear-encoded protein TACO1 is required for COX1 translation by an unknown mechanism, raising the question if and how it functionally interacts with this feedback system. An important topic for future research is the question that if the assembly of other mammalian OXPHOS complexes with dual genetic origin also involves specific factors for direct coupling of mitochondrial translation to import of nuclear-encoded subunits. The assembly of OXPHOS complexes with dual genetic origin is a logistically more complicated variation of the general problem of balancing the levels of different subunits of protein complexes. Employing ribosome profiling in bacteria and yeast, Li et al., 2014Li G.W. Burkhardt D. Gross C. Weissman J.S. Cell. 2014; 157: 624-635Abstract Full Text Full Text PDF PubMed Scopus (787) Google Scholar found that most subunits of stable protein complexes are produced at rates proportional to their stoichiometry in the complex, ensuring that the subunits are present in the amounts required for proper and efficient assembly (Li et al., 2014Li G.W. Burkhardt D. Gross C. Weissman J.S. Cell. 2014; 157: 624-635Abstract Full Text Full Text PDF PubMed Scopus (787) Google Scholar). Thus, the balanced and coordinated synthesis of proteins is a fundamental cellular strategy for dealing with components of oligomeric complexes. While feedback control loops limit unbalanced synthesis of mitochondrial subunits, the reverse issue is how mitochondrial expression is induced for enhanced mitochondrial biogenesis. This question was recently addressed in yeast cells undergoing adaptation from anaerobic to aerobic growth (Couvillion et al., 2016Couvillion M.T. Soto I.C. Shipkovenska G. Churchman L.S. Nature. 2016; 533: 499-503Crossref PubMed Scopus (184) Google Scholar). Profiling of cytosolic and mitochondrial ribosomes revealed that both machineries execute coordinated translation programs that depend on cytosolic translation and protein import into mitochondria. This observation may reflect the fact that some nuclear-encoded yeast translational activators are rate limiting for expression of their mitochondrial targets (Herrmann et al., 2013Herrmann J.M. Woellhaf M.W. Bonnefoy N. Biochim. Biophys. Acta. 2013; 1833: 286-294Crossref PubMed Scopus (107) Google Scholar). It may also point toward a further layer of mitochondrial translational regulation that, like in mammals, may involve the import of nuclear-encoded structural subunits of OXPHOS complexes (Richter-Dennerlein et al., 2016Richter-Dennerlein R. Oeljeklaus S. Lorenzi I. Ronsör C. Bareth B. Schendzielorz A.B. Wang C. Warscheid B. Rehling P. Dennerlein S. Cell. 2016; 167 (this issue): 471-483Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). In mammalian cells, mitochondrial biogenesis is typically induced during differentiation. A recent study reported that, during mammalian muscle differentiation, mitochondrial protein expression is regulated via the microRNA miR-1, which is imported into mitochondria and interacts with the Argonaute protein Ago2 (Zhang et al., 2014Zhang X. Zuo X. Yang B. Li Z. Xue Y. Zhou Y. Huang J. Zhao X. Zhou J. Yan Y. et al.Cell. 2014; 158: 607-619Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar). In contrast to classical miRNA-mediated silencing pathways, the miR-1-Ago2 complex enhances the translation of several subunits of OXPHOS complexes, including COX1. Thus, the fundamental principles of activation of mitochondrial translation by cytosolic factors and control by translational feedback loops are valid for fungi and metazoa, whereas distinct molecular mechanisms are involved to reach these goals. Mitochondrial Protein Synthesis Adapts to Influx of Nuclear-Encoded ProteinRichter-Dennerlein et al.CellSeptember 29, 2016In BriefMitochondrial translation displays plasticity, allowing the adaptation to the availability of a nuclear-encoded complex subunit. Full-Text PDF Open Access