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Impaired Mitochondrial Translation in Human Disease Newcastle University ePrints Boczonadi V, Horvath R. Mitochondria: Impaired mitochondrial translation in human disease. International Journal of Biochemistry & Cell Biology 2014, 48, 77-84. Copyright: Copyright © 2014 The Authors. Published by Elsevier Ltd. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited. DOI link to article: http://dx.doi.org/10.1016/j.biocel.2013.12.011 Date deposited: 11th February 2014 This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works License ePrints – Newcastle University ePrints http://eprint.ncl.ac.uk The International Journal of Biochemistry & Cell Biology 48 (2014) 77–84 Contents lists available at ScienceDirect The International Journal of Biochemistry & Cell Biology journal homepage: www.elsevier.com/locate/biocel Organelles in focus ଝ Mitochondria: Impaired mitochondrial translation in human disease ∗ Veronika Boczonadi, Rita Horvath Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK a r t i c l e i n f o a b s t r a c t Article history: Defects of the mitochondrial protein synthesis cause a subgroup of mitochondrial diseases, which are Received 28 September 2013 usually associated with decreased activities of multiple respiratory chain (RC) enzymes. The clinical pre- Received in revised form sentations of these disorders are often disabling, progressive or fatal, affecting the brain, liver, skeletal 13 November 2013 muscle, heart and other organs. Currently there are no effective cures for these disorders and treatment is Accepted 26 December 2013 at best symptomatic. The diagnosis in patients with multiple respiratory chain complex defects is particu- Available online 8 January 2014 larly difficult because of the massive number of nuclear genes potentially involved in intra-mitochondrial protein synthesis. Many of these genes are not yet linked to human disease. Whole exome sequencing Keywords: rapidly changed the diagnosis of these patients by identifying the primary defect in DNA, and preventing Mitochondrial respiratory chain the need for invasive and complex biochemical testing. Better understanding of the mitochondrial protein Mitochondrial translation Human mitochondrial disease synthesis apparatus will help us to explore disease mechanisms and will provide clues for developing Tissue specific presentation novel therapies. Cytosolic translation © 2014 The Authors. Published by Elsevier Ltd. All rights reserved. 1. Introduction Organelle facts • Mitochondrial diseases affect at least 1 in 5000 of the popu- Mitochondrial protein synthesis requires several mitochon- lation and produce diverse clinical phenotypes often presented drial and nuclear-encoded factors for optimal translation. • as multi-systemic disorders (DiMauro et al., 2013; Ylikallio and The clinical presentation of diseases due to defective mito- Suomalainen, 2012; Vafai and Mootha, 2012). In addition to chondrial protein synthesis is very variable and tissue the nucleus, human cells also harbour DNA in the mitochon- specific presentations are common. • The reasons behind the tissue specificity are largely dria (mtDNA), which is essential for cell viability (Tuppen et al., unknown. 2010). This small (16.5 kb) genome is found in multiple copies in • Besides mitochondrial tRNA mutations and mtDNA dele- mitochondria, the subcellular organelles that often constitute more tions or depletion, autosomal recessive mutations have than 20% of the total cell volume. OXPHOS (oxidative phosphor- been reported in genes encoding ribosomal proteins, ribo- ylation) is responsible for the production of ATP by generating some assembly proteins, mitochondrial aminoacyl-tRNA a proton gradient across the inner membrane of the mitochon- synthetases, tRNA modifying enzymes and initiation, elon- dria which is used by the mammalian cells (Greaves et al., 2012). gation and termination factors of translation. • The mitochondrial OXPHOS system comprises around 150 different Frequent and clinically recognisable genetic causes of proteins out of which only 13 polypeptide subunits are encoded by human diseases due to impaired mitochondrial translation the mtDNA. In addition, the mtDNA encodes the small and large are caused by mutations in mitochondrial tRNA synthetase and tRNA modifying genes. rRNAs, and 22 distinct mitochondrial tRNAs that are necessary for • The potential interaction between cytosolic and mitochon- the translation of only the mitochondrial-encoded proteins (Smits drial translation requires further investigations. et al., 2010; Rötig, 2011; Chrzanowska-Lightowlers et al., 2011). The nuclear-encoded subunits of the respiratory chain (RC) complexes as well as proteins that are inevitable for normal mitochondrial protein synthesis (such as OXPHOS assembly, mtDNA metabolism ଝ and maintenance, mitochondrial cofactor biosynthesis, mitoribo- This is an open-access article distributed under the terms of the Creative Com- somal subunits and assembly factors, regulators of mitochondrial mons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the expression and translation, etc.) are encoded by the nuclear genome original author and source are credited. (nDNA) and synthetised in the cytosol before transported into the ∗ Corresponding author at: Institute of Genetic Medicine, Newcastle University, organelle (Vafai and Mootha, 2012). The mitochondrial ribosomal Central Parkway, Newcastle upon Tyne NE1 3BZ, UK. Tel.: +44 191 2418855; proteins assemble with mitochondrial ribosomes 12S rRNA and 16S fax: +44 191 2418666. rRNA to form the mitochondrial ribosome (Pietromonaco et al., E-mail address: [email protected] (R. Horvath). 1357-2725/$ – see front matter © 2014 The Authors. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.biocel.2013.12.011 78 V. Boczonadi, R. Horvath / The International Journal of Biochemistry & Cell Biology 48 (2014) 77–84 V. Boczonadi, R. Horvath / The International Journal of Biochemistry & Cell Biology 48 (2014) 77–84 79 1991). Lately it was also reported that import of 5S rRNA is also the affected children die early (Valente et al., 2007; Smeitink et al., transported to the mitochondria being an essential component of 2006; Coenen et al., 2004; Smits et al., 2011a,b). the mitochondrial ribosomes (Smirnov et al., 2011). 2.3. Termination 2. Organelle function The mitochondrial release factor (mtRF1a) recognises the stop codon and binds to the mitoribosome, induces hydrolysis of the The components responsible for the proper mitochondrial peptidyl-tRNA bond in the A-site releasing the mature protein from translation are different from their cytosolic counterparts and they the site. Other termination release factors such as mtRF1, C12orf65 are more related to those of bacteria however the mechanisms of and ICT1 are also thought to play an essential role in the termination the translation follows the same major steps: initiation, elongation, (Richter et al., 2010). As a last step mitochondrial recycling factors termination and recycling of the ribosome (Christian and Spremulli, (mtRRF1 and mtRRF2) translocate to the A-site to induce the release 2012) (Fig. 1). of the mRNA (Chrzanowska-Lightowlers et al., 2011). Up to date only the C12orf65 has been identified as a disease causing gene. 2.1. Initiation Affected patients develop optic atrophy and ophthalmoplegia with Leigh syndrome (Antonicka et al., 2010). The process of mitochondrial translation starts with the for- mation of the initiation complex. The separation of the two 2.4. Regulatory mechanisms mitochondrial ribosomal subunits (28S and 39S) (Kuzmenko et al., 2013) allow this complex to be formed which consists of the 28S The expression of mitochondrial proteins is regulated by their subunit, mRNA and fMET-tRNA and IF2/3mt (Koc and Spremulli, own translational activators that bind mitochondrial mRNAs usu- 2002; Christian and Spremulli, 2009). This is followed by the ally to their 5‘-untranslated regions, and each mitochondrial mRNA entrance of the mRNA into the IF3mt:28S subunit complex. IF3mt has its own translational activator(s), which has been first shown is thought to support the correct position of mRNA to bind the in yeast (Herrmann et al., 2013). Recent studies showed that these small subunit at the peptidyl (P) site of the mitoribosome. When the translational activators can be part of a feedback control loops appropriate start codon is present, the formylmethionin-tRNA can which only permit translation if the downstream assembly of bind to the first codon with the help of IF2mt. The association of the nascent translation products can occur (Herrmann et al., 2013). mitoribosome stimulates the release of the initiation factors and Recently mutations in nuclear-encoded translational activators of the elongation on the 55S ribosome commence. MTFMT is critical mitochondrial proteins such as TACO1 were also implicated in for efficient human mitochondrial translation and reveal a human human disease (Weraarpachai et al., 2009). A regulatory role of disorder of Met-tRNA(Met) formylation (Tucker et al., 2011; Neeve aminoacyl-tRNA synthetases has been suggested in both cytosolic et al., 2013). and mitochondrial translation
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