Mechanism of Mitochondrial Protein Translation in Mammalian Cell
YANG Na1),2), YU Min3)*, XIONG Wei1),2)*
1)Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Dali University, Dali 671000, Yunnan，China;2)Key Laboratory of Clinical Biochemistry of Yunnan Province, School of Basic Medical Sciences, Dali University, Dali 671000, Yunnan, China;3)Laboratory of Biochemistry and Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China
Abstract：Within eukaryotic cells, mitochondria are responsible for fundamental energy conversion and metabolic pathways. Mitochondria have their own ribosomes (mitoribosomes) for the translation of mRNAs encoded by mitochondrial DNAs． Recently, scientists have become more and more aware of the protein factors involved in mitochondrial protein translation and its translational regulation mechanism. Herein we highlight recent advances in mitochondrial translation (mt-translation). The translation process of mitochondrial proteins is divided into four stages: initiation, elongation, termination and recycling. This article reviews the structure and function of mitochondrial ribosomal proteins (MRPs), as well as the properties and functions of mitochondrial protein translational factors. Furthermore, mt-translation is directly regulated by translational activators, mitomiRs, mt-translation regulation assembly intermediate of COX (MITRAC), and post-translational modifications of ribosomal proteins. This article also reviews the regulation and mechanism of mitochondrial protein translation, and lays a foundation for further elucidating the mechanism of mitochondrial translation in the pathogenesis of mitochondria-related diseases.
杨娜，余敏，熊伟. 哺乳动物线粒体蛋白质翻译及其调控机制[J]. 中国生物化学与分子生物学报, 2020, 36(8): 879-887.
YANG Na, YU Min, XIONG Wei. Mechanism of Mitochondrial Protein Translation in Mammalian Cell. Chinese Journal of Biochemistry and Molecular Biol, 2020, 36(8): 879-887.
[1]Wanltz F, Giegé P.Strinking diversity of mitochondria-specific translation processes across eukaryotes[J].Trends Biochem Sci, 2020, 45(2):149-162
[2]Christian BE, Spremulli LL.Preferential selection of the 5'-terminal start codon on leaderless mRNAs by mammalian mitochondrial ribosome[J].J Biol Chem, 2010, 285(36):28379-
[3]Al-Faresi RAZ, Lightowlers RN, Chrzanowska-Lightowlers ZMA.Mammalian mitochondrial translation - revealing consequences of divergent evolution[J].Biochem Soc Trans, 2019, 47(5):1429-1436
[4]Jones CN, Wilkinson KA, Hung KT, et al.Lack of secondary structure characterizes the 5′ ends of mammalian mitochondrial mRNAs[J].RNA, 2008, 14(5):862-871
[5]O' Brien TW.Evolution of a protein-rich mitochondrial ribosome: implications for human genetic disease[J].Gene, 2002, 286(1):73-79
[6]Sharma MR, Koc EC, Datta PP, et al.Structure of the mammalian mitochondrial ribosome reveals an expanded functional role for its component proteins[J].Cell, 2003, 115(1):97-108
[7]Mai N, Chrzanowsa-Lightowlers ZMA, Lightowlers RN.The process of mammalian mitochondrial protein synthesis[J].Cell Tissue Res, 2017, 367(1):5-20
[8]周玮, 刘次全.线粒体核糖体——细胞器中的翻译机器生命的化学[J].Chem Life, 2010, 30(1):70-75
[9]Gopisetty G, Thangarajan R.Mammalian mitochondrial ribosomal small subunit (MRPS) genes: A putative role in human disease[J].Gene, 2016, 589(1):27-35
[10]Brown A, Amunts A, Bai XC, et al.Structure of the large ribosomal subunit from human mitochondria[J].Science, 2014, 346(6210):718-722
[11]Lightowlers RN, Rozanska A, Chrzanowska-Lightowlers ZM.Mitochondrial protein synthesis: figuring the fundamentals,complexities and complications,of mammalian mitochondrial translation[J].FEBS Lett, 2014, 588(15):2496-2503
[12] O’Brien TW, O’Brien BJ, Norman RA.Nuclear MRP genes and mitochondrial disease [J]. Gene, 2005, 354: 147-151
[13]De Silva D, Tu YT, Amunts A, et al.Mitochondrial ribosome assembly in health and disease[J].Cell Cycle, 2015, 14(14):2226-2250
[14]Smits P, Smeitink JAM, van den Heuvel LP, et al.Reconstructing the evolution of the mitochondrial ribosomal proteome[J].Nucleic Acids Res, 2007, 35(14):4686-4703
[15]张利桃，杨利军，杨涛.线粒体核糖体蛋白质与人类恶性肿瘤中国生物化学与分子生物学报[J].Chin J Biochem Mol Biol, 2019, 35(6):620-624
[16]Shutt TE, Shadel GS.A compendium of human mitochondrial gene expression machinery with links to disease[J].Environ Mol Mutagen, 2010, 51(5):360-379
[17]Chicherin IV, Baleva MV, Levitskii SA, et al.Mitochondrial translation initiation factor 3: structure,functions,interactions,and implication in human health and disease[J].Biochemistry (Mosc), 2019, 84(10):1143-1150
[18]Kuzmenko A, Atkinson GC, Levitskii S, et al.Mitochondrial translation initiation machinery: conservation and diversification[J].Biochimie, 2014, 100(100):132-140
[19]Luo Y, Su R, Wang Y, et al.Schizosaccharomyces pombe Mti2 and Mti3 act in conjunction during mitochondrial translation initiation[J].FEBS J, 2019, 286(22):4542-4553
[20]D' Souza AR, Minczuk M.Mitochondrial transcription and translation: overview[J].Essays Biochem, 2018, 62(3):309-320
[21]Spencer AC, Spremulli LL.Interaction of mitochondrial initiation factor 2 with mitochondrial fMet-tRNA[J].Nucleic Acids Res, 2004, 32(18):5464-5470
[22]Macdonald R, Barnes K, Hastings C, et al.Mitochondrial abnormalities in Parkinson’s disease and Alzheimer’s disease: can mitochondria be targeted therapeutically?[J].Biochem Soc Trans, 2018, 46(4):891-909
[23] Koripella RK, Sharma MR, Haque ME, et al.Structure of human mitochondrial translation initiation factor 3 bound to the small ribosomal subunit [J]. iScience, 2019, 12: 76-86
[24]Ayyub SA, Dobriyal D, Varshney U.Contributions of the N- and C-terminal domains of initiation factor 3 to its functions in the fidelity of initiation and antiassociation of the ribosomal subunits[J].J Bacteriol, 2017, 199(11):p-i
[25]Nagao A, Suzuki T, Suzuki T.Aminoacyl-tRNA surveillance by EF-Tu in mammalian mitochondria[J].Nucleic Acids Symp Ser (Oxf), 2007, 51(1):41-42
[26]He K, Guo X, Liu Y, et al.TUFM downregulation induces epithelial-mesenchymal transition and invasion in lung cancer cells via a mechanism involving AMPK-GSK3β signaling[J].Cell Mol Life Sci, 2016, 73(10):2105-2121
[27] Watanabe Y I, Suematsu T, Ohtsuki T.Losing the stem-loop structure from metazoan mitochondrial tRNAs and co-evolution of interacting factors [J]. Front Genet, 2014, 5: 109
[28]Sato A, Suematsu T, Aihara KK, et al.Duplication of Drosophila melanogaster mitochondrial EF-Tu: pre-adaptation to T-arm truncation and exclusion of bulky aminoacyl residues[J].Biochem J, 2017, 474(6):957-969
[29]Suzuki H, Ueda T, Taguchi H, et al.Chaperone properties of mammalian mitochondrial translation elongation factor Tu[J].J Biol Chem, 2007, 282(6):4076-4084
[30]Di Nottia M, Montanari A, Verrigni D, et al.Novel mutation in mitochondrial Elongation Factor EF-Tu associated to dysplastic leukoencephalopathy and defective mitochondrial DNA translation[J].Biochim Biophys Acta Mol Basis Dis, 2017, 1863(4):961-967
[31]Schwartzbach CJ, Spremulli LL.Interaction of animal mitochondrial EF-TuEF-Ts with aminoacyl-tRNA,guanine nucleotides,and ribosomes[J].J Biol Chem, 1991, 266(25):16324-
[32]Perli E, Pisano A, Glasgow RIC, et al.Novel compound mutations in the mitochondrial translation elongation factor (TSFM) gene cause severe cardiomyopathy with myocardial fibro-adipose replacement[J].Sci Rep, 2019, 9(1):5108-
[33]Scala M, Brigati G, Fiorillo C, et al.Novel homozygous TSFM pathogenic variant associated with encephalocardiomyopathy with sensorineural hearing loss and peculiar neuroradiologic findings[J].Neurogenetics, 2019, 20(3):165-172
[34]Tsuboi M, Morita H, Nozaki Y, et al.EF-G2mt is an exclusive recycling factor in mammalian mitochondrial protein synthesis[J].Mol Cell, 2009, 35(4):502-510
[35] Ravn K, Sch?newolf-Greulich B, Hansen RM, et al.Neonatal mitochondrial hepatoencephalopathy caused by novel GFM1 mutations [J]. Mol Genet Metab Rep, 2015, 3: 5-10
[36]Li R, Guan MX.Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial dysfunctions due to the tRNALeu(UUR) A3243G mutation,associated with mitochondrial encephalomyopathy,lactic acidosis,and stroke-like symptoms and diabetes[J].Mol Cell Biol, 2010, 30(9):2147-2154
[37] Cao X, Qin Y.Mitochondrial translation factors reflect coordination between organelles and cytoplasmic translation via mTOR signaling: Implication in disease [J]. Free Radic Biol Med, 2016, 100: 231-237
[38]Heller JLE, Kamalampeta R, Wieden HJ.Taking a step back from back-translocation: an integrative view of LepAEF4's cellular function[J].Mol Cell Biol, 2017, 37(12):e00653-16
[39]Gao Y, Bai X, Zhang D, et al.Mammalian elongation factor 4 regulates mitochondrial translation essential for spermatogenesis[J].Nat Struct Mol Biol, 2016, 23(5):441-449
[40]Zhu P, Liu Y, Zhang F, et al.Human elongation factor 4 regulates cancer bioenergetics by acting as a mitochondrial translation switch[J].Cancer Res, 2018, 78(11):2813-2824
[41]Koripella RK, Sharma MR, Risteff P, et al.Structural insights into unique features of the human mitochondrial ribosome recycling[J].Proc Natl Acad Sci U S A, 2019, 116(17):8283-
[42]Rorbach J, Richter R, Wessels HJ, et al.The human mitochondrial ribosome recycling factor is essential for cell viability[J].Nucleic Acids Res, 2008, 36(18):5787-5799
[43] Huynen MA, Duarte I, Chrzanowska-Lightowlers ZMA, et al.Structure based hypothesis of a mitochondrial ribosome rescue mechanism [J]. Biol Direct, 2012, 7: 14
[44]Soleimanpour-Lichaei HR, Kühl I, Gaisne M, et al.mtRF1a is a human mitochondrial translation release factor decoding the major termination codons UAA and UAG[J].Mol Cell, 2007, 27(5):745-757
[45]Chrzanowska-Lightowlers ZMA, Pajak A, Lightowlers RN.Termination of protein synthesis in mammalian mitochondria[J].J Biol Chem, 2011, 286(40):34479-34485
[46]Fox TD.Mitochondrial protein synthesis,import,and assembly[J].Genetics, 2012, 192(4):1203-1234
[47]Weraarpachai W, Antonicka H, Sasarman F, et al.Mutation in TACO1,encoding a translational activator of COX I,results in cytochrome c oxidase deficiency and late-onset Leigh syndrome[J].Nat Genet, 2009, 41(7):833-837
[48]Seeger J, Schrank B, Pyle A, et al.Clinical and neuropathological findings in patients with TACO1 mutations[J].Neuromuscul Disord, 2010, 20(11):720-724
[49]Gruschke S, Kehrein K, R?mpler K, et al.Cbp3-Cbp6 interacts with the yeast mitochondrial ribosomal tunnel exit and promotes cytochrome b synthesis and assembly[J].J Cell Biol, 2011, 193(6):1101-1114
[50]Ott M, Amunts A, Brown A.Organization and regulation of mitochondrial protein synthesis[J].Annu Rev Biochem, 2016, 85(6):77-101
[51]Zeng X, Hourset A, Tzagoloff A.The Saccharomyces cerevisiae ATP22 gene codes for the mitochondrial ATPase subunit 6-specific translation factor[J].Genetics, 2007, 175(1):55-63
[52]Herrmann JM, Woellhaf MW, Bonnefoy N.Control of protein synthesis in yeast mitochondria: the concept of translational activators[J].Biochim Biophys Acta, 2013, 1833(2):286-294
[53]Perez-Martinez X, Broadley SA, Fox TD.Mss51p promotes mitochondrial Cox1p synthesis and interacts with newly synthesized Cox1p[J].EMBO J, 2003, 22(21):5951-5961
[54]Jonas S, Izaurralde E.Towards a molecular understanding of microRNA-mediated gene silencing[J].Nat Rev Genet, 2015, 16(7):421-433
[55]Vasudevan S, Tong Y, Steitz JA.Switching from repression to activation: microRNAs can up-regulate translation[J].Science, 2007, 318(5858):1931-1934
[56] Bandiera S, Mategot R, Girard M, et al.MitomiRs delineating the intracellular localization of microRNAs at mitochondria [J]. Free Radic Biol Med, 2013, 64: 12-19
[57]Das S, Bedja D, Campbell N, et al.miR-181c regulates the mitochondrial genome,bioenergetics,and propensity for heart failure in vivo[J].PLoS One, 2014, 9(5):e96820-
[58]Zhang X, Zuo X, Yang B, et al.MicroRNA directly enhances mitochondrial translation during muscle differentiation[J].Cell, 2014, 158(3):607-619
[59] Li H, Dai B, Fan J, et al.The different roles of miRNA-92a-2-5p and let-7b-5p in mitochondrial translation in db/db mice [J]. Mol Ther Nucleic Acids, 2019, 17: 424-435
[60]Dennerlein S, Rehling P.Human mitochondrial COX1 assembly into cytochrome C oxidase at a glance[J].J Cell Sci, 2015, 128(5):833-837
[61]Mick DU, Fox TD, Rehling P.Inventory control: cytochrome C oxidase assembly regulates mitochondrial translation[J].Nat Rev Mol Cell Biol, 2011, 12(1):14-20
[62]Ostergaard E, Weraarpachai W, Ravn K, et al.Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy,exercise intolerance,obesity,and short stature[J].J Med Genet, 2015, 52(3):203-207
[63]Dennerlein S, Oeljeklaus S, Jans D, et al.MITRAC7 acts as a COX1-specific chaperone and reveals a checkpoint during cytochrome C oxidase assembly[J].Cell Rep, 2015, 12(10):1644-1655
[64]Wang C, Richter-Dennerlein R, Pacheu-Grau D, et al.MITRAC15COA1 promotes mitochondrial translation in a ND2 ribosome-nascent chain complex[J].EMBO Rep, 2020, 21(1):e48833-
[65]Mick DU, Dennerlein S, Wiese H, et al.MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation[J].Cell, 2012, 151(7):1528-1541
[66]Soung GY, Miller JL, Koc H, et al.Comprehensive analysis of phosphorylated proteins of Escherichia coli ribosomes[J].J Proteome Res, 2009, 8(7):3390-3402
[67]He H, Chen M, Scheffler NK, et al.Phosphorylation of mitochondrial elongation factor Tu in ischemic myocardium: basis for chloramphenicol-mediated cardioprotection[J].Circ Res, 2001, 89(5):461-467
[68]Han MJ, Chiu DT, Koc EC.Regulation of mitochondrial ribosomal protein S29 (MRPS29) expression by a 5'-upstream open reading frame[J].Mitochondrion, 2010, 10(3):274-283
[69]Miller JL, Cimen H, Koc H, et al.Phosphorylated proteins of the mammalian mitochondrial ribosome: implications in protein synthesis[J].J Proteome Res, 2009, 8(10):4789-4798
[70] Ishizawa T, Nozaki Y, Ueda T, et al.The human mitochondrial translation release factor HMRF1L is methylated in the GGQ motif by the methyltransferase HMPrmC [J]. Biochem Biophys Res Commun. 2008, 373(1): 99-103
