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Techniques for investigating mitochondrial gene expression

  • Park, Dongkeun (Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology) ;
  • Lee, Soyeon (Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology) ;
  • Min, Kyung-Tai (Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology)
  • Received : 2019.09.25
  • Published : 2020.01.31

Abstract

The mitochondrial genome encodes 13 proteins that are components of the oxidative phosphorylation system (OXPHOS), suggesting that precise regulation of these genes is crucial for maintaining OXPHOS functions, including ATP production, calcium buffering, cell signaling, ROS production, and apoptosis. Furthermore, heteroplasmy or mis-regulation of gene expression in mitochondria frequently is associated with human mitochondrial diseases. Thus, various approaches have been developed to investigate the roles of genes encoded by the mitochondrial genome. In this review, we will discuss a wide range of techniques available for investigating the mitochondrial genome, mitochondrial transcription, and mitochondrial translation, which provide a useful guide to understanding mitochondrial gene expression.

Keywords

References

  1. Anderson S, Bankier AT, Barrell BG et al (1981) Sequence and organization of the human mitochondrial genome. Nature 290, 457-465 https://doi.org/10.1038/290457a0
  2. Chomyn A, Mariottini P, Cleeter MWJ et al (1985) Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase. Nature 314, 592-597 https://doi.org/10.1038/314592a0
  3. Antonicka H and Shoubridge Eric A (2015) Mitochondrial RNA Granules Are Centers for Posttranscriptional RNA Processing and Ribosome Biogenesis. Cell Rep 10, 920-932 https://doi.org/10.1016/j.celrep.2015.01.030
  4. Signes A and Fernandez-Vizarra E (2018) Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes. Essays Biochem 62, 255-270 https://doi.org/10.1042/EBC20170098
  5. Hartl F-U, Pfanner N, Nicholson DW and Neupert W (1989) Mitochondrial protein import. Biochim Biophys Acta Biomembr 988, 1-45 https://doi.org/10.1016/0304-4157(89)90002-6
  6. Omura T (1998) Mitochondria-Targeting Sequence, a Multi-Role Sorting Sequence Recognized at All Steps of Protein Import into Mitochondria. J Biochem 123, 1010-1016 https://doi.org/10.1093/oxfordjournals.jbchem.a022036
  7. Bereiter-Hahn J and Voth M (1994) Dynamics of mitochondria in living cells: Shape changes, dislocations, fusion, and fission of mitochondria. Microsc Res Tech 27, 198-219 https://doi.org/10.1002/jemt.1070270303
  8. Lewis MR and Lewis WH (1915) Mitochondria (and other cytoplasmic structures) in tissue cultures. Am J Anat 17, 339-401 https://doi.org/10.1002/aja.1000170304
  9. Shutt TE and Shadel GS (2010) A compendium of human mitochondrial gene expression machinery with links to disease. Environ Mol Mutagen 51, 360-379 https://doi.org/10.1002/em.20571
  10. Couvillion MT, Soto IC, Shipkovenska G and Churchman LS (2016) Synchronized mitochondrial and cytosolic translation programs. Nature 533, 499-503 https://doi.org/10.1038/nature18015
  11. Amunts A, Brown A, Toots J, Scheres SHW and Ramakrishnan V (2015) The structure of the human mitochondrial ribosome. Science 348, 95-98 https://doi.org/10.1126/science.aaa1193
  12. Taanman JW (1999) The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta Bioenerg 1410, 103-123 https://doi.org/10.1016/S0005-2728(98)00161-3
  13. Rooney JP, Ryde IT, Sanders LH et al (2015) PCR based determination of mitochondrial DNA copy number in multiple species. Methods Mol Biol 1241, 23-38 https://doi.org/10.1007/978-1-4939-1875-1_3
  14. Ashar FN, Zhang Y, Longchamps RJ et al (2017) Association of Mitochondrial DNA Copy Number With Cardiovascular Disease. JAMA Cardiol 2, 1247-1255 https://doi.org/10.1001/jamacardio.2017.3683
  15. Reznik E, Miller ML, Senbabaoglu Y et al (2016) Mitochondrial DNA copy number variation across human cancers. Elife 5, e10769 https://doi.org/10.7554/elife.10769
  16. Wai T, Ao A, Zhang X, Cyr D, Dufort D and Shoubridge EA (2010) The role of mitochondrial DNA copy number in mammalian fertility. Biol Reprod 83, 52-62 https://doi.org/10.1095/biolreprod.109.080887
  17. Pyle A, Anugrha H, Kurzawa-Akanbi M, Yarnall A, Burn D and Hudson G (2016) Reduced mitochondrial DNA copy number is a biomarker of Parkinson's disease. Neurobiol Aging 38, 216.e217-216.e210
  18. Srivastava S and Moraes CT (2001) Manipulating mitochondrial DNA heteroplasmy by a mitochondrially targeted restriction endonuclease. Hum Mol Genet 10, 3093-3099 https://doi.org/10.1093/hmg/10.26.3093
  19. Bibikova M, Beumer K, Trautman JK and Carroll D (2003) Enhancing gene targeting with designed zinc finger nucleases. Science 300, 764-764 https://doi.org/10.1126/science.1079512
  20. Cermak T, Doyle EL, Christian M et al (2011) Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting. Nucleic Acids Res 39, e82-e82
  21. Cong L, Ran FA, Cox D et al (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819-823 https://doi.org/10.1126/science.1231143
  22. Taylor RW and Turnbull DM (2005) Mitochondrial DNA mutations in human disease. Nat Rev Genet 6, 389-402 https://doi.org/10.1038/nrg1606
  23. Minczuk M, Papworth MA, Miller JC, Murphy MP and Klug A (2008) Development of a single-chain, quasi-dimeric zinc-finger nuclease for the selective degradation of mutated human mitochondrial DNA. Nucleic Acids Res 36, 3926-3938 https://doi.org/10.1093/nar/gkn313
  24. Minczuk M, Papworth MA, Kolasinska P, Murphy MP and Klug A (2006) Sequence-specific modification of mitochondrial DNA using a chimeric zinc finger methylase. Proc Natl Acad Sci U S A 103, 19689-19694 https://doi.org/10.1073/pnas.0609502103
  25. Bacman SR, Williams SL, Pinto M, Peralta S and Moraes CT (2013) Specific elimination of mutant mitochondrial genomes in patient-derived cells by mitoTALENs. Nat Med 19, 1111-1113 https://doi.org/10.1038/nm.3261
  26. Jo A, Ham S, Lee GH et al (2015) Efficient Mitochondrial Genome Editing by CRISPR/Cas9. Biomed Res Int 2015, 305716 https://doi.org/10.1155/2015/305716
  27. Gammage PA, Rorbach J, Vincent AI, Rebar EJ and Minczuk M (2014) Mitochondrially targeted ZFNs for selective degradation of pathogenic mitochondrial genomes bearing large-scale deletions or point mutations. EMBO Mol Med 6, 458-466 https://doi.org/10.1002/emmm.201303672
  28. Gammage PA, Viscomi C, Simard ML et al (2018) Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo. Nat Med 24, 1691-1695 https://doi.org/10.1038/s41591-018-0165-9
  29. Hashimoto M, Bacman SR, Peralta S et al (2015) MitoTALEN: A General Approach to Reduce Mutant mtDNA Loads and Restore Oxidative Phosphorylation Function in Mitochondrial Diseases. Mol Ther 23, 1592-1599 https://doi.org/10.1038/mt.2015.126
  30. Yu H, Koilkonda RD, Chou TH et al (2012) Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber's hereditary optic neuropathy in a mouse model. Proc Natl Acad Sci U S A 109, E1238-1247 https://doi.org/10.1073/pnas.1119577109
  31. Ban-Ishihara R, Ishihara T, Sasaki N, Mihara K and Ishihara N (2013) Dynamics of nucleoid structure regulated by mitochondrial fission contributes to cristae reformation and release of cytochrome c. Proc Natl Acad Sci U S A 110, 11863-11868 https://doi.org/10.1073/pnas.1301951110
  32. Lewis SC, Uchiyama LF and Nunnari J (2016) ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science 353, aaf5549 https://doi.org/10.1126/science.aaf5549
  33. Villa AM, Fusi P, Pastori V et al (2012) Ethidium bromide as a marker of mtDNA replication in living cells. J Biomed Opt 17, 046001 https://doi.org/10.1117/1.JBO.17.4.046001
  34. Jevtic V, Kindle P and Avilov SV (2018) SYBR Gold dye enables preferential labelling of mitochondrial nucleoids and their time-lapse imaging by structured illumination microscopy. PLoS One 13, e0203956 https://doi.org/10.1371/journal.pone.0203956
  35. Sasaki T, Sato Y, Higashiyama T and Sasaki N (2017) Live imaging reveals the dynamics and regulation of mitochondrial nucleoids during the cell cycle in Fucci2-HeLa cells. Sci Rep 7, 11257 https://doi.org/10.1038/s41598-017-10843-8
  36. Calkins MJ and Reddy PH (2011) Assessment of newly synthesized mitochondrial DNA using BrdU labeling in primary neurons from Alzheimer's disease mice: Implications for impaired mitochondrial biogenesis and synaptic damage. Biochim Biophys Acta 1812, 1182-1189 https://doi.org/10.1016/j.bbadis.2011.04.006
  37. Davis AF and Clayton DA (1996) In situ localization of mitochondrial DNA replication in intact mammalian cells. J Cell Biol 135, 883-893 https://doi.org/10.1083/jcb.135.4.883
  38. Rajala N, Gerhold JM, Martinsson P, Klymov A and Spelbrink JN (2014) Replication factors transiently associate with mtDNA at the mitochondrial inner membrane to facilitate replication. Nucleic Acids Res 42, 952-967 https://doi.org/10.1093/nar/gkt988
  39. Leibowitz RD (1971) The effect of ethidium bromide on mitochondrial DNA synthesis and mitochondrial DNA structure in HeLa cells. J Cell Biol 51, 116-122 https://doi.org/10.1083/jcb.51.1.116
  40. Warren EB, Aicher AE, Fessel JP and Konradi C (2017) Mitochondrial DNA depletion by ethidium bromide decreases neuronal mitochondrial creatine kinase: Implications for striatal energy metabolism. PLoS One 12, e0190456 https://doi.org/10.1371/journal.pone.0190456
  41. Lentz SI, Edwards JL, Backus C, McLean LL, Haines KM and Feldman EL (2010) Mitochondrial DNA (mtDNA) biogenesis: visualization and duel incorporation of BrdU and EdU into newly synthesized mtDNA in vitro. J Histochem Cytochem 58, 207-218 https://doi.org/10.1369/jhc.2009.954701
  42. Alan L, Zelenka J, Jezek J, Dlaskova A and Jezek P (2010) Fluorescent in situ hybridization of mitochondrial DNA and RNA. Acta Biochim Pol 57, 403-408
  43. Hurd TR, Herrmann B, Sauerwald J, Sanny J, Grosch M and Lehmann R (2016) Long Oskar Controls Mitochondrial Inheritance in Drosophila melanogaster. Dev Cell 39, 560-571 https://doi.org/10.1016/j.devcel.2016.11.004
  44. Koo DH, Singh B, Jiang J et al (2018) Single molecule mtDNA fiber FISH for analyzing numtogenesis. Anal Biochem 552, 45-49 https://doi.org/10.1016/j.ab.2017.03.015
  45. Chatre L and Ricchetti M (2013) Large heterogeneity of mitochondrial DNA transcription and initiation of replication exposed by single-cell imaging. J Cell Sci 126, 914-926 https://doi.org/10.1242/jcs.114322
  46. Alam TI, Kanki T, Muta T et al (2003) Human mitochondrial DNA is packaged with TFAM. Nucleic Acids Res 31, 1640-1645 https://doi.org/10.1093/nar/gkg251
  47. McArthur K, Whitehead LW, Heddleston JM et al (2018) BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science 359, eaao6047 https://doi.org/10.1126/science.aao6047
  48. Ikeda M, Ide T, Fujino T et al (2015) Overexpression of TFAM or twinkle increases mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. PLoS One 10, e0119687 https://doi.org/10.1371/journal.pone.0119687
  49. Maniura-Weber K, Goffart S, Garstka HL, Montoya J and Wiesner RJ (2004) Transient overexpression of mitochondrial transcription factor A (TFAM) is sufficient to stimulate mitochondrial DNA transcription, but not sufficient to increase mtDNA copy number in cultured cells. Nucleic Acids Res 32, 6015-6027 https://doi.org/10.1093/nar/gkh921
  50. Kuznetsova I, Siira SJ, Shearwood AJ, Ermer JA, Filipovska A and Rackham O (2017) Simultaneous processing and degradation of mitochondrial RNAs revealed by circularized RNA sequencing. Nucleic Acids Res 45, 5487-5500 https://doi.org/10.1093/nar/gkx104
  51. Schneider A (1994) Import of RNA into mitochondria. Trends Cell Biol 4, 282-286 https://doi.org/10.1016/0962-8924(94)90218-6
  52. Wang G, Chen HW, Oktay Y et al (2010) PNPASE regulates RNA import into mitochondria. Cell 142, 456-467 https://doi.org/10.1016/j.cell.2010.06.035
  53. Wang G, Shimada E, Zhang J et al (2012) Correcting human mitochondrial mutations with targeted RNA import. Proc Natl Acad Sci U S A 109, 4840-4845 https://doi.org/10.1073/pnas.1116792109
  54. Bandiera S, Mategot R, Girard M, Demongeot J and Henrion-Caude A (2013) MitomiRs delineating the intracellular localization of microRNAs at mitochondria. Free Radic Biol Med 64, 12-19 https://doi.org/10.1016/j.freeradbiomed.2013.06.013
  55. Gregory RI, Chendrimada TP, Cooch N and Shiekhattar R (2005) Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell 123, 631-640 https://doi.org/10.1016/j.cell.2005.10.022
  56. Bandiera S, Ruberg S, Girard M et al (2011) Nuclear outsourcing of RNA interference components to human mitochondria. PLoS One 6, e20746 https://doi.org/10.1371/journal.pone.0020746
  57. Maniataki E and Mourelatos Z (2005) Human mitochondrial tRNAMet is exported to the cytoplasm and associates with the Argonaute 2 protein. RNA 11, 849-852 https://doi.org/10.1261/rna.2210805
  58. Dasgupta N, Peng Y, Tan Z, Ciraolo G, Wang D and Li R (2015) miRNAs in mtDNA-less cell mitochondria. Cell Death Discov 1, 15004 https://doi.org/10.1038/cddiscovery.2015.4
  59. Jagannathan R, Thapa D, Nichols CE et al (2015) Translational Regulation of the Mitochondrial Genome Following Redistribution of Mitochondrial MicroRNA in the Diabetic Heart. Circ Cardiovasc Genet 8, 785-802 https://doi.org/10.1161/CIRCGENETICS.115.001067
  60. Das S, Bedja D, Campbell N et al (2014) miR-181c regulates the mitochondrial genome, bioenergetics, and propensity for heart failure in vivo. PLoS One 9, e96820 https://doi.org/10.1371/journal.pone.0096820
  61. Zhang X, Zuo X, Yang B et al (2014) MicroRNA directly enhances mitochondrial translation during muscle differentiation. Cell 158, 607-619 https://doi.org/10.1016/j.cell.2014.05.047
  62. Kim KM, Noh JH, Abdelmohsen K and Gorospe M (2017) Mitochondrial noncoding RNA transport. BMB Rep 50, 164-174 https://doi.org/10.5483/BMBRep.2017.50.4.013
  63. Antonicka H, Sasarman F, Nishimura T, Paupe V and Shoubridge EA (2013) The mitochondrial RNA-binding protein GRSF1 localizes to RNA granules and is required for posttranscriptional mitochondrial gene expression. Cell Metab 17, 386-398 https://doi.org/10.1016/j.cmet.2013.02.006
  64. Ozawa T, Natori Y, Sato M and Umezawa Y (2007) Imaging dynamics of endogenous mitochondrial RNA in single living cells. Nat Methods 4, 413-419 https://doi.org/10.1038/nmeth1030
  65. Cheong C-G and Hall TMT (2006) Engineering RNA sequence specificity of Pumilio repeats. Proceedings of the National Academy of Sciences 103, 13635-13639 https://doi.org/10.1073/pnas.0606294103
  66. Yan X, Hoek TA, Vale RD and Tanenbaum ME (2016) Dynamics of Translation of Single mRNA Molecules In Vivo. Cell 165, 976-989 https://doi.org/10.1016/j.cell.2016.04.034
  67. Wang C, Han B, Zhou R and Zhuang X (2016) Real-Time Imaging of Translation on Single mRNA Transcripts in Live Cells. Cell 165, 990-1001 https://doi.org/10.1016/j.cell.2016.04.040
  68. Wu B, Eliscovich C, Yoon YJ and Singer RH (2016) Translation dynamics of single mRNAs in live cells and neurons. Science 352, 1430-1435 https://doi.org/10.1126/science.aaf1084
  69. Chatenay-Lapointe M and Shadel GS (2011) Repression of mitochondrial translation, respiration and a metabolic cycle-regulated gene, SLF1, by the yeast Pumilio-family protein Puf3p. PLoS One 6, e20441 https://doi.org/10.1371/journal.pone.0020441
  70. Lagouge M, Mourier A, Lee HJ et al (2015) SLIRP Regulates the Rate of Mitochondrial Protein Synthesis and Protects LRPPRC from Degradation. PLoS Genet 11, e1005423 https://doi.org/10.1371/journal.pgen.1005423
  71. Richter-Dennerlein R, Oeljeklaus S, Lorenzi I et al (2016) Mitochondrial Protein Synthesis Adapts to Influx of Nuclear-Encoded Protein. Cell 167, 471-483 e410 https://doi.org/10.1016/j.cell.2016.09.003
  72. Morscher RJ, Ducker GS, Li SH et al (2018) Mitochondrial translation requires folate-dependent tRNA methylation. Nature 554, 128-132 https://doi.org/10.1038/nature25460
  73. Richter U, Lahtinen T, Marttinen P, Suomi F and Battersby BJ (2015) Quality control of mitochondrial protein synthesis is required for membrane integrity and cell fitness. J Cell Biol 211, 373-389 https://doi.org/10.1083/jcb.201504062
  74. Ostronoff LK, Izquierdo JM, Enriquez JA, Montoya J and Cuezva JM (1996) Transient activation of mitochondrial translation regulates the expression of the mitochondrial genome during mammalian mitochondrial differentiation. Biochem J 316, 183-191 https://doi.org/10.1042/bj3160183
  75. Christian BE and Spremulli LL (2009) Evidence for an active role of IF3mt in the initiation of translation in mammalian mitochondria. Biochemistry 48, 3269-3278 https://doi.org/10.1021/bi8023493
  76. Tibbetts AS, Oesterlin L, Chan SY, Kramer G, Hardesty B and Appling DR (2003) Mammalian mitochondrial initiation factor 2 supports yeast mitochondrial translation without formylated initiator tRNA. J Biol Chem 278, 31774-31780 https://doi.org/10.1074/jbc.M304962200
  77. Lee C, Tibbetts AS, Kramer G and Appling DR (2009) Yeast AEP3p is an accessory factor in initiation of mitochondrial translation. J Biol Chem 284, 34116-34125 https://doi.org/10.1074/jbc.M109.055350
  78. Estell C, Stamatidou E, El-Messeiry S and Hamilton A (2017) In situ imaging of mitochondrial translation shows weak correlation with nucleoid DNA intensity and no suppression during mitosis. J Cell Sci 130, 4193-4199 https://doi.org/10.1242/jcs.206714
  79. Frazier AE, Thorburn DR and Compton AG (2019) Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology. J Biol Chem 294, 5386-5395 https://doi.org/10.1074/jbc.r117.809194