1932

Abstract

Mammalian mitochondrial DNA (mtDNA) is replicated and transcribed by phage-like DNA and RNA polymerases, and our understanding of these processes has progressed substantially over the last several decades. Molecular mechanisms have been elucidated by biochemistry and structural biology and essential in vivo roles established by cell biology and mouse genetics. Single molecules of mtDNA are packaged by mitochondrial transcription factor A into mitochondrial nucleoids, and their level of compaction influences the initiation of both replication and transcription. Mutations affecting the molecular machineries replicating and transcribing mtDNA are important causes of human mitochondrial disease, reflecting the critical role of the genome in oxidative phosphorylation system biogenesis. Mechanisms controlling mtDNA replication and transcription still need to be clarified, and future research in this area is likely to open novel therapeutic possibilities for treating mitochondrial dysfunction.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-biochem-052621-092014
2024-08-02
2025-02-09
Loading full text...

Full text loading...

/deliver/fulltext/biochem/93/1/annurev-biochem-052621-092014.html?itemId=/content/journals/10.1146/annurev-biochem-052621-092014&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Zaremba-Niedzwiedzka K, Caceres EF, Saw JH, Backstrom D, Juzokaite L, et al. 2017.. Asgard archaea illuminate the origin of eukaryotic cellular complexity. . Nature 541::35358
    [Crossref] [Google Scholar]
  2. 2.
    Martijn J, Vosseberg J, Guy L, Offre P, Ettema TJG. 2018.. Deep mitochondrial origin outside the sampled alphaproteobacteria. . Nature 557::1015
    [Crossref] [Google Scholar]
  3. 3.
    Lane N, Martin W. 2010.. The energetics of genome complexity. . Nature 467::92934
    [Crossref] [Google Scholar]
  4. 4.
    Stewart JB, Larsson NG. 2014.. Keeping mtDNA in shape between generations. . PLOS Genet. 10::e1004670
    [Crossref] [Google Scholar]
  5. 5.
    Lang BF, Gray MW, Burger G. 1999.. Mitochondrial genome evolution and the origin of eukaryotes. . Annu. Rev. Genet. 33::35197
    [Crossref] [Google Scholar]
  6. 6.
    Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, et al. 1981.. Sequence and organization of the human mitochondrial genome. . Nature 290::45765
    [Crossref] [Google Scholar]
  7. 7.
    Bogenhagen D, Clayton DA. 1974.. The number of mitochondrial deoxyribonucleic acid genomes in mouse L and human HeLa cells. Quantitative isolation of mitochondrial deoxyribonucleic acid. . J. Biol. Chem. 249::799195
    [Crossref] [Google Scholar]
  8. 8.
    Sutovsky P, Moreno RD, Ramalho-Santos J, Dominko T, Simerly C, Schatten G. 1999.. Ubiquitin tag for sperm mitochondria. . Nature 402::37172
    [Crossref] [Google Scholar]
  9. 9.
    Kaneda H, Hayashi J, Takahama S, Taya C, Lindahl KF, Yonekawa H. 1995.. Elimination of paternal mitochondrial DNA in intraspecific crosses during early mouse embryogenesis. . PNAS 92::454246
    [Crossref] [Google Scholar]
  10. 10.
    Smeitink J, van den Heuvel L, DiMauro S. 2001.. The genetics and pathology of oxidative phosphorylation. . Nat. Rev. Genet. 2::34252
    [Crossref] [Google Scholar]
  11. 11.
    Hatefi Y. 1985.. The mitochondrial electron transport and oxidative phosphorylation system. . Annu. Rev. Biochem. 54::101569
    [Crossref] [Google Scholar]
  12. 12.
    Larsson NG, Wang J, Wilhelmsson H, Oldfors A, Rustin P, et al. 1998.. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. . Nat. Genet. 18::23136
    [Crossref] [Google Scholar]
  13. 13.
    Shutt TE, Gray MW. 2006.. Bacteriophage origins of mitochondrial replication and transcription proteins. . Trends Genet. 22::9095
    [Crossref] [Google Scholar]
  14. 14.
    Berk AJ, Clayton DA. 1974.. Mechanism of mitochondrial DNA replication in mouse L-cells: asynchronous replication of strands, segregation of circular daughter molecules, aspects of topology and turnover of an initiation sequence. . J. Mol. Biol. 86::80124
    [Crossref] [Google Scholar]
  15. 15.
    Tan BG, Mutti CD, Shi Y, Xie X, Zhu X, et al. 2022.. The human mitochondrial genome contains a second light strand promoter. . Mol. Cell 82::364660.e9
    [Crossref] [Google Scholar]
  16. 16.
    Kornberg AB, Baker TA. 1992.. DNA Replication. New York:: Freeman
    [Google Scholar]
  17. 17.
    Robberson DL, Kasamatsu H, Vinograd J. 1972.. Replication of mitochondrial DNA. Circular replicative intermediates in mouse L cells. . PNAS 69::73741
    [Crossref] [Google Scholar]
  18. 18.
    Falkenberg M, Gaspari M, Rantanen A, Trifunovic A, Larsson NG, Gustafsson CM. 2002.. Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA. . Nat. Genet. 31::28994
    [Crossref] [Google Scholar]
  19. 19.
    Antonicka H, Sasarman F, Nishimura T, Paupe V, Shoubridge EA. 2013.. The mitochondrial RNA-binding protein GRSF1 localizes to RNA granules and is required for posttranscriptional mitochondrial gene expression. . Cell Metab. 17::38698
    [Crossref] [Google Scholar]
  20. 20.
    Jourdain AA, Koppen M, Wydro M, Rodley CD, Lightowlers RN, et al. 2013.. GRSF1 regulates RNA processing in mitochondrial RNA granules. . Cell Metab. 17::399410
    [Crossref] [Google Scholar]
  21. 21.
    Lee KW, Okot-Kotber C, LaComb JF, Bogenhagen DF. 2013.. Mitochondrial ribosomal RNA (rRNA) methyltransferase family members are positioned to modify nascent rRNA in foci near the mitochondrial DNA nucleoid. . J. Biol. Chem. 288::3138699
    [Crossref] [Google Scholar]
  22. 22.
    Jiang S, Koolmeister C, Misic J, Siira S, Kuhl I, et al. 2019.. TEFM regulates both transcription elongation and RNA processing in mitochondria. . EMBO Rep. 20::e48101
    [Crossref] [Google Scholar]
  23. 23.
    Ojala D, Montoya J, Attardi G. 1981.. tRNA punctuation model of RNA processing in human mitochondria. . Nature 290::47074
    [Crossref] [Google Scholar]
  24. 24.
    Montoya J, Ojala D, Attardi G. 1981.. Distinctive features of the 5′-terminal sequences of the human mitochondrial mRNAs. . Nature 290::46570
    [Crossref] [Google Scholar]
  25. 25.
    Holzmann J, Frank P, Loffler E, Bennett KL, Gerner C, Rossmanith W. 2008.. RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme. . Cell 135::46274
    [Crossref] [Google Scholar]
  26. 26.
    Rossmanith W, Tullo A, Potuschak T, Karwan R, Sbisa E. 1995.. Human mitochondrial tRNA processing. . J. Biol. Chem. 270::1288591
    [Crossref] [Google Scholar]
  27. 27.
    Brzezniak LK, Bijata M, Szczesny RJ, Stepien PP. 2011.. Involvement of human ELAC2 gene product in 3′ end processing of mitochondrial tRNAs. . RNA Biol. 8::61626
    [Crossref] [Google Scholar]
  28. 28.
    Sanchez MI, Mercer TR, Davies SM, Shearwood AM, Nygard KK, et al. 2011.. RNA processing in human mitochondria. . Cell Cycle 10::290416
    [Crossref] [Google Scholar]
  29. 29.
    Jourdain AA, Popow J, de la Fuente MA, Martinou JC, Anderson P, Simarro M. 2017.. The FASTK family of proteins: emerging regulators of mitochondrial RNA biology. . Nucleic Acids Res. 45::1094147
    [Crossref] [Google Scholar]
  30. 30.
    Clemente P, Calvo-Garrido J, Pearce SF, Schober FA, Shigematsu M, et al. 2022.. ANGEL2 phosphatase activity is required for non-canonical mitochondrial RNA processing. . Nat. Commun. 13::5750
    [Crossref] [Google Scholar]
  31. 31.
    Montoya J, Christianson T, Levens D, Rabinowitz M, Attardi G. 1982.. Identification of initiation sites for heavy-strand and light-strand transcription in human mitochondrial DNA. . PNAS 79::719599
    [Crossref] [Google Scholar]
  32. 32.
    Yan B, Tzertzinis G, Schildkraut I, Ettwiller L. 2022.. Comprehensive determination of transcription start sites derived from all RNA polymerases using ReCappable-seq. . Genome Res. 32::16274
    [Crossref] [Google Scholar]
  33. 33.
    Litonin D, Sologub M, Shi Y, Savkina M, Anikin M, et al. 2010.. Human mitochondrial transcription revisited: only TFAM and TFB2M are required for transcription of the mitochondrial genes in vitro. . J. Biol. Chem. 285::1812933
    [Crossref] [Google Scholar]
  34. 34.
    Gustafsson CM, Falkenberg M, Larsson NG. 2016.. Maintenance and expression of mammalian mitochondrial DNA. . Annu. Rev. Biochem. 85::13360
    [Crossref] [Google Scholar]
  35. 35.
    Kelly JL, Lehman IR. 1986.. Yeast mitochondrial RNA polymerase. Purification and properties of the catalytic subunit. . J. Biol. Chem. 261::1034047
    [Crossref] [Google Scholar]
  36. 36.
    Masters BS, Stohl LL, Clayton DA. 1987.. Yeast mitochondrial RNA polymerase is homologous to those encoded by bacteriophages T3 and T7. . Cell 51::8999
    [Crossref] [Google Scholar]
  37. 37.
    Ringel R, Sologub M, Morozov YI, Litonin D, Cramer P, Temiakov D. 2011.. Structure of human mitochondrial RNA polymerase. . Nature 478::26973
    [Crossref] [Google Scholar]
  38. 38.
    Schwinghammer K, Cheung AC, Morozov YI, Agaronyan K, Temiakov D, Cramer P. 2013.. Structure of human mitochondrial RNA polymerase elongation complex. . Nat. Struct. Mol. Biol. 20::1298303
    [Crossref] [Google Scholar]
  39. 39.
    Morozov YI, Agaronyan K, Cheung AC, Anikin M, Cramer P, Temiakov D. 2014.. A novel intermediate in transcription initiation by human mitochondrial RNA polymerase. . Nucleic Acids Res. 42::388493
    [Crossref] [Google Scholar]
  40. 40.
    Posse V, Hoberg E, Dierckx A, Shahzad S, Koolmeister C, et al. 2014.. The amino terminal extension of mammalian mitochondrial RNA polymerase ensures promoter specific transcription initiation. . Nucleic Acids Res. 42::363847
    [Crossref] [Google Scholar]
  41. 41.
    Hillen HS, Morozov YI, Sarfallah A, Temiakov D, Cramer P. 2017.. Structural basis of mitochondrial transcription initiation. . Cell 171::107281.e10
    [Crossref] [Google Scholar]
  42. 42.
    Zamudio-Ochoa A, Morozov YI, Sarfallah A, Anikin M, Temiakov D. 2022.. Mechanisms of mitochondrial promoter recognition in humans and other mammalian species. . Nucleic Acids Res. 50::276581
    [Crossref] [Google Scholar]
  43. 43.
    Posse V, Gustafsson CM. 2017.. Human mitochondrial transcription factor B2 is required for promoter melting during initiation of transcription. . J. Biol. Chem. 292::263745
    [Crossref] [Google Scholar]
  44. 44.
    Shutt TE, Gray MW. 2006.. Homologs of mitochondrial transcription factor B, sparsely distributed within the eukaryotic radiation, are likely derived from the dimethyladenosine methyltransferase of the mitochondrial endosymbiont. . Mol. Biol. Evol. 23::116979
    [Crossref] [Google Scholar]
  45. 45.
    Metodiev MD, Lesko N, Park CB, Camara Y, Shi Y, et al. 2009.. Methylation of 12S rRNA is necessary for in vivo stability of the small subunit of the mammalian mitochondrial ribosome. . Cell Metab. 9::38697
    [Crossref] [Google Scholar]
  46. 46.
    Nicholas LM, Valtat B, Medina A, Andersson L, Abels M, et al. 2017.. Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic β-cells. . Mol. Metab. 6::65163
    [Crossref] [Google Scholar]
  47. 47.
    Fisher RP, Clayton DA. 1985.. A transcription factor required for promoter recognition by human mitochondrial RNA polymerase. Accurate initiation at the heavy- and light-strand promoters dissected and reconstituted in vitro. . J. Biol. Chem. 260::1133038
    [Crossref] [Google Scholar]
  48. 48.
    Parisi MA, Clayton DA. 1991.. Similarity of human mitochondrial transcription factor 1 to high mobility group proteins. . Science 252::96569
    [Crossref] [Google Scholar]
  49. 49.
    Farge G, Falkenberg M. 2019.. Organization of DNA in mammalian mitochondria. . Int. J. Mol. Sci. 20::2770
    [Crossref] [Google Scholar]
  50. 50.
    Kukat C, Davies KM, Wurm CA, Spahr H, Bonekamp NA, et al. 2015.. Cross-strand binding of TFAM to a single mtDNA molecule forms the mitochondrial nucleoid. . PNAS 112::1128893
    [Crossref] [Google Scholar]
  51. 51.
    Kukat C, Wurm CA, Spahr H, Falkenberg M, Larsson NG, Jakobs S. 2011.. Super-resolution microscopy reveals that mammalian mitochondrial nucleoids have a uniform size and frequently contain a single copy of mtDNA. . PNAS 108::1353439
    [Crossref] [Google Scholar]
  52. 52.
    Kaufman BA, Durisic N, Mativetsky JM, Costantino S, Hancock MA, et al. 2007.. The mitochondrial transcription factor TFAM coordinates the assembly of multiple DNA molecules into nucleoid-like structures. . Mol. Biol. Cell 18::322536
    [Crossref] [Google Scholar]
  53. 53.
    Bogenhagen DF, Wang Y, Shen EL, Kobayashi R. 2003.. Protein components of mitochondrial DNA nucleoids in higher eukaryotes. . Mol. Cell Proteom. 2::120516
    [Crossref] [Google Scholar]
  54. 54.
    Farge G, Mehmedovic M, Baclayon M, van den Wildenberg SM, Roos WH, et al. 2014.. In vitro-reconstituted nucleoids can block mitochondrial DNA replication and transcription. . Cell Rep. 8::6674
    [Crossref] [Google Scholar]
  55. 55.
    Farge G, Laurens N, Broekmans OD, van den Wildenberg SM, Dekker LC, et al. 2012.. Protein sliding and DNA denaturation are essential for DNA organization by human mitochondrial transcription factor A. . Nat. Commun. 3::1013
    [Crossref] [Google Scholar]
  56. 56.
    Ngo HB, Kaiser JT, Chan DC. 2011.. The mitochondrial transcription and packaging factor Tfam imposes a U-turn on mitochondrial DNA. . Nat. Struct. Mol. Biol. 18::129096
    [Crossref] [Google Scholar]
  57. 57.
    Rubio-Cosials A, Sidow JF, Jimenez-Menendez N, Fernandez-Millan P, Montoya J, et al. 2011.. Human mitochondrial transcription factor A induces a U-turn structure in the light strand promoter. . Nat. Struct. Mol. Biol. 18::128189
    [Crossref] [Google Scholar]
  58. 58.
    Ngo HB, Lovely GA, Phillips R, Chan DC. 2014.. Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation. . Nat. Commun. 5::3077
    [Crossref] [Google Scholar]
  59. 59.
    Fisher RP, Topper JN, Clayton DA. 1987.. Promoter selection in human mitochondria involves binding of a transcription factor to orientation-independent upstream regulatory elements. . Cell 50::24758
    [Crossref] [Google Scholar]
  60. 60.
    Chang DD, Clayton DA. 1984.. Precise identification of individual promoters for transcription of each strand of human mitochondrial DNA. . Cell 36::63543
    [Crossref] [Google Scholar]
  61. 61.
    Wong TS, Rajagopalan S, Freund SM, Rutherford TJ, Andreeva A, et al. 2009.. Biophysical characterizations of human mitochondrial transcription factor A and its binding to tumor suppressor p53. . Nucleic Acids Res. 37::676583
    [Crossref] [Google Scholar]
  62. 62.
    Gaspari M, Falkenberg M, Larsson NG, Gustafsson CM. 2004.. The mitochondrial RNA polymerase contributes critically to promoter specificity in mammalian cells. . EMBO J. 23::460614
    [Crossref] [Google Scholar]
  63. 63.
    Posse V, Shahzad S, Falkenberg M, Hallberg BM, Gustafsson CM. 2015.. TEFM is a potent stimulator of mitochondrial transcription elongation in vitro. . Nucleic Acids Res. 43::261524
    [Crossref] [Google Scholar]
  64. 64.
    Agaronyan K, Morozov YI, Anikin M, Temiakov D. 2015.. Replication-transcription switch in human mitochondria. . Science 347::54851
    [Crossref] [Google Scholar]
  65. 65.
    Minczuk M, He J, Duch AM, Ettema TJ, Chlebowski A, et al. 2011.. TEFM (c17orf42) is necessary for transcription of human mtDNA. . Nucleic Acids Res. 39::428499
    [Crossref] [Google Scholar]
  66. 66.
    Hillen HS, Parshin AV, Agaronyan K, Morozov YI, Graber JJ, et al. 2017.. Mechanism of transcription anti-termination in human mitochondria. . Cell 171::108293.e13
    [Crossref] [Google Scholar]
  67. 67.
    Van Haute L, O'Connor E, Diaz-Maldonado H, Munro B, Polavarapu K, et al. 2023.. TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease. . Nat. Commun. 14::1009
    [Crossref] [Google Scholar]
  68. 68.
    Olahova M, Peter B, Szilagyi Z, Diaz-Maldonado H, Singh M, et al. 2021.. POLRMT mutations impair mitochondrial transcription causing neurological disease. . Nat. Commun. 12::1135
    [Crossref] [Google Scholar]
  69. 69.
    Terzioglu M, Ruzzenente B, Harmel J, Mourier A, Jemt E, et al. 2013.. MTERF1 binds mtDNA to prevent transcriptional interference at the light-strand promoter but is dispensable for rRNA gene transcription regulation. . Cell Metab. 17::61826
    [Crossref] [Google Scholar]
  70. 70.
    Kruse B, Narasimhan N, Attardi G. 1989.. Termination of transcription in human mitochondria: identification and purification of a DNA binding protein factor that promotes termination. . Cell 58::39197
    [Crossref] [Google Scholar]
  71. 71.
    Fernandez-Silva P, Martinez-Azorin F, Micol V, Attardi G. 1997.. The human mitochondrial transcription termination factor (mTERF) is a multizipper protein but binds to DNA as a monomer, with evidence pointing to intramolecular leucine zipper interactions. . EMBO J. 16::106679
    [Crossref] [Google Scholar]
  72. 72.
    Asin-Cayuela J, Schwend T, Farge G, Gustafsson CM. 2005.. The human mitochondrial transcription termination factor (mTERF) is fully active in vitro in the non-phosphorylated form. . J. Biol. Chem. 280::25499505
    [Crossref] [Google Scholar]
  73. 73.
    Doda JN, Wright CT, Clayton DA. 1981.. Elongation of displacement-loop strands in human and mouse mitochondrial DNA is arrested near specific template sequences. . PNAS 78::611620
    [Crossref] [Google Scholar]
  74. 74.
    Bogenhagen D, Clayton DA. 1978.. Mechanism of mitochondrial DNA replication in mouse L-cells: kinetics of synthesis and turnover of the initiation sequence. . J. Mol. Biol. 119::4968
    [Crossref] [Google Scholar]
  75. 75.
    Jemt E, Persson O, Shi Y, Mehmedovic M, Uhler JP, et al. 2015.. Regulation of DNA replication at the end of the mitochondrial D-loop involves the helicase TWINKLE and a conserved sequence element. . Nucleic Acids Res. 43::926275
    [Crossref] [Google Scholar]
  76. 76.
    Frick DN, Richardson CC. 2001.. DNA primases. . Annu. Rev. Biochem. 70::3980
    [Crossref] [Google Scholar]
  77. 77.
    Cantatore P, Attardi G. 1980.. Mapping of nascent light and heavy strand transcripts on the physical map of HeLa cell mitochondrial DNA. . Nucleic Acids Res. 8::260525
    [Crossref] [Google Scholar]
  78. 78.
    Chang DD, Hauswirth WW, Clayton DA. 1985.. Replication priming and transcription initiate from precisely the same site in mouse mitochondrial DNA. . EMBO J. 4::155967
    [Crossref] [Google Scholar]
  79. 79.
    Chang DD, Clayton DA. 1985.. Priming of human mitochondrial DNA replication occurs at the light-strand promoter. . PNAS 82::35155
    [Crossref] [Google Scholar]
  80. 80.
    Wanrooij S, Fuste JM, Farge G, Shi Y, Gustafsson CM, Falkenberg M. 2008.. Human mitochondrial RNA polymerase primes lagging-strand DNA synthesis in vitro. . PNAS 105::1112227
    [Crossref] [Google Scholar]
  81. 81.
    Fuste JM, Wanrooij S, Jemt E, Granycome CE, Cluett TJ, et al. 2010.. Mitochondrial RNA polymerase is needed for activation of the origin of light-strand DNA replication. . Mol. Cell 37::6778
    [Crossref] [Google Scholar]
  82. 82.
    Kuhl I, Miranda M, Posse V, Milenkovic D, Mourier A, et al. 2016.. POLRMT regulates the switch between replication primer formation and gene expression of mammalian mtDNA. . Sci. Adv. 2::e1600963
    [Crossref] [Google Scholar]
  83. 83.
    Bonekamp NA, Jiang M, Motori E, Garcia Villegas R, Koolmeister C, et al. 2021.. High levels of TFAM repress mammalian mitochondrial DNA transcription in vivo. . Life Sci. Alliance 4::e202101034
    [Crossref] [Google Scholar]
  84. 84.
    Bruser C, Keller-Findeisen J, Jakobs S. 2021.. The TFAM-to-mtDNA ratio defines inner-cellular nucleoid populations with distinct activity levels. . Cell Rep. 37::110000
    [Crossref] [Google Scholar]
  85. 85.
    Isaac SR, Tullius TW, Hansen KG, Dubocanin D, Couvillion M, et al. 2024.. Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA. . Nat. Struct. Mol. Biol. 31:56877
    [Google Scholar]
  86. 86.
    Nass MM, Nass S. 1963.. Intramitochondrial fibers with DNA characteristics. I. Fixation and electron staining reactions. . J. Cell Biol. 19::593611
    [Crossref] [Google Scholar]
  87. 87.
    Nass S, Nass MM. 1963.. Intramitochondrial fibers with DNA characteristics. II. Enzymatic and other hydrolytic treatments. . J. Cell Biol. 19::61329
    [Crossref] [Google Scholar]
  88. 88.
    Guttes E, Guttes S. 1964.. Thymidine incorporation by mitochondria in Physarum polycephalum. . Science 145::105758
    [Crossref] [Google Scholar]
  89. 89.
    Schneider WC, Kuff EL. 1965.. The isolation and some properties of rat liver mitochondrial deoxyribonucleic acid. . PNAS 54::165058
    [Crossref] [Google Scholar]
  90. 90.
    Taylor RW, Turnbull DM. 2005.. Mitochondrial DNA mutations in human disease. . Nat. Rev. Genet. 6::389402
    [Crossref] [Google Scholar]
  91. 91.
    Meyer RR, Simpson MV. 1968.. DNA biosynthesis in mitochondria: partial purification of a distinct DNA polymerase from isolated rat liver mitochondria. . PNAS 61::13037
    [Crossref] [Google Scholar]
  92. 92.
    Kalf GF, Ch'ih JJ. 1968.. Purification and properties of deoxyribonucleic acid polymerase from rat liver mitochondria. . J. Biol. Chem. 243::490416
    [Crossref] [Google Scholar]
  93. 93.
    Gray H, Wong TW. 1992.. Purification and identification of subunit structure of the human mitochondrial DNA polymerase. . J. Biol. Chem. 267::583541
    [Crossref] [Google Scholar]
  94. 94.
    Yakubovskaya E, Chen Z, Carrodeguas JA, Kisker C, Bogenhagen DF. 2006.. Functional human mitochondrial DNA polymerase γ forms a heterotrimer. . J. Biol. Chem. 281::37482
    [Crossref] [Google Scholar]
  95. 95.
    Fan L, Kim S, Farr CL, Schaefer KT, Randolph KM, et al. 2006.. A novel processive mechanism for DNA synthesis revealed by structure, modeling and mutagenesis of the accessory subunit of human mitochondrial DNA polymerase. . J. Mol. Biol. 358::122943
    [Crossref] [Google Scholar]
  96. 96.
    Olson MW, Wang Y, Elder RH, Kaguni LS. 1995.. Subunit structure of mitochondrial DNA polymerase from Drosophila embryos. Physical and immunological studies. . J. Biol. Chem. 270::2893237
    [Crossref] [Google Scholar]
  97. 97.
    Pinz KG, Bogenhagen DF. 2000.. Characterization of a catalytically slow AP lyase activity in DNA polymerase γ and other family A DNA polymerases. . J. Biol. Chem. 275::1250914
    [Crossref] [Google Scholar]
  98. 98.
    Kaguni LS. 2004.. DNA polymerase γ, the mitochondrial replicase. . Annu. Rev. Biochem. 73::293320
    [Crossref] [Google Scholar]
  99. 99.
    Insdorf NF, Bogenhagen DF. 1989.. DNA polymerase γ from Xenopus laevis. II. A 3′→5′ exonuclease is tightly associated with the DNA polymerase activity. . J. Biol. Chem. 264::21498503
    [Crossref] [Google Scholar]
  100. 100.
    Longley MJ, Nguyen D, Kunkel TA, Copeland WC. 2001.. The fidelity of human DNA polymerase γ with and without exonucleolytic proofreading and the p55 accessory subunit. . J. Biol. Chem. 276::3855562
    [Crossref] [Google Scholar]
  101. 101.
    Park J, Herrmann GK, Mitchell PG, Sherman MB, Yin YW. 2023.. Polγ coordinates DNA synthesis and proofreading to ensure mitochondrial genome integrity. . Nat. Struct. Mol. Biol. 30::81223
    [Crossref] [Google Scholar]
  102. 102.
    Carrodeguas JA, Theis K, Bogenhagen DF, Kisker C. 2001.. Crystal structure and deletion analysis show that the accessory subunit of mammalian DNA polymerase γ, PolγB, functions as a homodimer. . Mol. Cell 7::4354
    [Crossref] [Google Scholar]
  103. 103.
    Carrodeguas JA, Pinz KG, Bogenhagen DF. 2002.. DNA binding properties of human pol γB. . J. Biol. Chem. 277::5000814
    [Crossref] [Google Scholar]
  104. 104.
    Farge G, Pham XH, Holmlund T, Khorostov I, Falkenberg M. 2007.. The accessory subunit B of DNA polymerase γ is required for mitochondrial replisome function. . Nucleic Acids Res. 35::90211
    [Crossref] [Google Scholar]
  105. 105.
    Lee YS, Lee S, Demeler B, Molineux IJ, Johnson KA, Yin YW. 2010.. Each monomer of the dimeric accessory protein for human mitochondrial DNA polymerase has a distinct role in conferring processivity. . J. Biol. Chem. 285::149099
    [Crossref] [Google Scholar]
  106. 106.
    Krasich R, Copeland WC. 2017.. DNA polymerases in the mitochondria: a critical review of the evidence. . Front. Biosci. 22::692709
    [Crossref] [Google Scholar]
  107. 107.
    Korhonen JA, Gaspari M, Falkenberg M. 2003.. TWINKLE has 5′ → 3′ DNA helicase activity and is specifically stimulated by mitochondrial single-stranded DNA-binding protein. . J. Biol. Chem. 278::4862732
    [Crossref] [Google Scholar]
  108. 108.
    Korhonen JA, Pham XH, Pellegrini M, Falkenberg M. 2004.. Reconstitution of a minimal mtDNA replisome in vitro. . EMBO J. 23::242329
    [Crossref] [Google Scholar]
  109. 109.
    Milenkovic D, Matic S, Kuhl I, Ruzzenente B, Freyer C, et al. 2013.. TWINKLE is an essential mitochondrial helicase required for synthesis of nascent D-loop strands and complete mtDNA replication. . Hum. Mol. Genet. 22::198393
    [Crossref] [Google Scholar]
  110. 110.
    Ikeda M, Ide T, Fujino T, Arai S, Saku K, 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
    [Crossref] [Google Scholar]
  111. 111.
    Tyynismaa H, Sembongi H, Bokori-Brown M, Granycome C, Ashley N, et al. 2004.. Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA copy number. . Hum. Mol. Genet. 13::321927
    [Crossref] [Google Scholar]
  112. 112.
    Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, et al. 2001.. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. . Nat. Genet. 28::22331
    [Crossref] [Google Scholar]
  113. 113.
    Patel SS, Picha KM. 2000.. Structure and function of hexameric helicases. . Annu. Rev. Biochem. 69::65197
    [Crossref] [Google Scholar]
  114. 114.
    Korhonen JA, Pande V, Holmlund T, Farge G, Pham XH, et al. 2008.. Structure–function defects of the TWINKLE linker region in progressive external ophthalmoplegia. . J. Mol. Biol. 377::691705
    [Crossref] [Google Scholar]
  115. 115.
    Holmlund T, Farge G, Pande V, Korhonen J, Nilsson L, Falkenberg M. 2009.. Structure–function defects of the twinkle amino-terminal region in progressive external ophthalmoplegia. . Biochim. Biophys. Acta Mol. Basis Dis. 1792::13239
    [Crossref] [Google Scholar]
  116. 116.
    Riccio AA, Bouvette J, Perera L, Longley MJ, Krahn JM, et al. 2022.. Structural insight and characterization of human Twinkle helicase in mitochondrial disease. . PNAS 119::e2207459119
    [Crossref] [Google Scholar]
  117. 117.
    Shutt TE, Gray MW. 2006.. Twinkle, the mitochondrial replicative DNA helicase, is widespread in the eukaryotic radiation and may also be the mitochondrial DNA primase in most eukaryotes. . J. Mol. Evol. 62::58899
    [Crossref] [Google Scholar]
  118. 118.
    Farge G, Holmlund T, Khvorostova J, Rofougaran R, Hofer A, Falkenberg M. 2008.. The N-terminal domain of TWINKLE contributes to single-stranded DNA binding and DNA helicase activities. . Nucleic Acids Res. 36::393403
    [Crossref] [Google Scholar]
  119. 119.
    Johnson LC, Singh A, Patel SS. 2023.. The N-terminal domain of human mitochondrial helicase Twinkle has DNA-binding activity crucial for supporting processive DNA synthesis by polymerase γ. . J. Biol. Chem. 299::102797
    [Crossref] [Google Scholar]
  120. 120.
    Miralles Fuste J, Shi Y, Wanrooij S, Zhu X, Jemt E, et al. 2014.. In vivo occupancy of mitochondrial single-stranded DNA binding protein supports the strand displacement mode of DNA replication. . PLOS Genet. 10::e1004832
    [Crossref] [Google Scholar]
  121. 121.
    Jiang M, Xie X, Zhu X, Jiang S, Milenkovic D, et al. 2021.. The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication. . Sci. Adv. 7::eabf8631
    [Crossref] [Google Scholar]
  122. 122.
    Tapper DP, Clayton DA. 1981.. Mechanism of replication of human mitochondrial DNA. Localization of the 5′ ends of nascent daughter strands. . J. Biol. Chem. 256::510915
    [Crossref] [Google Scholar]
  123. 123.
    Phillips AF, Millet AR, Tigano M, Dubois SM, Crimmins H, et al. 2017.. Single-molecule analysis of mtDNA replication uncovers the basis of the common deletion. . Mol. Cell 65::52738.e6
    [Crossref] [Google Scholar]
  124. 124.
    Clayton DA. 1991.. Replication and transcription of vertebrate mitochondrial DNA. . Annu. Rev. Cell Biol. 7::45378
    [Crossref] [Google Scholar]
  125. 125.
    Wanrooij S, Miralles Fuste J, Stewart JB, Wanrooij PH, Samuelsson T, et al. 2012.. In vivo mutagenesis reveals that OriL is essential for mitochondrial DNA replication. . EMBO Rep. 13::113037
    [Crossref] [Google Scholar]
  126. 126.
    Sarfallah A, Zamudio-Ochoa A, Anikin M, Temiakov D. 2021.. Mechanism of transcription initiation and primer generation at the mitochondrial replication origin OriL. . EMBO J. 40::e107988
    [Crossref] [Google Scholar]
  127. 127.
    Falkenberg M. 2018.. Mitochondrial DNA replication in mammalian cells: overview of the pathway. . Essays Biochem. 62::28796
    [Crossref] [Google Scholar]
  128. 128.
    Brown TA, Cecconi C, Tkachuk AN, Bustamante C, Clayton DA. 2005.. Replication of mitochondrial DNA occurs by strand displacement with alternative light-strand origins, not via a strand-coupled mechanism. . Genes Dev. 19::246676
    [Crossref] [Google Scholar]
  129. 129.
    Basu S, Xie X, Uhler JP, Hedberg-Oldfors C, Milenkovic D, et al. 2020.. Accurate mapping of mitochondrial DNA deletions and duplications using deep sequencing. . PLOS Genet. 16::e1009242
    [Crossref] [Google Scholar]
  130. 130.
    Lewis JS, Jergic S, Dixon NE. 2016.. The E. coli DNA replication fork. . Enzymes 39::3188
    [Crossref] [Google Scholar]
  131. 131.
    Yasukawa T, Reyes A, Cluett TJ, Yang MY, Bowmaker M, et al. 2006.. Replication of vertebrate mitochondrial DNA entails transient ribonucleotide incorporation throughout the lagging strand. . EMBO J. 25::535871
    [Crossref] [Google Scholar]
  132. 132.
    Reyes A, Kazak L, Wood SR, Yasukawa T, Jacobs HT, Holt IJ. 2013.. Mitochondrial DNA replication proceeds via a ‘bootlace’ mechanism involving the incorporation of processed transcripts. . Nucleic Acids Res. 41::583750
    [Crossref] [Google Scholar]
  133. 133.
    Holt IJ, Jacobs HT. 2014.. Unique features of DNA replication in mitochondria: a functional and evolutionary perspective. . BioEssays 36::102431
    [Crossref] [Google Scholar]
  134. 134.
    Holt IJ, Lorimer HE, Jacobs HT. 2000.. Coupled leading- and lagging-strand synthesis of mammalian mitochondrial DNA. . Cell 100::51524
    [Crossref] [Google Scholar]
  135. 135.
    Kang D, Miyako K, Kai Y, Irie T, Takeshige K. 1997.. In vivo determination of replication origins of human mitochondrial DNA by ligation-mediated polymerase chain reaction. . J. Biol. Chem. 272::1527579
    [Crossref] [Google Scholar]
  136. 136.
    Pham XH, Farge G, Shi Y, Gaspari M, Gustafsson CM, Falkenberg M. 2006.. Conserved sequence box II directs transcription termination and primer formation in mitochondria. . J. Biol. Chem. 281::2464752
    [Crossref] [Google Scholar]
  137. 137.
    Posse V, Al-Behadili A, Uhler JP, Clausen AR, Reyes A, et al. 2019.. RNase H1 directs origin-specific initiation of DNA replication in human mitochondria. . PLOS Genet. 15::e1007781
    [Crossref] [Google Scholar]
  138. 138.
    Xu B, Clayton DA. 1995.. A persistent RNA-DNA hybrid is formed during transcription at a phylogenetically conserved mitochondrial DNA sequence. . Mol. Cell. Biol. 15::58089
    [Crossref] [Google Scholar]
  139. 139.
    Xu B, Clayton DA. 1996.. RNA–DNA hybrid formation at the human mitochondrial heavy-strand origin ceases at replication start sites: an implication for RNA–DNA hybrids serving as primers. . EMBO J. 15::313543
    [Crossref] [Google Scholar]
  140. 140.
    Wanrooij PH, Uhler JP, Simonsson T, Falkenberg M, Gustafsson CM. 2010.. G-quadruplex structures in RNA stimulate mitochondrial transcription termination and primer formation. . PNAS 107::1607277
    [Crossref] [Google Scholar]
  141. 141.
    Wanrooij PH, Uhler JP, Shi Y, Westerlund F, Falkenberg M, Gustafsson CM. 2012.. A hybrid G-quadruplex structure formed between RNA and DNA explains the extraordinary stability of the mitochondrial R-loop. . Nucleic Acids Res. 40::1033444
    [Crossref] [Google Scholar]
  142. 142.
    Bennett JL, Clayton DA. 1990.. Efficient site-specific cleavage by RNase MRP requires interaction with two evolutionarily conserved mitochondrial RNA sequences. . Mol. Cell. Biol. 10::2191201
    [Google Scholar]
  143. 143.
    Lee DY, Clayton DA. 1997.. RNase mitochondrial RNA processing correctly cleaves a novel R loop at the mitochondrial DNA leading-strand origin of replication. . Genes Dev. 11::58292
    [Crossref] [Google Scholar]
  144. 144.
    Kiss T, Filipowicz W. 1992.. Evidence against a mitochondrial location of the 7–2/MRP RNA in mammalian cells. . Cell 70::1116
    [Crossref] [Google Scholar]
  145. 145.
    Kiss T, Marshallsay C, Filipowicz W. 1992.. 7–2/MRP RNAs in plant and mammalian cells: association with higher order structures in the nucleolus. . EMBO J. 11::373746
    [Crossref] [Google Scholar]
  146. 146.
    Cerritelli SM, Frolova EG, Feng C, Grinberg A, Love PE, Crouch RJ. 2003.. Failure to produce mitochondrial DNA results in embryonic lethality in Rnaseh1 null mice. . Mol. Cell 11::80715
    [Crossref] [Google Scholar]
  147. 147.
    Misic J, Milenkovic D, Al-Behadili A, Xie X, Jiang M, et al. 2022.. Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion. . Nucleic Acids Res. 50::874966
    [Crossref] [Google Scholar]
  148. 148.
    Gillum AM, Clayton DA. 1979.. Mechanism of mitochondrial DNA replication in mouse L-cells: RNA priming during the initiation of heavy-strand synthesis. . J. Mol. Biol. 135::35368
    [Crossref] [Google Scholar]
  149. 149.
    Holmes JB, Akman G, Wood SR, Sakhuja K, Cerritelli SM, et al. 2015.. Primer retention owing to the absence of RNase H1 is catastrophic for mitochondrial DNA replication. . PNAS 112::933439
    [Crossref] [Google Scholar]
  150. 150.
    Del Dotto V, Ullah F, Di Meo I, Magini P, Gusic M, et al. 2020.. SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder. . J. Clin. Investig. 130::10825
    [Crossref] [Google Scholar]
  151. 151.
    Piro-Megy C, Sarzi E, Tarres-Sole A, Pequignot M, Hensen F, et al. 2020.. Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy. . J. Clin. Investig. 130::14356
    [Crossref] [Google Scholar]
  152. 152.
    Mazina OM, Somarowthu S, Kadyrova LY, Baranovskiy AG, Tahirov TH, et al. 2020.. Replication protein A binds RNA and promotes R-loop formation. . J. Biol. Chem. 295::1420313
    [Crossref] [Google Scholar]
  153. 153.
    Brown GG, Gadaleta G, Pepe G, Saccone C, Sbisa E. 1986.. Structural conservation and variation in the D-loop-containing region of vertebrate mitochondrial DNA. . J. Mol. Biol. 192::50311
    [Crossref] [Google Scholar]
  154. 154.
    McShane E, Couvillion M, Ietswaart R, Prakash G, Smalec BM, et al. 2024.. A kinetic dichotomy between mitochondrial and nuclear gene expression processes. . Mol. Cell 84:154155
    [Google Scholar]
  155. 155.
    Roberti M, Musicco C, Polosa PL, Milella F, Gadaleta MN, Cantatore P. 1998.. Multiple protein-binding sites in the TAS-region of human and rat mitochondrial DNA. . Biochem. Biophys. Res. Commun. 243::3640
    [Crossref] [Google Scholar]
  156. 156.
    Wu CC, Lin JLJ, Yang-Yen HF, Yuan HS. 2019.. A unique exonuclease ExoG cleaves between RNA and DNA in mitochondrial DNA replication. . Nucleic Acids Res. 47::540519
    [Crossref] [Google Scholar]
  157. 157.
    Pertea G, Pertea M. 2020.. GFF utilities: GffRead and GffCompare. . F1000Res 9::304
    [Crossref] [Google Scholar]
  158. 158.
    Macao B, Uhler JP, Siibak T, Zhu X, Shi Y, et al. 2015.. The exonuclease activity of DNA polymerase γ is required for ligation during mitochondrial DNA replication. . Nat. Commun. 6::7303
    [Crossref] [Google Scholar]
  159. 159.
    Uhler JP, Falkenberg M. 2015.. Primer removal during mammalian mitochondrial DNA replication. . DNA Repair 34::2838
    [Crossref] [Google Scholar]
  160. 160.
    Al-Behadili A, Uhler JP, Berglund AK, Peter B, Doimo M, et al. 2018.. A two-nuclease pathway involving RNase H1 is required for primer removal at human mitochondrial OriL. . Nucleic Acids Res. 46::947183
    [Crossref] [Google Scholar]
  161. 161.
    Karlowicz A, Dubiel AB, Czerwinska J, Bledea A, Purzycki P, et al. 2022.. In vitro reconstitution reveals a key role of human mitochondrial EXOG in RNA primer processing. . Nucleic Acids Res. 50::79918007
    [Crossref] [Google Scholar]
  162. 162.
    Nicholls TJ, Zsurka G, Peeva V, Scholer S, Szczesny RJ, et al. 2014.. Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease. . Hum. Mol. Genet. 23::614762
    [Crossref] [Google Scholar]
  163. 163.
    Kornblum C, Nicholls TJ, Haack TB, Scholer S, Peeva V, et al. 2013.. Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. . Nat. Genet. 45::21419
    [Crossref] [Google Scholar]
  164. 164.
    Uhler JP, Thorn C, Nicholls TJ, Matic S, Milenkovic D, et al. 2016.. MGME1 processes flaps into ligatable nicks in concert with DNA polymerase γ during mtDNA replication. . Nucleic Acids Res. 44::586171
    [Crossref] [Google Scholar]
  165. 165.
    Lakshmipathy U, Campbell C. 1999.. The human DNA ligase III gene encodes nuclear and mitochondrial proteins. . Mol. Cell. Biol. 19::386976
    [Crossref] [Google Scholar]
  166. 166.
    Puebla-Osorio N, Lacey DB, Alt FW, Zhu C. 2006.. Early embryonic lethality due to targeted inactivation of DNA ligase III. . Mol. Cell. Biol. 26::393541
    [Crossref] [Google Scholar]
  167. 167.
    Nicholls TJ, Nadalutti CA, Motori E, Sommerville EW, Gorman GS, et al. 2018.. Topoisomerase 3α is required for decatenation and segregation of human mtDNA. . Mol. Cell 69::923.e6
    [Crossref] [Google Scholar]
  168. 168.
    Erdinc D, Rodriguez-Luis A, Fassad MR, Mackenzie S, Watson CM, et al. 2023.. Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability. . EMBO Mol. Med. 15::e16775
    [Crossref] [Google Scholar]
  169. 169.
    Menger KE, Chapman J, Diaz-Maldonado H, Khazeem MM, Deen D, et al. 2022.. Two type I topoisomerases maintain DNA topology in human mitochondria. . Nucleic Acids Res. 50::1115474
    [Crossref] [Google Scholar]
  170. 170.
    Zhang H, Barcelo JM, Lee B, Kohlhagen G, Zimonjic DB, et al. 2001.. Human mitochondrial topoisomerase I. . PNAS 98::1060813
    [Crossref] [Google Scholar]
  171. 171.
    Cortopassi GA, Arnheim N. 1990.. Detection of a specific mitochondrial DNA deletion in tissues of older humans. . Nucleic Acids Res. 18::692733
    [Crossref] [Google Scholar]
  172. 172.
    Goldstein A, Falk MJ. 2003.. Single large-scale mitochondrial DNA deletion syndromes. . In GeneReviews®, ed. MP Adam, GM Mirzaa, RA Pagon, SE Wallace, LJH Bean, et al., updated September 28, 2023 . Seattle, WA:: Univ. Wash.
    [Google Scholar]
  173. 173.
    Lawless C, Greaves L, Reeve AK, Turnbull DM, Vincent AE. 2020.. The rise and rise of mitochondrial DNA mutations. . Open Biol. 10::200061
    [Crossref] [Google Scholar]
  174. 174.
    Holt IJ, Harding AE, Morgan-Hughes JA. 1988.. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. . Nature 331::71719
    [Crossref] [Google Scholar]
  175. 175.
    Moraes CT, DiMauro S, Zeviani M, Lombes A, Shanske S, et al. 1989.. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. . N. Engl. J. Med. 320::129399
    [Crossref] [Google Scholar]
  176. 176.
    Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, et al. 1988.. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. . Neurology 38::133946
    [Crossref] [Google Scholar]
  177. 177.
    Wanrooij S, Falkenberg M. 2010.. The human mitochondrial replication fork in health and disease. . Biochim. Biophys. Acta Bioenerg. 1797::137888
    [Crossref] [Google Scholar]
  178. 178.
    El-Hattab AW, Craigen WJ, Scaglia F. 2017.. Mitochondrial DNA maintenance defects. . Biochim. Biophys. Acta Mol. Basis Dis. 1863::153955
    [Crossref] [Google Scholar]
  179. 179.
    Filograna R, Mennuni M, Alsina D, Larsson NG. 2021.. Mitochondrial DNA copy number in human disease: the more the better?. FEBS Lett. 595::9761002
    [Crossref] [Google Scholar]
  180. 180.
    Schon EA, Rizzuto R, Moraes CT, Nakase H, Zeviani M, DiMauro S. 1989.. A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA. . Science 244::34649
    [Crossref] [Google Scholar]
  181. 181.
    Krishnan KJ, Reeve AK, Samuels DC, Chinnery PF, Blackwood JK, et al. 2008.. What causes mitochondrial DNA deletions in human cells?. Nat. Genet. 40::27579
    [Crossref] [Google Scholar]
  182. 182.
    Shoffner JM, Lott MT, Voljavec AS, Soueidan SA, Costigan DA, Wallace DC. 1989.. Spontaneous Kearns–Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. . PNAS 86::795256
    [Crossref] [Google Scholar]
  183. 183.
    Moretton A, Morel F, Macao B, Lachaume P, Ishak L, et al. 2017.. Selective mitochondrial DNA degradation following double-strand breaks. . PLOS ONE 12::e0176795
    [Crossref] [Google Scholar]
  184. 184.
    Bacman SR, Williams SL, Moraes CT. 2009.. Intra- and inter-molecular recombination of mitochondrial DNA after in vivo induction of multiple double-strand breaks. . Nucleic Acids Res. 37::421826
    [Crossref] [Google Scholar]
  185. 185.
    Nissanka N, Minczuk M, Moraes CT. 2019.. Mechanisms of mitochondrial DNA deletion formation. . Trends Genet. 35::23544
    [Crossref] [Google Scholar]
  186. 186.
    Persson O, Muthukumar Y, Basu S, Jenninger L, Uhler JP, et al. 2019.. Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions. . Nat. Commun. 10::759
    [Crossref] [Google Scholar]
  187. 187.
    Viguera E, Canceill D, Ehrlich SD. 2001.. Replication slippage involves DNA polymerase pausing and dissociation. . EMBO J. 20::258795
    [Crossref] [Google Scholar]
  188. 188.
    Doimo M, Chaudhari N, Abrahamsson S, L'Hote V, Nguyen TVH, et al. 2023.. Enhanced mitochondrial G-quadruplex formation impedes replication fork progression leading to mtDNA loss in human cells. . Nucleic Acids Res. 51::7392408
    [Crossref] [Google Scholar]
  189. 189.
    Damas J, Carneiro J, Goncalves J, Stewart JB, Samuels DC, et al. 2012.. Mitochondrial DNA deletions are associated with non-B DNA conformations. . Nucleic Acids Res. 40::760621
    [Crossref] [Google Scholar]
  190. 190.
    Oliveira PH, da Silva CL, Cabral JM. 2013.. An appraisal of human mitochondrial DNA instability: new insights into the role of non-canonical DNA structures and sequence motifs. . PLOS ONE 8::e59907
    [Crossref] [Google Scholar]
  191. 191.
    Samuels DC, Schon EA, Chinnery PF. 2004.. Two direct repeats cause most human mtDNA deletions. . Trends Genet. 20::39398
    [Crossref] [Google Scholar]
  192. 192.
    Sommerville EW, Chinnery PF, Gorman GS, Taylor RW. 2014.. Adult-onset Mendelian PEO associated with mitochondrial disease. . J. Neuromuscul. Dis. 1::11933
    [Crossref] [Google Scholar]
  193. 193.
    Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, et al. 2004.. Premature ageing in mice expressing defective mitochondrial DNA polymerase. . Nature 429::41723
    [Crossref] [Google Scholar]
  194. 194.
    Matic S, Jiang M, Nicholls TJ, Uhler JP, Dirksen-Schwanenland C, et al. 2018.. Mice lacking the mitochondrial exonuclease MGME1 accumulate mtDNA deletions without developing progeria. . Nat. Commun. 9::1202
    [Crossref] [Google Scholar]
  195. 195.
    Bratic A, Kauppila TE, Macao B, Gronke S, Siibak T, et al. 2015.. Complementation between polymerase- and exonuclease-deficient mitochondrial DNA polymerase mutants in genomically engineered flies. . Nat. Commun. 6::8808
    [Crossref] [Google Scholar]
  196. 196.
    Rubalcava-Gracia D, Garcia-Villegas R, Larsson NG. 2023.. No role for nuclear transcription regulators in mammalian mitochondria?. Mol. Cell 83::83242
    [Crossref] [Google Scholar]
  197. 197.
    Gaines G, Rossi C, Attardi G. 1987.. Markedly different ATP requirements for rRNA synthesis and mtDNA light strand transcription versus mRNA synthesis in isolated human mitochondria. . J. Biol. Chem. 262::190715
    [Crossref] [Google Scholar]
  198. 198.
    Amiott EA, Jaehning JA. 2006.. Mitochondrial transcription is regulated via an ATP “sensing” mechanism that couples RNA abundance to respiration. . Mol. Cell 22::32938
    [Crossref] [Google Scholar]
  199. 199.
    Amiott EA, Jaehning JA. 2006.. Sensitivity of the yeast mitochondrial RNA polymerase to +1 and +2 initiating nucleotides. . J. Biol. Chem. 281::3498288
    [Crossref] [Google Scholar]
  200. 200.
    Nicholls TJ, Spahr H, Jiang S, Siira SJ, Koolmeister C, et al. 2019.. Dinucleotide degradation by REXO2 maintains promoter specificity in mammalian mitochondria. . Mol. Cell 76::78496.e6
    [Crossref] [Google Scholar]
  201. 201.
    Aloni Y, Attardi G. 1971.. Symmetrical in vivo transcription of mitochondrial DNA in HeLa cells. . PNAS 68::175761
    [Crossref] [Google Scholar]
  202. 202.
    Piechota J, Tomecki R, Gewartowski K, Szczesny R, Dmochowska A, et al. 2006.. Differential stability of mitochondrial mRNA in HeLa cells. . Acta Biochim. Pol. 53::15768
    [Crossref] [Google Scholar]
  203. 203.
    Mercer TR, Neph S, Dinger ME, Crawford J, Smith MA, et al. 2011.. The human mitochondrial transcriptome. . Cell 146::64558
    [Crossref] [Google Scholar]
  204. 204.
    Pearce SF, Rebelo-Guiomar P, D'Souza AR, Powell CA, Van Haute L, Minczuk M. 2017.. Regulation of mammalian mitochondrial gene expression: recent advances. . Trends Biochem. Sci. 42::62539
    [Crossref] [Google Scholar]
  205. 205.
    Ojala D, Attardi G. 1974.. Identification of discrete polyadenylate-containing RNA components transcribed from HeLa cell mitochondrial DNA. . PNAS 71::56367
    [Crossref] [Google Scholar]
  206. 206.
    Cantatore P, Loguercio Polosa P, Mustich A, Petruzzella V, Gadaleta MN. 1988.. Faithful and highly efficient RNA synthesis in isolated mitochondria from rat liver. . Curr. Genet. 14::47782
    [Crossref] [Google Scholar]
  207. 207.
    Zhu X, Xie X, Das H, Tan BG, Shi Y, et al. 2022.. Non-coding 7S RNA inhibits transcription via mitochondrial RNA polymerase dimerization. . Cell 185::230923.e24
    [Crossref] [Google Scholar]
  208. 208.
    Szczesny RJ, Borowski LS, Malecki M, Wojcik MA, Stepien PP, Golik P. 2012.. RNA degradation in yeast and human mitochondria. . Biochim. Biophys. Acta Gene Regul. Mech. 1819::102734
    [Crossref] [Google Scholar]
  209. 209.
    Ekstrand MI, Falkenberg M, Rantanen A, Park CB, Gaspari M, et al. 2004.. Mitochondrial transcription factor A regulates mtDNA copy number in mammals. . Hum. Mol. Genet. 13::93544
    [Crossref] [Google Scholar]
  210. 210.
    Lu B, Lee J, Nie X, Li M, Morozov YI, et al. 2013.. Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease. . Mol. Cell 49::12132
    [Crossref] [Google Scholar]
  211. 211.
    De Gaetano A, Gibellini L, Bianchini E, Borella R, De Biasi S, et al. 2020.. Impaired mitochondrial morphology and functionality in Lonp1wt/− mice. . J. Clin. Med. 9::1783
    [Crossref] [Google Scholar]
  212. 212.
    Peter B, Waddington CL, Olahova M, Sommerville EW, Hopton S, et al. 2018.. Defective mitochondrial protease LonP1 can cause classical mitochondrial disease. . Hum. Mol. Genet. 27::174353
    [Crossref] [Google Scholar]
  213. 213.
    Feric M, Demarest TG, Tian J, Croteau DL, Bohr VA, Misteli T. 2021.. Self-assembly of multi-component mitochondrial nucleoids via phase separation. . EMBO J. 40::e107165
    [Crossref] [Google Scholar]
  214. 214.
    Lagouge M, Mourier A, Lee HJ, Spahr H, Wai T, et al. 2015.. SLIRP regulates the rate of mitochondrial protein synthesis and protects LRPPRC from degradation. . PLOS Genet. 11::e1005423
    [Crossref] [Google Scholar]
  215. 215.
    Bonekamp NA, Peter B, Hillen HS, Felser A, Bergbrede T, et al. 2020.. Small-molecule inhibitors of human mitochondrial DNA transcription. . Nature 588::71216
    [Crossref] [Google Scholar]
  216. 216.
    Mennuni M, Filograna R, Felser A, Bonekamp NA, Giavalisco P, et al. 2022.. Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR-Cas9 screen. . EMBO Rep. 23::e53054
    [Crossref] [Google Scholar]
  217. 217.
    Bailey LJ, Cluett TJ, Reyes A, Prolla TA, Poulton J, et al. 2009.. Mice expressing an error-prone DNA polymerase in mitochondria display elevated replication pausing and chromosomal breakage at fragile sites of mitochondrial DNA. . Nucleic Acids Res. 37::232735
    [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-biochem-052621-092014
Loading
/content/journals/10.1146/annurev-biochem-052621-092014
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error