Staff Profile

Research

Sir Henry Dale Fellow (2019-2026), Wellcome Centre for Mitochondrial Research, Newcastle University.

Rosetrees and Stoneygate Trust Research Fellow (2018-2025), Wellcome Centre for Mitochondrial Research, Newcastle University.

Research associate, University of Gothenburg (2014-2018). Lab of Prof. Claes Gustafsson.

Investigator Scientist, MRC Mitochondrial Biology Unit, Cambridge (2013-2014), lab of Dr Michal Minczuk.

Education

PhD Mitochondrial Genetics, University of Cambridge (2009-2013), lab of Dr Michal Minczuk.

BSc (Hons.) Molecular Biology and Biochemistry, University of Durham (2006-2009)

Mitochondrial DNA maintenance, propagation and disease

Human cells contain several thousand copies of the mitochondrial genome (mtDNA) which are packaged into nucleoprotein complexes termed nucleoids. These genomes are replicated throughout the cell cycle, and are found evenly distributed around the dynamic mitochondrial network. At the end of mtDNA replication the genomes must be disentangled and resolved, before then being distributed within the cell. Our work uses molecular, biochemical and cell biology techniques to study these processes in human cells. The aims of this work are: (1) to determine how mtDNA is disentangled following DNA replication; (2) to identify and characterise factors that are required for mtDNA resolution and segregation; and (3) to elucidate the molecular basis of human mitochondrial diseases linked to impaired mtDNA resolution and segregation.

Research Team

Katja Menger - Research Associate

Christin Albus - Research Associate

Ashley Ngan - PhD Student

BGM3060 - Diagnostic Medical Genetics - Lecturer

CMB3000 - Project Supervisor

MMB8030 - Genetic Medicine - Lecturer

MMB8034 - Mitochondrial Biology and Medicine - Module co-lead and lecturer

MRes Induction Week - Lecturer

BMS undergraduate tutor

MRes tutor

• Articles

  • Bernardino Gomes TM, Vincent AE, Menger KE, Stewart JB, Nicholls TJ. Mechanisms and pathologies of human mitochondrial DNA replication and deletion formation. Biochemical Journal 2024, 481(11), 683-715.
  • Erdinc D, Rodriguez-Luis A, Fassad MR, Mackenzie S, Watson CM, Valenzuela S, Xie X, Menger KE, Sergeant K, Craig K, Hopton S, Falkous G, Poulton J, Garcia-Moreno H, Giunti P, de Moura Aschoff CA, Morales Saute JA, Kirby AJ, Toro C, Wolfe L, Novacic D, Greenbaum L, Eliyahu A, Barel O, Anikster Y, McFarland R, Gorman GS, Schaefer AM, Gustafsson CM, Taylor RW, Falkenberg M, Nicholls TJ. Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability. EMBO Molecular Medicine 2023, 15(5), e16775.
  • Menger KE, Chapman J, Díaz-Maldonado H, Khazeem MM, Deen D, Erdinc D, Casement JW, Di Leo V, Pyle A, Rodríguez-Luis A, Cowell IG, Falkenberg M, Austin CA, Nicholls TJ. Two type I topoisomerases maintain DNA topology in human mitochondria. Nucleic Acids Research 2022, gkac857.
  • Tan BG, Mutti CD, Shi Y, Xie X, Zhu X, Silva-Pinheiro P, Menger KE, Díaz-Maldonado H, Wei W, Nicholls TJ, Chinnery PF, Minczuk M, Falkenberg M, Gustafsson CM. The human mitochondrial genome contains a second light strand promoter. Molecular Cell 2022, 82(19), 3646-3660.e9.
  • Misic J, Milenkovic D, Al-Behadili A, Xie X, Jiang M, Jiang S, Filograna R, Koolmeister C, Siira SJ, Jenninger L, Filipovska A, Clausen AR, Caporali L, Valentino ML, La Morgia C, Carelli V, Nicholls TJ, Wredenberg A, Falkenberg M, Larsson NG. Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion. Nucleic Acids Research 2022, 50(15), 8749–8766.
  • Jiang M, Xie X, Zhu X, Jiang S, Milenkovic D, Misic J, Shi Y, Tandukar N, Li X, Atanassov I, Jenninger L, Hoberg E, Albarran-Gutierrez S, Szilagyi Z, Macao B, Siira SJ, Carelli V, Griffith JD, Gustafsson CM, Nicholls TJ, Filipovska A, Larsson NG, Falkenberg M. The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication. Science Advances 2021, 7(27), eabf8631.
  • Strakova A, Nicholls TJ, Baez-Ortega A, Ní Leathlobhair M, Sampson AT, Hughes K, Bolton IAG, Gori K, Wang J, Airikkala-Otter I, Allen JL, Allum KM, Arnold CL, Bansse-Issa L, Bhutia TN, Bisson JL, Blank K, Briceño C, Castillo Domracheva A, Corrigan AM, Cran HR, Crawford JT, Cutter SM, Davis E, de Castro KF, De Nardi AB, de Vos AP, Keenan LD, Donelan EM, Espinoza Huerta AR, Faramade IA, Fazil A, Fotopoulou E, Fruean SN, Gallardo-Arrieta F, Glebova O, Gouletsou PG, Häfelin Manrique RF, Henriques JJGP, Horta RS, Ignatenko N, Kane Y, King C, Koenig D, Krupa A, Kruzeniski SJ, Lanza-Perea M, Lazyan M, Lopez Quintana AM, Losfelt T, Marino G, Martínez Castañeda S, Martínez-López MF, Masuruli BM, Meyer M, Migneco EJ, Nakanwagi B, Neal KB, Neunzig W, Nixon SJ, Ortega-Pacheco A, Pedraza-Ordoñez F, Peleteiro MC, Polak K, Pye RJ, Ramirez-Ante JC, Reece JF, Rojas Gutierrez J, Sadia H, Schmeling SK, Shamanova O, Sherlock AG, Steenland-Smit AE, Svitich A, Tapia Martínez LJ, Ngoka IT, Torres CG, Tudor EM, van der Wel MG, Vitalaru BA, Vural SA, Walkinton O, Wehrle-Martinez AS, Widdowson SAE, Zvarich I, Chinnery PF, Falkenberg M, Gustafsson CM, Murchison EP. Recurrent Horizontal Transfer Identifies Mitochondrial Positive Selection in a Transmissible Cancer. Nature Communications 2020, 11, 3059.
  • Lehmann D, Tuppen HAL, Campbell G, Alston CL, Lawless C, Rosa HS, Rocha MC, Reeve AK, Nicholls TJ, Deschauer M, Zierz S, Taylor RW, Turnbull DM, Vincent AE. Understanding mitochondrial DNA maintenance disorders at the single muscle fibre level. Nucleic Acids Research 2019, 47(14), 7430–7443.
  • Andreazza S, Samstag CL, Sanchez-Martinez A, Fernandez-Vizarra E, Gomez-Duran A, Lee JJ, Tufi R, Hipp MJ, Schmidt EK, Nicholls TJ, Gammage PA, Chinnery PF, Minczuk M, Pallanck LJ, Kennedy SR, Whitworth AJ. Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila. Nature Communications 2019, 10, 3280.
  • Nicholls TJ, Spåhr H, Jiang S, Siira SJ, Koolmeister C, Sharma S, Kauppila JHK, Jiang M, Kaever V, Rackham O, Chabes A, Falkenberg M, Filipovska A, Larsson NG, Gustafsson CM. Dinucleotide degradation by REXO2 maintains promoter specificity in mammalian mitochondria. Molecular Cell 2019, 76, 1-13.
  • Nicholls TJ, Nadalutti CA, Motori E, Sommerville EW, Gorman GS, Basu S, Hoberg E, Turnbull DM, Chinnery PF, Larsson N-G, Larsson E, Falkenberg M, Taylor RW, Griffith JD, Gustafsson CM. Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA. Molecular Cell 2018, 69(1), 9-23.e6.
  • Matic S, Jiang M, Nicholls TJ, Uhler JP, Dirksen-Schwanenland C, Polosa PL, Simard ML, Li X, Atanassov I, Rackham O, Filipovska A, Stewart JB, Falkenberg M, Larsson NG, Milenkovic D. Mice lacking the mitochondrial exonuclease MGME1 accumulate mtDNA deletions without developing progeria. Nature Communications 2018, 9(1), 1202.
  • Uhler JP, Thörn C, Nicholls TJ, Matic S, Milenkovic D, Gustafsson CM, Falkenberg M. MGME1 processes flaps into ligatable nicks in concert with DNA polymerase γ during mtDNA replication. Nucleic Acids Research 2016, 44(12), 5861-5871.
  • Kopajtich R, Nicholls TJ, Rorbach J, Metodiev MD, Freisinger P, Mandel H, Vanlander A, Ghezzi D, Carrozzo R, Taylor RW, Marquard K, Murayama K, Wieland T, Schwarzmayr T, Mayr JA, Pearce SF, Powell CA, Saada A, Ohtake A, Invemizzi F, Lamantea E, Sommerville EW, Pyle A, Chinnery PF, Crushell E, Okazaki Y, Kohda M, Kishita Y, Tokuzawa Y, Assouline Z, Rio M, Feillet F, de Camaret BM, Chretien D, Munnich A, Menten B, Sante T, Smet J, Regal L, Lorber A, Khoury A, Zeviani M, Strom TM, Meitinger T, Bertini ES, Van Coster R, Klopstock T, Rotig A, Haack TB, Minczuk M, Prokisch H. Mutations in GTPBP3 Cause a Mitochondrial Translation Defect Associated with Hypertrophic Cardiomyopathy, Lactic Acidosis, and Encephalopathy. American Journal of Human Genetics 2014, 95(6), 708-720.
  • Rorbach J, Boesch P, Gammage PA, Nicholls TJ, Pearce SF, Patel D, Hauser A, Perocchi F, Minczuk M. MRM2 and MRM3 are involved in biogenesis of the large subunit of the mitochondrial ribosome. Molecular Biology of the Cell 2014, 25(17), 2539-2676.
  • Nicholls TJ, Zsurka G, Peeva V, Schöler S, Szczesny RJ, Cysewski D, Reyes A, Kornblum C, Sciacco M, Moggio M, Dziembowski A, Kunz WS, Minczuk M. Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease. Human Molecular Genetics 2014, 23(23), 6147-6162.
  • Kornblum C, Nicholls TJ, Haack TB, Schöler S, Peeva V, Danhauser K, Hallmann K, Zsurka G, Rorbach J, Iuso A, Wieland T, Sciacco M, Ronchi D, Comi GP, Moggio M, Quinzii CM, DiMauro S, Calvo SE, Mootha VK, Klopstock T, Strom TM, Meitinger T, Minczuk M, Kunz WS, Prokisch H. Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Nature Genetics 2013, 45, 214–219.
  • Haack TB, Kopajtich R, Freisinger P, Wieland T, Rorbach J, Nicholls TJ, Baruffini E, Walther A, Danhauser K, Zimmermann FA, Husain RA, Schum J, Mundy H, Ferrero I, Strom TM, Meitinger T, Taylor RW, Minczuk M, Mayr JA, Prokisch H. ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. American Journal of Human Genetics 2013, 93(2), 211-223.
  • Rorbach J, Nicholls TJ, Minczuk M. PDE12 removes mitochondrial RNA poly(A) tails and controls translation in human mitochondria. Nucleic Acids Research 2011, 39(17), 7750–7763.

• Reviews

  • Menger KE, Rodriguez-Luis A, Chapman J, Nicholls TJ. Controlling the topology of mammalianmitochondrial DNA. Open Biology 2021, 11(9), 210168.
  • Chapman J, Ng YS, Nicholls TJ. The Maintenance of Mitochondrial DNA Integrity and Dynamics by Mitochondrial Membranes. Life 2020, 10(9), 164.
  • Nicholls TJ, Gustafsson CM. Separating and Segregating the Human Mitochondrial Genome. Trends in Biochemical Sciences 2018, 43(11), 869-881.
  • Powell CA, Nicholls TJ, Minczuk M. Nuclear-encoded factors involved in post-transcriptional processing and modification of mitochondrial tRNAs in human disease. Frontiers in Genetics 2015, 6, 79.
  • Van Haute L, Pearce SF, Powell CA, D'Souza AR, Nicholls TJ, Minczuk M. Mitochondrial transcript maturation and its disorders. Journal of Inherited Metabolic Disease 2015, 38(4), 655-680.
  • Nicholls TJ, Minczuk M. In D-loop: 40 years of mitochondrial 7S DNA. Experimental Gerontology 2014, 56, 175-181.
  • Nicholls TJ, Rorbach J, Minczuk M. Mitochondria: mitochondrial RNA metabolism and human disease. International Journal of Biochemistry and Cell Biology 2013, 45(4), 845-849.