Wellcome Trust Centre For Mitochondrial Research

Tom Nicholls

Biography

I was awarded a Bsc (Hons) in Molecular Biology and Biochemistry from Durham University in 2009, then moved to Cambridge to study for a PhD under the supervision of Dr Michal Minczuk at the MRC Mitochondrial Biology Unit. This began my interest in the genetics of mitochondria and the molecular basis of mitochondrial diseases. After completing my PhD I moved to the lab of Prof. Claes Gustafsson at the University of Gothenburg, Sweden, where I spent four years studying mitochondrial DNA replication and transcription. In November 2018 I moved to the Wellcome Centre for Mitochondrial Research as a Newcastle University Research Fellow (NURF), funded by the Rosetrees and Stoneygate Trust. Soon afterwards I was awarded a Sir Henry Dale Fellowship, funded by Wellcome and the Royal Society, to study how the mitochondrial genome is replicated and distributed within human cells.

Research Project

Mitochondrial DNA maintenance, propagation and disease.

Principal Investigators: Dr Tom Nicholls

Other staff members involved: Dr Katja Menger

Project Details

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.

Email: Thomas.Nicholls@newcastle.ac.uk

Sponsor/Funder: Wellcome Trust, Royal Society, Rosetrees and Stoneygate Trusts

Publications

Lehmann D, Tuppen HAL, Campbell GE, Alston CL, Lawless C, Rosa HS, Rocha MC, Reeve AK, Nicholls TJ, Deschauer M, et al. (2019). Understanding mitochondrial DNA maintenance disorders at the single muscle fibre level. Nucleic Acids Res. doi: 1093/nar/gkz472.

Nicholls TJ and Gustafsson CM. (2018). Separating and segregating the human mitochondrial genome. Trends Biochem Sci. 43(11): 869-881.

Matic S, Jiang M, Nicholls TJ, Uhler JP, Dirksen-Schwanenland C, Polosa PL, Simard M-L, Li X, Atanassov I, Rackham O, et al (2018). Mice lacking the mitochondrial exonuclease MGME1 accumulate mtDNA deletions without developing progeria. Nature Commun; 9(1): 1202.

Nicholls TJ, Nadalutti CA, Motori E, Sommerville EW, Gorman GS, Basu S, Hoberg E, Turnbull DM, Chinnery PF, Larsson NG, et al. (2018). Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA. Mol Cell; 69 (1): 9-23.

Uhler JP, Thörn C, Nicholls TJ, Matic S, Milenkovic D, Gustafsson CM, and Falkenberg M. (2016). MGME1 processes flaps into ligatable nicks in concert with DNA polymerase γ during mtDNA replication. Nucleic Acids Res; 44(12): 5861-71.

Van Haute L, Pearce SF, Powell CA, D’Souza AR, Nicholls TJ, and Minczuk M. (2015). Mitochondrial transcript maturation and its disorders. J Inherit Metab Dis 38(4): 655-80.

Powell CA, Nicholls TJ, and Minczuk M. (2015). Nuclear-encoded factors involved in post-transcriptional processing and modification of mitochondrial tRNAs in human disease. Front Genet. 6:79.

Kopajtich R*, Nicholls TJ*, Rorbach J*, Metodiev MD*, Freisinger P, Mandel H, Vanlander A, Ghezzi D, Carrozzo R, Taylor RW et al. (2014). Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy. Am J Hum Genet; 95(6): 708-20.

Rorbach J, Boesch P, Gammage PA, Nicholls TJ, Pearce SF, Patel D, Hauser A, Perocchi F, and Minczuk M. (2014). MRM2 and MRM3 are involved in biogenesis of the large subunit of the mitochondrial ribosome. Mol Biol Cell 25(17): 2542-55.

Nicholls TJ*, Zsurka G*, Peeva V, Schöler S, Szczesny RJ, Cysewski D, Reyes A, Kornblum C, Sciacco M, Moggio M, et al. (2014). Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease. Hum Mol Genet; 23(23): 6147-62.

Nicholls TJ and Minczuk M. (2014). In D-loop: 40 years of mitochondrial 7S DNA. Exp. Gerontol. 56:175-81.

Haack TB, Kopajtich R, Freisinger P, Wieland T, Rorbach J, Nicholls TJ, Baruffini E, Walther A, Danhauser K, Zimmermann FA et al. (2013). ELAC2 mutations cause a mitochondrial RNA processing defect associated with hypertrophic cardiomyopathy. Am J Hum Genet; 93(2): 211-23.

Nicholls TJ, Rorbach J and Minczuk M. (2013) Mitochondria: mitochondrial RNA metabolism and human disease. Int J Biochem Cell Biol. 45(4): 845-9.

Kornblum C*, Nicholls TJ*, Haack TB*, Schöler S, Peeva V, Danhauser K, Hallmann K, Zsurka G, Rorbach J, Iuso A et al. (2013). Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Nat Genet; 45(2): 214-9.

Rorbach J, Nicholls TJ, Minczuk M. (2011). PDE12 removes mitochondrial RNA poly(A) tails and controls translation in human mitchondria. Nucleic Acids Res; 39 (17): 7750-63.