Wellcome Trust Centre For Mitochondrial Research

Laura Greaves

Biography

I am a Newcastle University Research Fellow working within the Wellcome Centre for Mitochondrial Research. My group is focussed on investigating the role of mitochondrial DNA mutations in ageing stem cells and cancer. I am interested in elucidating the mechanisms by which mitochondrial DNA mutations occur and clonally expand within individual cells with age, and the functional consequences of these mutations on cellular homeostasis and tumour development.

I first became interested in mitochondrial genetics in 2002 when I began my PhD studies looking at the presence of mitochondrial DNA mutations in ageing human colonic epithelium. Upon discovering the high frequency of these mutations I wanted to pursue this area further to investigate their functional consequences at the cellular and tissue level, and to determine how they contribute to human ageing and disease.

Laura

Research Project: Investigating the role of mitochondrial DNA mutations in ageing and cancer

Other staff members involved: Anna Smith, Carla Bradshaw, Julia Whitehall, Ashwin Sachdeva, Tianhong Su, David Houghton

Project Details

1.Investigating the link between age-related accumulation of mitochondrial dysfunction and cancer development:  We have shown that there is an accumulation of mitochondrial DNA mutations in a number of tissues as we get older.  These mutations cause changes in the molecular mechanisms of cellular energy metabolism and are also prevalent in human cancers.  We are using model systems to induce cancer in cells with mitochondrial dysfunction to see if there is any advantage to a tumour having alterations in their metabolic pathways due to age-related mitochondrial dysfunction.  We are focussing on the colon and the prostate in particular, as age is the biggest risk factor for developing cancer in these tissues. We hope to develop targeted therapies to slow cancer growth based on our findings.

2.What is the effect of age-related mitochondrial DNA mutations on stem cell function? We know that there are changes in cellular metabolism due to age-related mitochondrial DNA mutations but we do not know what effect this has on the function of the cell as a whole, and in particular on stem cell regeneration.  In this project we are testing the regenerative capacity of stem cells with mtDNA mutations and seeing whether we can modulate the regenerative response.

3.Why are inherited mtDNA mutations lost from stem cell populations with age?  In contrast to ageing cells, some stem cell populations in patients with inherited mitochondrial DNA diseases are able to selectively deplete the levels of mutated mitochondrial DNA over time.  We are investigating the underlying cellular and molecular mechanisms in the hope of harnessing these mechanisms to modulate the accumulation of age-related mitochondrial DNA mutations.

4.What are the mechanisms underlying intestinal pathogenesis in patients with mitochondrial DNA disease. We know that bowel problems are common in patients with mitochondrial DNA disease.  We are investigating the effects of mitochondrial DNA mutations on intestinal motility, the gut microbiome and gut inflammation with aim of modulating these features to reduce symptoms.

Contact: laura.greaves@ncl.ac.uk

Sponsor/Funder: Newcastle University Research Fellowship, LLHW Newcastle University Centre for Ageing and Vitality

Collaborators

Dr Rakesh Heer, Newcastle University, UK; Dr Seamus Kelly, Newcastle University, UK; Professor John Mathers, Newcastle University, UK;  Dr Stuart McDonald, Barts Cancer Institute, QMUL, London, UK; Professor Fiona Oakley, Newcastle University, UK; Dr Joao Passos, Mayo Clinic, Rochester, USA; Professor Owen Sansom, Beatson Institute for Cancer Research, Glasgow, UK; Dr James Stewart, Max Planck Institute for the Biology of Ageing, Cologne, Germany; Professor Doug Winton, Cancer Research UK, Cambridge Institute, UK

Publications

Su T; Grady JP; Afshar S; McDonald SA; Taylor RW; Turnbull DM; Greaves LC, 2018. Inherited pathogenic mitochondrial DNA mutations and gastrointestinal stem cell populations.  J Pathol.

Simard ML; Mourier A; Greaves LC; Taylor RW; Stewart JB, 2018. A novel histochemistry assay to assess and quantify focal cytochrome c oxidase deficiency.  J Pathol 245(3):311-323

Su T; Turnbull DM; Greaves LC, 2018. Roles of Mitochondrial DNA Mutations in Stem Cell Ageing.  Genes (Basel) 9.

Houghton D; Stewart CJ; Stamp C; Nelson A; Aj Ami NJ; Petrosino JF; Wipat A; Trenell MI; Turnbull DM; Greaves LC, 2018. Impact of Age-Related Mitochondrial Dysfunction and Exercise on Intestinal Microbiota Composition.  J Gerontol A Biol Sci Med Sci 73(5):571-578

Stamp C; Zupanic A; Sachdeva A; Stoll EA; Shanley DP; Mathers JC; Kirkwood TBL; Heer R; Simons BD; Turnbull DM; Greaves LC, 2018. Predominant Asymmetrical Stem Cell Fate Outcome Limits the Rate of Niche Succession in Human Colonic Crypts.  EBioMedicine 31:166-173

Bury AG; Pyle A; Elson JL; Greaves L; Morris CM; Hudson G; Pienaar IS, 2017. Mitochondrial DNA changes in pedunculopontine cholinergic neurons in Parkinson disease.  Ann Neurol 82(6):1016-1021

Moad M; Hannezo E; Buczacki SJ; Wilson L; El-Sherif A; Sims D; Pickard R; Wright NA; Williamson SC; Turnbull DM; Taylor RW; Greaves L; Robson CN; Simons BD; Heer R, 2017. Multipotent Basal Stem Cells, Maintained in Localized Proximal Niches, Support Directed Long-Ranging Epithelial Flows in Human Prostates.  Cell Rep 20(7):1609-1622

Ordean A; Graves L; Chisamore B; Greaves L; Dunlop A, 2017. Prevalence and Consequences of Perinatal Substance Use-Growing Worldwide Concerns.  Subst Abuse 11:1178221817704692

Kauppila JHK; Baines HL; Bratic A; Simard ML; Freyer C; Mourier A; Stamp C; Filograna R; Larsson NG; Greaves LC; Stewart JB, 2016. A Phenotype-Driven Approach to Generate Mouse Models with Pathogenic mtDNA Mutations Causing Mitochondrial Disease.  Cell Rep 16(11):2980-2990

Dobson PF; Rocha MC; Grady JP; Chrysostomou A; Hipps D; Watson S; Greaves LC; Deehan DJ; Turnbull DM, 2016. Unique quadruple immunofluorescence assay demonstrates mitochondrial respiratory chain dysfunction in osteoblasts of aged and PolgA(-/-) mice.  Sci Rep 6:31907

Correia-Melo C; Marques FD; Anderson R; Hewitt G; Hewitt R; Cole J; Carroll BM; Miwa S; Birch J; Merz A; Rushton MD; Charles M; Jurk D; Tait SW; Czapiewski R; Greaves L; Nelson G; Bohlooly-Y M; Rodriguez-Cuenca S; Vidal-Puig A; Mann D; Saretzki G; Quarato G; Green DR; Adams PD; von Zglinicki T; Korolchuk VI; Passos JF, 2016. Mitochondria are required for pro-ageing features of the senescent phenotype.  EMBO J 35(7):724-42

Elson JL; Smith PM; Greaves LC; Lightowlers RN; Chrzanowska-Lightowlers ZM; Taylor RW; Vila-Sanjurjo A, 2015. The presence of highly disruptive 16S rRNA mutations in clinical samples indicates a wider role for mutations of the mitochondrial ribosome in human disease.  Mitochondrion 25:17-27

Gorman GS; Blakely EL; Hornig-Do HT; Tuppen HA; Greaves LC; He L; Baker A; Falkous G; Newman J; Trenell MI; Lecky B; Petty RK; Turnbull DM; McFarland R; Taylor RW, 2015. Novel MTND1 mutations cause isolated exercise intolerance, complex I deficiency and increased assembly factor expression.  Clin Sci (Lond) 128(12):895-904

Deuse T; Wang D; Stubbendorff M; Itagaki R; Grabosch A; Greaves LC; Alawi M; Grünewald A; Hu X; Hua X; Velden J; Reichenspurner H; Robbins RC; Jaenisch R; Weissman IL; Schrepfer S, 2015. SCNT-derived ESCs with mismatched mitochondria trigger an immune response in allogeneic hosts.  Cell Stem Cell 16(1):33-8

Baines HL; Stewart JB; Stamp C; Zupanic A; Kirkwood TB; Larsson NG; Turnbull DM; Greaves LC, 2014. Similar patterns of clonally expanded somatic mtDNA mutations in the colon of heterozygous mtDNA mutator mice and ageing humans.  Mech Ageing Dev 139:22-30

Baines HL; Turnbull DM; Greaves LC, 2014. Human stem cell aging: do mitochondrial DNA mutations have a causal role?  Aging Cell 13(2):201-5

Jurk D; Wilson C; Passos JF; Oakley F; Correia-Melo C; Greaves L; Saretzki G; Fox C; Lawless C; Anderson R; Hewitt G; Pender SL; Fullard N; Nelson G; Mann J; van de Sluis B; Mann DA; von Zglinicki T, 2014. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice.  Nat Commun 2:4172

Di Foggia V; Zhang X; Licastro D; Gerli MF; Phadke R; Muntoni F; Mourikis P; Tajbakhsh S; Ellis M; Greaves LC; Taylor RW; Cossu G; Robson LG; Marino S, 2014. Bmi1 enhances skeletal muscle regeneration through MT1-mediated oxidative stress protection in a mouse model of dystrophinopathy.  J Exp Med 211(13):2617-33

Greaves LC; Nooteboom M; Elson JL; Tuppen HA; Taylor GA; Commane DM; Arasaradnam RP; Khrapko K; Taylor RW; Kirkwood TB; Mathers JC; Turnbull DM, 2014. Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing.  PLoS Genet 10(9):e1004620

Greaves LC; Elson JL; Nooteboom M; Grady JP; Taylor GA; Taylor RW; Mathers JC; Kirkwood TB; Turnbull DM, 2012. Comparison of mitochondrial mutation spectra in ageing human colonic epithelium and disease: absence of evidence for purifying selection in somatic mitochondrial DNA point mutations.  PLoS Genet 8(11):e1003082

Greaves LC; Reeve AK; Taylor RW; Turnbull DM, 2012. Mitochondrial DNA and disease.  J Pathol 226(2):274-86

Greaves LC; Barron MJ; Campbell-Shiel G; Kirkwood TB; Turnbull DM, 2011. Differences in the accumulation of mitochondrial defects with age in mice and humans.  Mech Ageing Dev 132(11-12):588-91

Blackwood JK; Williamson SC; Greaves LC; Wilson L; Rigas AC; Sandher R; Pickard RS; Robson CN; Turnbull DM; Taylor RW; Heer R, 2011. In situ lineage tracking of human prostatic epithelial stem cell fate reveals a common clonal origin for basal and luminal cells.  J Pathol 225(2):181-8

Greaves LC; Barron MJ; Plusa S; Kirkwood TB; Mathers JC; Taylor RW; Turnbull DM, 2010. Defects in multiple complexes of the respiratory chain are present in ageing human colonic crypts.  Exp Gerontol 45(7-8):573-9

Nooteboom M; Johnson R; Taylor RW; Wright NA; Lightowlers RN; Kirkwood TB; Mathers JC; Turnbull DM; Greaves LC, 2010. Age-associated mitochondrial DNA mutations lead to small but significant changes in cell proliferation and apoptosis in human colonic crypts.  Aging Cell 9(1):96-9

Yu-Wai-Man P; Lai-Cheong J; Borthwick GM; He L; Taylor GA; Greaves LC; Taylor RW; Griffiths PG; Turnbull DM, 2010. Somatic mitochondrial DNA deletions accumulate to high levels in aging human extraocular muscles.  Invest Ophthalmol Vis Sci 51(7):3347-53

Greaves LC; Yu-Wai-Man P; Blakely EL; Krishnan KJ; Beadle NE; Kerin J; Barron MJ; Griffiths PG; Dickinson AJ; Turnbull DM; Taylor RW, 2010. Mitochondrial DNA defects and selective extraocular muscle involvement in CPEO.  Invest Ophthalmol Vis Sci 51(7):3340-6

Mahad DJ; Ziabreva I; Campbell G; Laulund F; Murphy JL; Reeve AK; Greaves L; Smith KJ; Turnbull DM, 2009. Detection of cytochrome c oxidase activity and mitochondrial proteins in single cells.  J Neurosci Methods 184(2):310-9

Greaves LC; Beadle NE; Taylor GA; Commane D; Mathers JC; Khrapko K; Turnbull DM, 2009. Quantification of mitochondrial DNA mutation load.  Aging Cell 8(5):566-72

Greaves LC; Turnbull DM, 2009. Mitochondrial DNA mutations and ageing.  Biochim Biophys Acta 1790(10):1015-20

Krishnan KJ; Greaves LC; Reeve AK; Turnbull D, 2007. The ageing mitochondrial genome.  Nucleic Acids Res 35(22):7399-405

Krishnan KJ; Greaves LC; Reeve AK; Turnbull DM, 2007. Mitochondrial DNA mutations and aging.  Ann N Y Acad Sci 1100:227-40

Greaves LC; Taylor RW, 2006. Mitochondrial DNA mutations in human disease.  IUBMB Life 58(3):143-51

Wilkinson SC; Maas WJ; Nielsen JB; Greaves LC; van de Sandt JJ; Williams FM, 2006. Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies.  Int Arch Occup Environ Health 79(5):405-13

Greaves LC; Preston SL; Tadrous PJ; Taylor RW; Barron MJ; Oukrif D; Leedham SJ; Deheragoda M; Sasieni P; Novelli MR; Jankowski JA; Turnbull DM; Wright NA; McDonald SA, 2006. Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission.  Proc Natl Acad Sci U S A 103(3):714-9

Taylor RW; Barron MJ; Borthwick GM; Gospel A; Chinnery PF; Samuels DC; Taylor GA; Plusa SM; Needham SJ; Greaves LC; Kirkwood TB; Turnbull DM, 2003. Mitochondrial DNA mutations in human colonic crypt stem cells.  J Clin Invest 112(9):1351-60

Dickinson HO; Hutton JL; Greaves LH; Dummer TJ; Parker L, 2002. Deprivation and stillbirth risk in rural and urban areas.  Paediatr Perinat Epidemiol 16(3):249-54

Publication list retrieved from NCBI using ImpactPubs

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