Wellcome Trust Centre For Mitochondrial Research

Laura Greaves

Biography

LauraI am a senior research associate working with Professor Doug Turnbull 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.

Research Project

Principal Investigator:  Professor Doug Turnbull

Other staff members involved: Craig Stamp, Mr Seamus Kelly, Dr Iain McCallum

Project Details

Human ageing is characterised by gradual decline in function with reduced cellular metabolism and decreased ability to maintain tissue homeostasis. Central to this process is a decline in stem cell capacity to maintain and repair tissues and an increasing risk of malignant transformation. Mitochondrial DNA (mtDNA) mutations have been proposed to play a role in ageing and are frequently found in a number of ageing human stem cell populations and also in human tumours. These mtDNA mutations can accumulate within individual cells and eventually cause loss of mitochondrial respiratory chain function.

In this research project we are investigating the mechanism by which mtDNA mutations occur and accumulate to high levels in individual stem cells, and the effects of such mutations on tissue function and malignant transformation/tumour progression. In addition we are utilising mtDNA mutations in lineage tracing of stem cell populations both in normal and tumour tissues.

Contact: laura.greaves@ncl.ac.uk

Sponsor/Funder: Newcastle University Centre for Brain Ageing and Vitality, Northumbria NHS Trust

Collaborators

Dr James Stewart, (Max Plank Institute for the Biology of Ageing – Cologne, Germany)
Professor Nils Goran Larsson, (Max Plank Institute for the Biology of Ageing – Cologne, Germany)
Dr Rakesh Heer (Northern Institute for Cancer Research, Newcastle University)
Dr Karen Blyth (Beatson Institute for Cancer Research, Glasgow)
Professor Konstantin Khrapko (Molecular Gerontology, Harvard University, USA).

Publications

1. Greaves LC, Elson JL, Nooteboom N, Grady JP, Taylor GA, Taylor RW, Mathers JC, Kirkwood TBL, Turnbull DM. Comparison of mitochondrial mutation spectra in ageing human colonic epithelium and disease: absence of evidence for purifying selection in somatic mitochondrial DNA point mutations 2012 PloS Genetics In Press

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

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

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

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

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

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

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

9. Mahad DJ, Ziabreva I, Campbell G, Laulund F, Murphy JL, Reeve AK, Greaves LC, Smith KJ, Turnbull DM. Detection of cytochrome c oxidase activity and mitochondrial proteins in single cells. J Neurosci Methods. 2009 Nov 15;184(2):310-9.

10. Greaves LC, Beadle NE, Taylor GA, Commane D, Mathers JC, Khrapko K, Turnbull DM. Quantification of mitochondrial DNA mutation load. Aging Cell. 2009 Sep;8(5):566-72. Epub 2009 Jul 18.

11. Fellous TG, McDonald SA, Burkert J, Humphries A, Islam S, De-Alwis NM, Gutierrez-Gonzalez L, Tadrous PJ, Elia G, Kocher HM, Bhattacharya S, Mears L, El-Bahrawy M, Turnbull DM, Taylor RW, Greaves LC, Chinnery PF, Day CP, Wright NA, Alison MR. A methodological approach to tracing cell lineage in human epithelial tissues. Stem Cells. 2009 Jun;27(6):1410-20.

12. Greaves LC, Mathers JC, Taylor RW, Turnbull DM. Modelling mitochondrial DNA mutations in bacterial cytochrome c oxidase: link to colon cancer? Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):E57

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

14. Fellous TG, Islam S, Tadrous PJ, Elia G, Kocher HM, Bhattacharya S, Mears L, Turnbull DM, Taylor RW, Greaves LC, Chinnery PF, Taylor G, McDonald SA, Wright NA, Alison MR. Locating the stem cell niche and tracing hepatocyte lineages in human liver. Hepatology. 2009 May;49(5):1655-63.

15. McDonald SA, Greaves LC, Gutierrez-Gonzalez L, Rodriguez-Justo M, Deheragoda M, Leedham SJ, Taylor RW, Lee CY, Preston SL, Lovell M, Hunt T, Elia G, Oukrif D, Harrison R, Novelli MR, Mitchell I, Stoker DL, Turnbull DM, Jankowski JA, Wright NA. Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology. 2008 Feb;134(2):500-10.

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

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

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

19. McDonald SA, Preston SL, Greaves LC, Leedham SJ, Lovell MA, Jankowski JA, Turnbull DM, Wright NA. Clonal expansion in the human gut: mitochondrial DNA mutations show us the way. Cell Cycle. 2006 Apr;5(8):808-11

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

21. 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. Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission. Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):714-9.

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