Staff Profile
Professor Laura Greaves
Professor of Molecular Pathology
- Telephone: +44 (0) 191 208 3074
- Address: Mitochondrial Research Group
Biosciences Institute,
Newcastle University,
Medical School,
Framlington Place.
Newcastle Upon Tyne.
NE2 4HH.
I am a Professor of Molecular Pathology working within the Mitochondrial Research Group within the Biosciences Institute of the Faculty of Medical Sciences 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 stem cells with age, and the functional consequences of these mutations on cellular metabolism and colorectal cancer 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.
Qualifications
BSc(Hons) in Pharmacology from Newcastle University.
PhD entitled ‘Mitochondrial DNA mutations in ageing: A study in human colon’.
Research Interests
- 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.
- 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.
- 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.
- 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.
Faculty of Medical Sciences MRes Programme Deputy Curriculum Chair
Leading seminars and practical sessions for undergraduate students.
Lecturer on MRes in Mitochondrial Medicine
PhD Student supervisor
BSc and MRes dissertation project supervisor
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Articles
- Kelly G, Kataura T, Panek J, Gailing M, Salmonowicz H, Davis A, Kendall H, Brookes C, Ayine-Tora DM, Banks P, Nelson G, Dobby L, Pitrez PR, Booth L, Costello L, Richardson GD, Lovat P, Przyborski S, Ferreira L, Greaves L, Szczepanowska K, von Zglinicki T, Miwa S, Brown M, Flagler M, Oblong JE, Bascom CC, Carroll B, Reynisson J, Korolchuk VI. Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule. Developmental Cell 2024, 59(15), 1924-1939.e7.
- Victorelli S, Salmonowicz H, Chapman J, Martini H, Vizioli MG, Riley JS, Cloix C, Hall-Younger E, Machado Espindola-Netto J, Jurk D, Lagnado AB, Sales Gomez L, Farr JN, Saul D, Reed R, Kelly G, Eppard M, Greaves LC, Dou Z, Pirius N, Szczepanowska K, Porritt RA, Huang H, Huang TY, Mann DA, Masuda CA, Khosla S, Dai H, Kaufmann SH, Zacharioudakis E, Gavathiotis E, LeBrasseur NK, Lei X, Sainz AG, Korolchuk VI, Adams PD, Shadel GS, Tait SWG, Passos JF. Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature 2023, 622, 627-636.
- Yu X, Arden C, Berlinguer-Palmini R, Chen C, Bradshaw C, Smith AL, Whitehall J, White M, Anderson S, Kattner N, Shaw J, Turnbull D, Greaves LC, Walker M. Mitochondrial complex I subunit deficiency promotes pancreatic α-cell proliferation. Molecular Metabolism 2022, 60, 101489.
- Sachdeva A, Hart CA, Carey CD, Vincent AE, Greaves LC, Heer R, Oliveira P, Brown MD, Clarke NW, Turnbull DM. Automated quantitative high‑throughput multiplex immunofuorescence pipeline to evaluate OXPHOS defects in formalin‑fxed human prostate tissue. Scientific Reports 2022, 12, 6660.
- Fuller A, Okwose N, Scragg J, Eggett C, Luke P, Bandali A, Velicki R, Greaves L, MacGowan GA, Jakovljevic DG. The effect of age on mechanisms of exercise tolerance: Reduced arteriovenous oxygen difference causes lower oxygen consumption in older people. Experimental Gerontology 2021, 149, 111340.
- Stamp C, Whitehall JC, Smith ALM, Houghton D, Bradshaw C, Stoll EA, Blain AP, Turnbull DM, Greaves LC. Age-associated mitochondrial complex I deficiency is linked to increased stem cell proliferation rates in the mouse colon. Aging Cell 2021, 20(3), e13321.
- Lawless C, Greaves L, Reeve AK, Turnbull DM, Vincent AE. The rise and rise of mitochondrial DNA mutations. Open biology 2020, 10(5), 200061.
- Dobson PF, Dennis EP, Hipps D, Reeve A, Laude A, Bradshaw C, Stamp C, Smith A, Deehan DJ, Turnbull DM, Greaves LC. Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss. Scientific Reports 2020, 10(1), 11643.
- Smith ALM, Whitehall JC, Bradshaw C, Gay D, Robertson F, Blain AP, Hudson G, Pyle A, Houghton D, Hunt M, Sampson JN, Stamp C, Mallett G, Amarnath S, Leslie J, Oakley F, Wilson L, Baker A, Russell OM, Johnson R, Richardson CA, Gupta B, McCallum I, McDonald SAC, Kelly S, Mathers JC, Heer R, Taylor RW, Perkins ND, Turnbull DM, Sansom OJ, Greaves LC. Age-associated mitochondrial DNA mutations cause metabolic remodeling that contributes to accelerated intestinal tumorigenesis. Nature Cancer 2020, 1, 976-989.
- Anderson R, Lagnado A, Maggiorani D, Walaszczyk A, Dookun E, Chapman J, Birch J, Salmonowicz H, Ogrodnik M, Jurk D, Proctor C, Correia-Melo C, Victorelli S, Fielder E, Berlinguer-Palmini R, Owens WA, Greaves L, Kolsky K, Parini A, Douin-Echinard V, LeBrasseur N, Arthur H, Tual-Chalot S, Schafer M, Roos C, Miller J, Robertson N, Mann J, Adams P, Tchkonia T, Kirkland J, Mialet-Perez J, Richardson GD, Passos J. Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence. The EMBO Journal 2019, 38(5), e100492.
- Breininger SP, Malcomson FC, Afshar S, Turnbull DM, Greaves L, Mathers JC. Effects of obesity and weight loss on mitochondrial structure and function and implications for colorectal cancer risk. Proceedings of the Nutrition Society 2019, 78(3), 426-437.
- Malcomson FC, Breininger SP, ElGendy K, Joel A, Ranathunga T, Hill TR, Bradburn DM, Turnbull DM, Greaves LC, Mathers JC. Design and baseline characteristics of the Biomarkers Of Risk In Colorectal Cancer (BORICC) Follow-Up study: A 12+ years follow-up. Nutrition and Health 2019, 25(3), 231-238.
- Paish H, Reed L, Brown H, Bryan M, Govaere O, Leslie J, Barksby B, GarciaMacia M, Watson A, Xu X, Zaki M, Greaves L, Whitehall J, French J, White S, Manas D, Robinson S, Spoletini G, Griffiths C, Mann DA, Borthwick LA, Drinnan M, Mann J, Oakley F. A bioreactor technology for modelling fibrosis in human and rodent precision-cut liver slices. Hepatology 2019, 70(4), 1377-1391.
- Stamp C, Zupanic A, Sachdeva A, Stoll EA, Shanley DP, Mathers JC, Kirkwood TBL, Heer R, Simons BD, Turnbull DM, Greaves LC. Predominant Asymmetrical Stem Cell Fate Outcome Limits the Rate of Niche Succession in Human Colonic Crypts. EBioMedicine 2018, 31, 166-173.
- Su T, Grady JP, Afshar S, McDonald SAC, Taylor RW, Turnbull DM, Greaves LC. Inherited pathogenic mitochondrial DNA mutations and gastrointestinal stem cell populations. The Journal of Pathology 2018, 246(4), 427-432.
- Houghton D, Stewart CJ, Stamp C, Nelson A, Ajami NJ, Petrosino JF, Wipat A, Trenell MI, Turnbull DM, Greaves LC. Age-related mitochondrial dysfunction influences the mouse intestinal microbiome composition. The Journals of Gerontology: Series A, Biological Sciences & Medical Sciences 2018, 73(5), 571-578.
- Simard M-L, Mourier A, Greaves LC, Taylor RW, Stewart JB. A novel histochemistry assay to assess and quantify focal cytochrome c oxidase deficiency. Journal of Pathology 2018, 245(3), 311-323.
- Moad M, Hannezo E, Buczacki SJ, Wilson L, ElSherif A, Sims D, Pickard R, Wright NA, Williamson SC, Turnbull DM, Taylor RW, Greaves L, Robson CN, Simons BD, Heer R. Multipotent Basal Stem Cells, Maintained in Localized Proximal Niches, Support Directed Long-Ranging Epithelial Flows in Human Prostates. Cell Reports 2017, 20(7), 1609-1622.
- Bury AG, Pyle A, Elson JL, Greaves L, Morris CM, Hudson G, Pienaar IS. Mitochondrial DNA changes in pedunculopontine cholinergic neurons in Parkinson disease. Annals of Neurology 2017, 82(6), 1016-1021.
- Dobson PF, Rocha MC, Grady JP, Chrysostomou A, Hipps D, Watson S, Greaves LC, Deehan DJ, Turnbull DM. Unique quadruple immunofluorescence assay demonstrates mitochondrial respiratory chain dysfunction in osteoblasts of aged and PolgA -/- mice. Scientific Reports 2016, 6, 31907.
- Correia-Melo C, Marques FDM, Anderson R, Hewitt G, Hewitt R, Cole J, Carroll BM, Miwa S, Birch J, Merz A, Rushton MD, Charles M, Jurk D, Tait SWG, 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. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO Journal 2016, 35(7), 724-742.
- Tullo E, Greaves L, Wakeling L. Involving older people in the design, development, and delivery of an innovative module on aging for undergraduate students. Educational Gerontology 2016, 42(10), 698-705.
- Kauppila JHK, Baines HL, Bratic A, Simard ML, Freyer C, Mourier A, Stamp C, Filograna R, Larsson NG, Greaves LC, Stewart JB. A Phenotype-Driven Approach to Generate Mouse Models with Pathogenic mtDNA Mutations Causing Mitochondrial Disease. Cell Reports 2016, 16(11), 2980-2990.
- Elson JL, Smith PM, Greaves LC, Lightowlers RN, Chrzanowska-Lightowlers ZMA, Taylor RW, Vila-Sanjurjo A. 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 2015, 25, 17-27.
- Deuse T, Wang D, Stubbendorff M, Itagaki R, Grabosch A, Greaves LC, Alawi M, Grunewald A, Hu XM, Hua XQ, Velden J, Reichenspurner H, Robbins RC, Jaenisch R, Weissman IL, Schrepfer S. SCNT-Derived ESCs with Mismatched Mitochondria Trigger an Immune Response in Allogeneic Hosts. Cell Stem Cell 2015, 16(1), 33-38.
- Gorman GS, Blakely EL, Hornig-Do HT, Tuppen HAL, Greaves LC, He LP, Baker A, Falkous G, Newman J, Trenell MI, Lecky B, Petty RK, Turnbull DM, McFarland R, Taylor RW. Novel MTND1 mutations cause isolated exercise intolerance, complex I deficiency and increased assembly factor expression. Clinical Science 2015, 128(12), 895-904.
- Baines HL, Stewart JB, Stamp C, Zupanic A, Kirkwood TBL, Larsson NG, Turnbull DM, Greaves LC. Similar patterns of clonally expanded somatic mtDNA mutations in the colon of heterozygous mtDNA mutator mice and ageing humans. Mechanisms of Ageing and Development 2014, 139, 22-30.
- Greaves LC, Nooteboom M, Elson JL, Tuppen HAL, Taylor GA, Commane DM, Arasaradnam RP, Khrapko K, Taylor RW, Kirkwood TBL, Mathers JC, Turnbull DM. Clonal Expansion of Early to Mid-Life Mitochondrial DNA Point Mutations Drives Mitochondrial Dysfunction during Human Ageing. PLoS Genetics 2014, 10(9), e1004620.
- Jurk D, Wilson C, Passos J, Oakley F, Correia-Melo C, Greaves L, Saretzki G, Fox C, Lawless C, Anderson R, Hewitt G, Pender SLF, Fullard N, Nelson G, Mann J, van de Sluis B, Mann DA, von Zglinicki T. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nature Communications 2014, 5, 4172.
- Di Foggia V, Zhang XY, Licastro D, Gerli MFM, Phadke R, Muntoni F, Mourikis P, Tajbakhsh S, Ellis M, Greaves LC, Taylor RW, Cossu G, Robson LG, Marino S. Bmi1 enhances skeletal muscle regeneration through MT1-mediated oxidative stress protection in a mouse model of dystrophinopathy. Journal of Experimental Medicine 2014, 211(13), 2617-2633.
- Smith PM, Elson JL, Greaves LC, Wortmann SB, Rodenburg RJT, Lightowlers RN, Chrzanowska-Lightowlers ZMA, Taylor RW, Vila-Sanjurjo A. The role of the mitochondrial ribosome in human disease: Searching for mutations in 12S mitochondrial rRNA with high disruptive potential. Human Molecular Genetics 2013, 23(4), 949-969.
- Greaves LC, Elson JL, Nooteboom M, 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. PLoS Genetics 2012, 8(11), e1003082.
- Greaves LC, Barron MJ, Campbell-Shiel G, Kirkwood TBL, Turnbull DM. Differences in the accumulation of mitochondrial defects with age in mice and humans. Mechanisms of Ageing and Development 2011, 132(11-12), 588-591.
- 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. Journal of Pathology 2011, 225(2), 181-188.
- Yu Wai Man P, Lai-Cheong J, Borthwick GM, He LP, Taylor GA, Greaves LC, Taylor RW, Griffiths PG, Turnbull DM. Somatic Mitochondrial DNA Deletions Accumulate to High Levels in Aging Human Extraocular Muscles. Investigative Ophthalmology & Visual Science 2010, 51(7), 3347-3353.
- 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. Investigative Ophthalmology & Visual Science 2010, 51(7), 3340-3346.
- Greaves L, Barron M, Plusa S, Kirkwood T, Mathers J, Taylor R, Turnbull D. Defects in multiple complexes of the respiratory chain are present in ageing human colonic crypts. Experimental Gerontology 2010, 45(7-8), 573-579.
- Nooteboom M, Johnson R, Taylor RW, Wright NA, Lightowlers RN, Kirkwood TBL, 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, 9(1), 96-99.
- Greaves LC, Beadle NE, Taylor GA, Commane D, Mathers JC, Khrapko K, Turnbull DM. Quantification of mitochondrial DNA mutation load. Aging Cell 2009, 8(5), 566-572.
- 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 SAC, Wright NA, Alison MR. Locating the Stem Cell Niche and Tracing Hepatocyte Lineages in Human Liver. Hepatology 2009, 49(5), 1655-1663.
- Mahad DJ, Ziabreva I, Campbell G, Laulund F, Murphy JL, Reeve AK, Greaves L, Smith KJ, Turnbull DM. Detection of cytochrome c oxidase activity and mitochondrial proteins in single cells. Journal of Neuroscience Methods 2009, 184(2), 310-319.
- Fellous TG, McDonald SAC, Burkert J, Humphries A, Islam S, De-Alwis NMW, 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, 27(6), 1410-1420.
- McDonald SAC, 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 JAZ, Wright NA. Mechanisms of Field Cancerization in the Human Stomach: The Expansion and Spread of Mutated Gastric Stem Cells. Gastroenterology 2008, 134(2), 500-510.
- Arasaradnam RP, Greaves LC, Commane D, Greetham H, Bradburn M, Taylor RW, Turnbull DM, Mathers JC. Novel preliminary findings of mitochondrial DNA mutations in colonic crypts of patients with diverticular disease (the Boricc study). Gut 2007, 56, A45-A45.
- Krishnan KJ, Greaves LC, Reeve AK, Turnbull DM. Mitochondrial DNA mutations and aging. Biogerontology 2007, 1100, 227-240.
- Greaves LC, Preston SL, Tadrous PJ, Taylor RW, Barron MJ, Oukrif D, Leedham SJ, Deheragoda M, Sasieni P, Novelli MR, Jankowski JAZ, Turnbull DM, Wright NA, McDonald SAC. Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission. Proceedings of the National Academy of Sciences of the United States of America 2006, 103(3), 714-719.
- Arasaradnam RP, Greaves LC, Commane D, Mathers JC, Taylor RW, Turnbull DM. Mitochondrial DNA (MTDNA) mutations in human colonic crypts: A novel biomarker of colorectal cancer. GUT 2006, 55(S2), A24.
- Wilkinson SC, Maas WJM, Nielsen JB, Greaves LC, van de Sandt JJM, Williams FM. Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies. International Archives of Occupational and Environmental Health 2006, 79(5), 405-413.
- McDonald SAC, Preston SL, Greaves LC, Leedham SJ, Lovell MA, Jankowski JAZ, Turnbull DM, Wright NA. Clonal expansion in the human gut - Mitochondrial DNA mutations show us the way. Cell Cycle 2006, 5(8), 808-811.
- Taylor RW, Barron MJ, Borthwick GM, Gospel A, Chinnery PF, Samuels DC, Taylor GA, Plusa SM, Needham SJ, Greaves LC, Kirkwood TBL, Turnbull DM. Mitochondrial DNA mutations in human colonic crypt stem cells. Journal of Clinical Investigation 2003, 112(9), 1351-1360.
- Greaves LC, Wilkinson SC, Williams FM. Factors affecting percutaneous absorption of caffeine in vitro. Toxicology 2002, 178(1), 65-66.
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Conference Proceedings (inc. Abstract)
- Sachdeva A, El-Sherif A, Turnbull D, Greaves L, Heer R. Development of prostate intra-epithelial neoplasia in an aging series of PolgA mutator mice suggests a role for mitochondrial DNA mutations in prostate carcinogenesis. In: EAU16 – 31st Annual Congress of the European Association of Urology. 2016, Munich, Germany: Elsevier.
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Letter
- Greaves LC, Mathers JC, Taylor RW, Turnbull DM. Modelling mitochondrial DNA mutations in bacterial cytochrome c oxidase: Link to colon cancer?. Proceedings of the National Academy of Sciences of the United States of America 2009, 106(22), E57-E57.
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Reviews
- Smith ALM, Whitehall JC, Greaves LC. Mitochondrial DNA mutations in ageing and cancer. Molecular Oncology 2022, 16(18), 3276-3294.
- Whitehall JC, Greaves LC. Aberrant mitochondrial function in ageing and cancer. Biogerontology 2020, 21(4), 445-459.
- Su T, Turnbull DM, Greaves LC. Roles of mitochondrial DNA mutations in stem cell ageing. Genes 2018, 9(4), 182.
- Baines HL, Turnbull DM, Greaves LC. Human stem cell aging: do mitochondrial DNA mutations have a causal role?. Aging Cell 2014, 13(2), 201-205.
- Greaves LC, Reeve AK, Taylor RW, Turnbull DM. Mitochondrial DNA and disease. Journal of Pathology 2012, 226(2), 274-286.
- Greaves LC, Turnbull DM. Mitochondrial DNA mutations and ageing. Biochimica et biophysica acta - General subjects 2009, 1790(10), 1015-1020.
- Krishnan KJ, Greaves LC, Reeve AK, Turnbull D. The ageing mitochondrial genome. Nucleic Acids Research 2007, 35(22), 7399-7405.
- Greaves LC, Taylor RW. Mitochondrial DNA mutations in human disease. IUBMB Life 2006, 58(3), 143-151.