Prof Payam Gammage - Mitochondrial Oncogenetics
Introduction
Mitochondria are a cellular nexus, performing numerous signalling, biosynthetic and bioenergetic functions. In humans, mitochondria are composed of ~1200 proteins, the vast majority encoded in nuclear DNA, with a minor subset encoded in the spatially and heritably separate mitochondrial DNA (mtDNA).
The human mitochondrial genome is a genetically compact, circular, double-stranded DNA molecule of 16.5 kb, typically present at between 100 and 10,000 copies per cell on a cell type-specific basis. Encoded exclusively in mtDNA are subunits of the mitochondrial respiratory chain and ATP synthase, required for functional oxidative phosphorylation, and all RNA components necessary for their translation by mitochondrial ribosomes.
Mutations, deletions and rearrangements of mtDNA are a known source of hereditary metabolic disease in humans, causing a broad spectrum of pathology underpinned by mitochondrial dysfunction. Mutations of mtDNA are also found in approximately 60% of all solid tumours, often at levels that would result in profound mitochondrial dysfunction.
Mitochondrial dysregulation and dysfunction, particularly a switch from oxidative to glycolytic metabolism, is often observed in cancer. Our research focuses on determining the role of mitochondrial genetics and gene expression in human cancer.
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Lab Report
pdf Gammage Lab Report (2.26 MB)
Key Publications
Mahmood M, Liu EM, Shergold AL, Tolla E, Tait-Mulder J, Huerta-Uribe A, Shokry E, Young AL, Lilla S, Kim M, Park T, Boscenco S, Manchon JL, Rodríguez-Antona C, Walters RC, Springett RJ, Blaza JN, Mitchell L, Blyth K, Zanivan S, Sumpton D, Roberts EW, Reznik E, Gammage PA. Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma. Nat Cancer. 2024.
See the following CRUK blog for further insights into these findings: The secret in cancer cells that can make immunotherapy more effective
Kim M, Mahmood M, Reznik E, Gammage PA. Mitochondrial DNA is a major source of driver mutations in cancer. Trends in Cancer. 2022;8:1046-1059
Gorelick AN, Kim M, Chatila WK, La K, Hakimi AA, Berger MF, Taylor BS, Gammage PA, Reznik E. Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA. Nat Metab. 2021; 3:558–570
See the following articles for insights into this study: Mutations in overlooked DNA could have profound impact on bowel cancer survival and Mitochondrial DNA in cancer: small genome, big impact
Biography
Education and qualifications
2015: PhD, Biochemistry, University of Cambridge
2011: MSc, Neuroscience, University College London
Appointments
2024-present: Professor of Mitochondrial Biology, School of Cancer Sciences, University of Glasgow
2019-present: Junior Group Leader, Cancer Research UK Scotland Institute
2020 - 2024: Senior Lecturer, School of Cancer Sciences, University of Glasgow
2015-2019: Career Development Fellow, MRC Mitochondrial Biology Unit
2014-2015: Research Associate, MRC Mitochondrial Biology Unit
Awards and fellowships
2024-2027 EMBO Young Investigator
2022 National Institutes of Health, National Cancer Institute, USA, MERIT Award (R37)
2021 ERC Starting Grant
Current committee memberships
2020–present The Royal Society, UK, Open Science - Editorial Board
Recent Publications
2024
Kim M, Gorelick AN, Vàzquez-García I, Williams MJ, Salehi S, Shi H, Weiner AC, Ceglia N, Funnell T, Park T, Boscenco S, O’Flanagan CH, Jiang H, Grewal D, Tang C, Rusk N, Gammage PA, McPherson A, Aparicio S, Shah SP, Reznik E. Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes. Nature Genetics. 2024.
Mahmood M, Liu EM, Shergold AL, Tolla E, Tait-Mulder J, Huerta-Uribe A, Shokry E, Young AL, Lilla S, Kim M, Park T, Boscenco S, Manchon JL, Rodríguez-Antona C, Walters RC, Springett RJ, Blaza JN, Mitchell L, Blyth K, Zanivan S, Sumpton D, Roberts EW, Reznik E, Gammage PA. Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma. Nat Cancer. 2024.
2023
Mahmood M, Liu EM, Shergold AL, Tolla E, Tait-Mulder J, Uribe AH, Shokry E, Young AL, Lilla S, Kim M, Park T, Manchon JL, Rodriguez-Antona C, Walters RC, Springett RJ, Blaza JN, Zanivan S, Sumpton DA, Roberts EW, Reznik E, Gammage PA. Tumour mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade. bioRxiv. 2023;Volume:2023.2003.2021.533091.
Shaw AM, Gammage PA. Coupling Differential Centrifugation with Exonuclease Treatment and Size Exclusion Chromatography (DIFSEC) for Purification of mtDNA from Mammalian Cells. Methods Mol Biol. 2023;2615:31-40.
2022
Ganly I, Liu EM, Kuo F, Makarov V, Dong Y, Park J, Gong Y, Gorelick AN, Knauf JA, Benedetti E, Tait-Mulder J, Morris LGT, Fagin JA, Intelkofer AM, Krumsiek J, Gammage P, Ghossein R, Xu B, Chan TA, Reznik E. Mitonuclear genotype remodels the metabolic and microenvironmental landscape of Hürthle cell carcinoma. Sci Adv. 2022;8(25):eabn9699.
Kim M, Mahmood M, Reznik E, Gammage PA. Mitochondrial DNA is a major source of driver mutations in cancer. Trends in Cancer. 2022;8:1046-1059
2021
Gorelick AN, Kim M, Chatila WK, La K, Hakimi AA, Berger MF, Taylor BS, Gammage PA, Reznik E. Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA. Nat Metab. 2021; 3:558–570
See the following articles for insights into this study: Mutations in overlooked DNA could have profound impact on bowel cancer survival and Mitochondrial DNA in cancer: small genome, big impact
Rabas N, Palmer S, Mitchell L, Ismail S, Gohlke A, Riley JS, Tait SWG, Gammage P, Soares LL, Macpherson IR, Norman JC. PINK1 drives production of mtDNA-containing extracellular vesicles to promote invasiveness. J Cell Biol. 2021;220.
2020
Bacman SR, Gammage PA, Minczuk M, Moraes CT. Manipulation of mitochondrial genes and mtDNA heteroplasmy. Methods in cell biology. 2020;155:441-487.
Jackson CB, Turnbull DM, Minczuk M, Gammage PA. Therapeutic Manipulation of mtDNA Heteroplasmy: A Shifting Perspective. Trends in Molecular Medicine. 2020; 26: 698-709
Pinheiro P, A. Gammage P, Minczuk M. Chapter 19 - Mitochondrially targeted zinc finger nucleases. In: Gasparre G, Porcelli AM, eds. The Human Mitochondrial Genome. Academic Press; 2020:499-514.
2019
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.
Gammage PA, Frezza C. Mitochondrial DNA: the overlooked oncogenome? BMC biology. 2019;17:53. 
Hoitzing H, Gammage PA, Haute LV, Minczuk M, Johnston IG, Jones NS. Energetic costs of cellular and therapeutic control of stochastic mitochondrial DNA populations. PLoS computational biology. 2019;15:e1007023.
2018
Gammage PA, Minczuk M. Enhanced Manipulation of Human Mitochondrial DNA Heteroplasmy In Vitro Using Tunable mtZFN Technology. Methods in molecular biology (Clifton, NJ). 2018;1867:43-56.
Gammage PA, Moraes CT, Minczuk M. Mitochondrial Genome Engineering: The Revolution May Not Be CRISPR-Ized. Trends in genetics : TIG. 2018;34:101-110.
Gammage PA, Viscomi C, Simard ML, Costa ASH, Gaude E, Powell CA, Van Haute L, McCann BJ, Rebelo-Guiomar P, Cerutti R, Zhang L, Rebar EJ, Zeviani M, Frezza C, Stewart JB, Minczuk M. Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo. Nature medicine. 2018;24:1691-1695.
Gaude E, Schmidt C, Gammage PA, Dugourd A, Blacker T, Chew SP, Saez-Rodriguez J, O'Neill JS, Szabadkai G, Minczuk M, Frezza C. NADH Shuttling Couples Cytosolic Reductive Carboxylation of Glutamine with Glycolysis in Cells with Mitochondrial Dysfunction. Molecular cell. 2018;69:581-593.e587
Kullar PJ, Gomez-Duran A, Gammage PA, Garone C, Minczuk M, Golder Z, Wilson J, Montoya J, Hakli S, Karppa M, Horvath R, Majamaa K, Chinnery PF. Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family. Brain : a journal of neurology. 2018;141:55-62
McCann BJ, Cox A, Gammage PA, Stewart JB, Zernicka-Goetz M, Minczuk M. Delivery of mtZFNs into Early Mouse Embryos. Methods in molecular biology. 2018;1867:215-228.
Peeva V, Blei D, Trombly G, Corsi S, Szukszto MJ, Rebelo-Guiomar P, Gammage PA, Kudin AP, Becker C, Altmuller J, Minczuk M, Zsurka G, Kunz WS. Linear mitochondrial DNA is rapidly degraded by components of the replication machinery. Nature communications. 2018;9:1727.
2016
Gammage PA, Gaude E, Van Haute L, Rebelo-Guiomar P, Jackson CB, Rorbach J, Pekalski ML, Robinson AJ, Charpentier M, Concordet JP, Frezza C, Minczuk M. Near-complete elimination of mutant mtDNA by iterative or dynamic dose-controlled treatment with mtZFNs. Nucleic acids research. 2016;44:7804-7816.
Gammage PA, Van Haute L, Minczuk M. Engineered mtZFNs for Manipulation of Human Mitochondrial DNA Heteroplasmy. Methods in molecular biology (Clifton, NJ). 2016;1351:145-162.
