Dr Payam Gammage - Mitochondrial Oncogenetics

Introduction

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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.

Payam Figure

See the following two articles for an insight into Payam's work on the impact of mitcohondrial mutations in cancer:
Mutations in overlooked DNA could have profound impact on bowel cancer survival
Mitochondrial DNA in cancer: small genome, big impact


Lab Report

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Key Publications

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

Jackson CB, Turnbull DM, Minczuk M, Gammage PA. Therapeutic Manipulation of mtDNA Heteroplasmy: A Shifting Perspective. Trends in Molecular Medicine. 2020; 26: 698-709

Gammage PA, Frezza C. Mitochondrial DNA: the overlooked oncogenome? BMC Biology. 2019;17:53. F1000

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.

Biography

Education and qualifications

2015: PhD, Biochemistry, University of Cambridge
2011: MSc, Neuroscience, University College London

Appointments

2019-present: Junior Group Leader, Cancer Research UK Beatson Institute
2015-2019: Career Development Fellow, MRC Mitochondrial Biology Unit
2014-2015: Research Associate, MRC Mitochondrial Biology Unit

Recent Publications

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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

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. F1000

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.

Lab Members

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Postdoctoral Scientists

Andrew Shaw
Elisabetta Tolla

Scientific Officer

Jacqueline Tait-Mulder

PhD Student

Mahnoor Mahmood

Masters Student

Morgan McIntosh

Research

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Seminars

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