Dr Tom MacVicar - Mitochondrial Reprogramming in Cancer
Introduction
Remarkable cancer cell metabolic flexibility and plasticity enable tumours to grow and combat chemotherapy. Mitochondria are essential organelles that support tumour adaptation to altered metabolic demands and environmental challenges. Accordingly, mitochondrial form and function are dynamically reprogrammed during tumorigenesis. For instance, the levels of key mitochondrial inner membrane proteins, including metabolite transporters, are fine tuned in response to nutrient and oxygen availability to support cancer cell proliferation and survival.
Metabolite transporter proteins are required to exchange small molecules including amino acids and nucleotides between the mitochondria and the rest of the cell. The tightly regulated coupling of cytosolic and mitochondrial metabolic reactions across the inner mitochondrial membrane represents an essential but poorly understood facet of tumour metabolism. Our goal is to identify mitochondrial metabolite transporters that control cancer progression using genetic screening approaches in 3D tumour models combined with genetically engineered mouse models. We will also investigate how regulated mitochondrial nucleotide transport and metabolism contribute to tumorigenesis and cancer cell responses to nucleotide-analogue chemotherapy. These studies will improve our basic understanding of mitochondrial reprogramming in tumours and may identify novel therapeutic targets for cancers that depend on metabolic flexibility and plasticity, including pancreatic cancer.
EmailBiography
Education and qualifications
2013: PhD, School of Biochemistry, University of Bristol
2009: BSc, Biochemistry, University of Bristol
Appointments
2021-present: CRUK Career Development Fellow, Cancer Research UK Scotland Institute
2018-2021: Postdoctoral Researcher, Max Planck Institute for Biology of Ageing, Cologne, Germany
2014-2018: Postdoctoral Researcher, CECAD, Cologne, Germany
2013-2014: Postdoctoral Researcher, Department of Biochemistry, University of Bristol, UK
Honours and Awards
2016 Humboldt Research Fellowship for Postdoctoral Researchers
2015 EMBO Long-Term Postdoctoral Fellowship
Recent Publications
2023
Grotehans N, McGarry L, Nolte H, Xavier V, Kroker M, Narbona-Pérez Á J, Deshwal S, Giavalisco P, Langer T, MacVicar T. Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression. Embo j. 2023;10.15252/embj.2022113256:e113256.
2021
Murschall LM, Peker E, MacVicar T, Langer T, Riemer J. Protein Import Assay into Mitochondria Isolated from Human Cells. Bio Protoc. 2021;11(12):e4057.
Sprenger HG*, MacVicar T*, Bahat A, Fiedler KU, Hermans S, Ehrentraut D, Ried K, Milenkovic D, Bonekamp N, Larsson NG, Nolte H, Giavalisco P, Langer T. Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity. Nat Metab. 2021;3(5):636-650.*equal contribution
Willenborg S, Sanin DE, Jais A, Ding X, Ulas T, Nuchel J, Popovic M, MacVicar T, Langer T, Schultze JL, et al. (2021). Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. Cell Metab 33, 2398-2414 e2399. 1
Bahat A*, MacVicar T*, Langer T. Metabolism and Innate Immunity Meet at the Mitochondria. Front Cell Dev Biol. 2021;9:720490.*equal contribution
MacVicar T, Langer T. Mechanometabolism: Mitochondria promote resilience under pressure. Curr Biol. 2021;31(13):R859-r861.
2020
Murschall LM, Gerhards A, MacVicar T, Peker E, Hasberg L, Wawra S, Langer T, Riemer J. The C-terminal region of the oxidoreductase MIA40 stabilizes its cytosolic precursor during mitochondrial import. BMC Biol. 2020;18(1):96.
Ohba Y, MacVicar T, Langer T. Regulation of mitochondrial plasticity by the i-AAA protease YME1L. Biol Chem. 2020;401(6-7):877-890.
Wang Z, Liu F, Fan N, Zhou C, Li D, Macvicar T, Dong Q, Bruns CJ, Zhao Y. Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies. Front Oncol. 2020;10:589508.
2019
MacVicar T*, Ohba Y*, Nolte H, Mayer FC, Tatsuta T, Sprenger HG, Lindner B, Zhao Y, Li J, Bruns C, Krüger M, Habich M, Riemer J, Schwarzer R, Pasparakis M, Henschke S, Brüning JC, Zamboni N, Langer T. Lipid signalling drives proteolytic rewiring of mitochondria by YME1L. Nature. 2019;575(7782):361-365. *equal contribution
Richter F, Dennerlein S, Nikolov M, Jans DC, Naumenko N, Aich A, MacVicar T, Linden A, Jakobs S, Urlaub H, Langer T, Rehling P. ROMO1 is a constituent of the human presequence translocase required for YME1L protease import. J Cell Biol. 2019;218(2):598-614.
Sprenger HG, Wani G, Hesseling A, König T, Patron M, MacVicar T, Ahola S, Wai T, Barth E, Rugarli EI, Bergami M, Langer T. Loss of the mitochondrial i-AAA protease YME1L leads to ocular dysfunction and spinal axonopathy. EMBO Mol Med. 2019;11(1).
Ahola S, Langer T, MacVicar T. Mitochondrial Proteolysis and Metabolic Control. Cold Spring Harb Perspect Biol. 2019;11(7).
2018
Nolte H, MacVicar TD, Tellkamp F, Krüger M. Instant Clue: A Software Suite for Interactive Data Visualization and Analysis. Sci Rep. 2018;8(1):12648.
2016
Hartmann B, Wai T, Hu H, MacVicar T, Musante L, Fischer-Zirnsak B, Stenzel W, Gräf R, van den Heuvel L, Ropers HH, Wienker TF, Hübner C, Langer T, Kaindl AM. Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation. Elife. 2016;5.
MacVicar T, Langer T. OPA1 processing in cell death and disease - the long and short of it. J Cell Sci. 2016;129(12):2297-2306.
2015
MacVicar TD*, Mannack LV*, Lees RM, Lane JD. Targeted siRNA Screens Identify ER-to-Mitochondrial Calcium Exchange in Autophagy and Mitophagy Responses in RPE1 Cells. Int J Mol Sci. 2015;16(6):13356-13380. *equal contribution
2014
MacVicar TD, Lane JD. Impaired OMA1-dependent cleavage of OPA1 and reduced DRP1 fission activity combine to prevent mitophagy in cells that are dependent on oxidative phosphorylation. J Cell Sci. 2014;127(Pt 10):2313-2325.
2013
MacVicar T. Mitophagy. Essays Biochem. 2013;55:93-104.
2012
Betin VM, MacVicar TD, Parsons SF, Anstee DJ, Lane JD. A cryptic mitochondrial targeting motif in Atg4D links caspase cleavage with mitochondrial import and oxidative stress. Autophagy. 2012;8(4):664-676.
