Dr. Dylan Ryan
Assistant Professor, Biochemistry
Biography
Dylan obtained a Bachelor of science (BSc) degree in Biochemistry (2015) from the School of Biomolecular and Biomedical Science (SBBS) in University College Dublin (UCD). He was awarded the Michael G. Harrington medal and Joy Carey project prize for obtaining first place and best thesis project in the BSc (Hons) Biochemistry class. Following his degree, he completed a PhD in Immunology (2019) from The University of Dublin, Trinity College (TCD), carrying out research on inflammatory macrophage metabolism in the lab of Prof. Luke O'Neill. From 2019-2022, he undertook a postdoctoral research associate position in the lab of Dr. Christian Frezza in MRC Cancer Unit, University of Cambridge. Here, he focused on deciphering the consequences of mitochondrial TCA cycle dysfunction in kidney epithelial cells and macrophages. In 2022, he joined the lab of Prof. Mike Murphy in the MRC Mitochondrial Biology Unit (MBU), continuing his work on immunometabolism. Dylan obtained an MRC "Springboard to Independence" position beginning in March 2023, where he directed an independent research programme at the MBU, focused on investigating the intersection of mitochondria, metabolic reprogramming and macrophage biology in the context of primary mitochondrial DNA disease. In September 2025, Dylan joined the School of Biochemistry and Immunology in Trinity Biomedical Sciences Institute (TBSI) (TCD) as a tenure-track assistant professor in biochemistry where he is investigating the role of innate immunity in primary mitochondrial disorders. He has mentored undergraduate and PhD students throughout his career and is excited for this next stage in guiding other early career scientists looking to perform research in the fields of mitochondrial biology and immunometabolism.
Publications and Further Research Outputs
Peer-Reviewed Publications
Eloïse Marques, Stephen P. Burr, Alva M. Casey, Richard J. Stopforth, Chak Shun Yu, Keira Turner, Dane M. Wolf, Marisa Dilucca, Vincent Paupe, Suvagata Roy Chowdhury, Victoria J. Tyrrell, Robbin Kramer, Yamini M. Kanse, Chinmayi Pednekar, Chris A. Powell, James B. Stewart, Julien Prudent, Michael P. Murphy, Michal Minczuk, Valerie B. O"Donnell, Clare E. Bryant, Patrick F. Chinnery, Arthur Kaser, Alexander von Kriegsheim, Dylan G. Ryan, An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice, Nature Communications, 2025
Alva M. Casey, Dylan G. Ryan, Hiran A. Prag, Suvagata Roy Chowdhury, Eloïse Marques, Keira Turner, Anja V. Gruszczyk, Ming Yang, Dane M. Wolf, Jan Lj. Miljkovic, Joyce Valadares, Patrick F. Chinnery, Richard C. Hartley, Christian Frezza, Julien Prudent, Michael P. Murphy, Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1ß release during NLRP3 inflammasome activation, Nature Metabolism, 2025
Antonio M. A. Miranda, Liam McAllan, Guianfranco Mazzei, Ivan Andrew, Iona Davies, Meryem Ertugrul, Julia Kenkre, Hiromi Kudo, Joana Carrelha, Bhavik Patel, Sophie Newton, Weihua Zhang, Alice Pollard, Amy Cross, Oliver McCallion, Mikyung Jang, Ka Lok Choi, Scarlett Brown, Yasmin Rasool, Marco Adamo, Mohamed Elkalaawy, Andrew Jenkinson, Borzoueh Mohammadi, Majid Hashemi, Robert Goldin, Laurence Game, Joanna Hester, Fadi Issa, Dylan G. Ryan, Patricia Ortega, Ahmed R. Ahmed, Rachel L. Batterham, John C. Chambers, Jaspal S. Kooner, Damir Baranasic, Michela Noseda, Tricia Tan, William R. Scott, Selective remodelling of the adipose niche in obesity and weight loss, Nature, 2025
Pavel A Nash, Keira M Turner, Christopher A Powell, Lindsey Van Haute, Pedro Silva-Pinheiro, Felix Bubeck, Ellen Wiedtke, Eloïse Marques, Dylan G Ryan, Dirk Grimm, Payam A Gammage, Michal Minczuk, Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture, EMBO Molecular Medicine, 2025
Katarzyna Drzewicka, Katarzyna M. G"uchowska, Michal Ml"cki, Bart"omiej Hofman, Irina Tuszy"ska, Tristram A. J. Ryan, Katarzyna Piwowar, Bartosz Wilczy"ski, Dorota Dymkowska, Marcin M. Grzybowski, Barbara Dymek, Tomasz Rejczak, Kamil Lisiecki, Adam Go""biowski, Adam Jagielski, Angelika Muchowicz, Dylan Ryan, Krzysztof Zab"ocki, Luke A. J. O"Neill, Zbigniew Zas"ona, Chitinase-1 inhibition attenuates metabolic dysregulation and restores homeostasis in MASH animal models, Frontiers in Immunology, 2025
Zotta, Alessia and Toller-Kawahisa, Juliana and Palsson-McDermott, Eva M. and O'Carroll, Shane M. and Henry, Ã"rlaith C. and Day, Emily A. and McGettrick, Anne F. and Ward, Ross W. and Ryan, Dylan G. and Watson, Mark A. and Brand, Martin D. and Runtsch, Marah C. and Maitz, Kathrin and Lueger, Anna and Kargl, Julia and Miljkovic, Jan L. and Lavelle, Ed C. and O'Neill, Luke A.J., Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion, Science Advances , 11, (4), 2025
Lucas Rebuffet, Janine E. Melsen, Bertrand Escalière, Daniela Basurto-Lozada, Avinash Bhandoola, Niklas K. Björkström, Yenan T. Bryceson, Roberta Castriconi, Frank Cichocki, Marco Colonna, Daniel M. Davis, Andreas Diefenbach, Yi Ding, Muzlifah Haniffa, Amir Horowitz, Lewis L. Lanier, Karl-Johan Malmberg, Jeffrey S. Miller, Lorenzo Moretta, Emilie Narni-Mancinelli, Luke A. J. O"Neill, Chiara Romagnani, Dylan G. Ryan, Simona Sivori, Dan Sun, Constance Vagne, Eric Vivier, High-dimensional single-cell analysis of human natural killer cell heterogeneity, Nature Immunology, 2024
Eloïse Marques, Robbin Kramer, Dylan G. Ryan, Multifaceted mitochondria in innate immunity, npj Metabolic Health and Disease, 2024
Laura P. Kimble, Arezou Khosroshahi, Glenna S. Brewster, Sandra B. Dunbar, Dylan Ryan, Nicole Carlson, Ron Eldridge, Madelyn Houser, Elizabeth Corwin, Associations between TCA cycle plasma metabolites and fatigue in black females with systemic lupus erythematosus: An untargeted metabolomics pilot study, Lupus, 2024
Dylan Gerard Ryan, Christian Graham Peace, Alexander Hooftman, Basic Mechanisms of Immunometabolites in Shaping the Immune Response, Journal of Innate Immunity, 2023
Dylan Gerard Ryan, Christian Frezza, Metabolic symbiosis in pancreatic cancer, Nature Cancer, 2022
Christa P. Baker, Iain R. Phair, Alejandro J. Brenes, Abdelmadjid Atrih, Dylan G. Ryan, Roland Bruderer, Albena T. Dinkova-Kostova, Douglas J. Lamont, J. Simon C. Arthur, Andrew J.M. Howden, DIA label-free proteomic analysis of murine bone-marrow-derived macrophages, STAR Protocols, 3, (4), 2022, p101725
Marco Sciacovelli, Aurelien Dugourd, Lorea Valcarcel Jimenez, Ming Yang, Efterpi Nikitopoulou, Ana S. H. Costa, Laura Tronci, Veronica Caraffini, Paulo Rodrigues, Christina Schmidt, Dylan Gerard Ryan, Timothy Young, Vincent R. Zecchini, Sabrina H. Rossi, Charlie Massie, Caroline Lohoff, Maria Masid, Vassily Hatzimanikatis, Christoph Kuppe, Alex Von Kriegsheim, Rafael Kramann, Vincent Gnanapragasam, Anne Y. Warren, Grant D. Stewart, Ayelet Erez, Sakari Vanharanta, Julio Saez-Rodriguez, Christian Frezza, Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression, Nature Communications, 13, (1), 2022
Ryan, D.G. and Knatko, E.V. and Casey, A.M. and Hukelmann, J.L. and Dayalan Naidu, S. and Brenes, A.J. and Ekkunagul, T. and Baker, C. and Higgins, M. and Tronci, L. and Nikitopolou, E. and Honda, T. and Hartley, R.C. and O'Neill, L.A.J. and Frezza, C. and Lamond, A.I. and Abramov, A.Y. and Arthur, J.S.C. and Cantrell, D.A. and Murphy, M.P. and Dinkova-Kostova, A.T., Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response, iScience, 25, (2), 2022
Williams, N.C. and Ryan, D.G. and Costa, A.S.H. and Mills, E.L. and Jedrychowski, M.P. and Cloonan, S.M. and Frezza, C. and O'Neill, L.A., Signaling metabolite L-2-hydroxyglutarate activates the transcription factor HIF-1α in lipopolysaccharide-activated macrophages, Journal of Biological Chemistry, 298, (2), 2022
, IL-10-Mediated Refueling of Exhausted T Cell Mitochondria Boosts Anti-Tumour Immunity., Immunometabolism, 2021
Dylan Gerard Ryan and Ming Yang and Hiran A Prag and Giovanny Rodriguez Blanco and Efterpi Nikitopoulou and Marc Segarra-Mondejar and Christopher A Powell and Tim Young and Nils Burger and Jan Lj Miljkovic and Michal Minczuk and Michael P Murphy and Alex von Kriegsheim and Christian Frezza, Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism, eLife, 10, 2021
Ryan, D.G. and Frezza, C. and O'Neill, L.A., TCA cycle signalling and the evolution of eukaryotes, Current Opinion in Biotechnology, 68, 2021, p72-88
Ryan, D.G. and O'Neill, L.A.J., Krebs Cycle Reborn in Macrophage Immunometabolism, Annual Review of Immunology, 38, 2020, p289-313
Zbigniew Zaslona, Ewelina Flis, Mieszko M Wilk, Richard G Carroll, Eva M Palsson-McDermott, Mark M Hughes, Ciana Diskin, Kathy Banahan, Dylan G Ryan, Alexander Hooftman, Alicja Misiak, Jay Kearney, Gunter Lochnit, Wilhelm Bertrams, Timm Greulich, Bernd Schmeck, Oliver J McElvaney, Kingston H G Mills, Ed C Lavelle, Małgorzata Wygrecka, Emma M Creagh, Luke A J O'Neill, Caspase-11 promotes allergic airway inflammation, Nature Communications, 2020
, Coupling Krebs cycle metabolites to signalling in immunity and cancer., Nature metabolism, 2019
Olagnier D, Brandtoft A.M, Gunderstofte C, Villadsen N.L, Krapp C, Thielke A.L, Laustsen A, Peri S, Hansen A.L, Bonefeld L, Thyrsted J, Bruun V, Iversen M.B, Lin L, Artegoitia V.M, Su C, Yang L, Lin R, Balachandran S, Luo Y, Nyegaard M, Marrero B, Goldbach-Mansky R, Motwani M, Ryan D.G, Fitzgerald K.A, Oâ Neill L.A, Hollensen A.K, Damgaard C.K, de Paoli F, Bertram H.C, Jakobsen M.R, Poulsen T.B, Holm C.K, Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming, Nature Communications, 9, (1), 2018
Early JO, Menon D, Wyse CA, Cervantes-Silva MP, Zaslona Z, Carroll RG, Palsson-McDermott EM, Angiari S, Ryan DG, Corcoran SE, Timmons G, Geiger SS, Fitzpatrick DJ, O'Connell D, Xavier RJ, Hokamp K, O'Neill LAJ, Curtis AM., Circadian clock protein BMAL1 regulates IL-1ß in macrophages via NRF2., Proceedings of the National Academy of Sciences of the United States of America, 115, (36), 2018, pE8460-E8468
Baardman, J. and Verberk, S.G.S. and Prange, K.H.M. and van Weeghel, M. and van der Velden, S. and Ryan, D.G. and WÃŒst, R.C.I. and Neele, A.E. and Speijer, D. and Denis, S.W. and Witte, M.E. and Houtkooper, R.H. and O'neill, L.A. and Knatko, E.V. and Dinkova-Kostova, A.T. and Lutgens, E. and de Winther, M.P.J. and Van den Bossche, J., A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia, Cell Reports, 25, (8), 2018, p2044-2052.e5
Mills, E.L. and Ryan, D.G. and Prag, H.A. and Dikovskaya, D. and Menon, D. and Zaslona, Z. and Jedrychowski, M.P. and Costa, A.S.H. and Higgins, M. and Hams, E. and Szpyt, J. and Runtsch, M.C. and King, M.S. and McGouran, J.F. and Fischer, R. and Kessler, B.M. and McGettrick, A.F. and Hughes, M.M. and Carroll, R.G. and Booty, L.M. and Knatko, E.V. and Meakin, P.J. and Ashford, M.L.J. and Modis, L.K. and Brunori, G. and Sévin, D.C. and Fallon, P.G. and Caldwell, S.T. and Kunji, E.R.S. and Chouchani, E.T. and Frezza, C. and Dinkova-Kostova, A.T. and Hartley, R.C. and Murphy, M.P. and O'Neill, L.A., Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1, Nature, 556, (7699), 2018, p113-117
Ryan, D.G. and O'Neill, L.A.J., Krebs cycle rewired for macrophage and dendritic cell effector functions, FEBS Letters, 591, (19), 2017, p2992-3006
Mills E.L, Kelly B, Logan A, Costa A.S.H, Varma M, Bryant C.E, Tourlomousis P, DÀbritz J.H.M, Gottlieb E, Latorre I, Corr S.C, McManus G, Ryan D, Jacobs H.T, Szibor M, Xavier R.J, Braun T, Frezza C, Murphy M.P, O'Neill L.A, Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages, Cell, 167, (2), 2016, p457 - 470.e13
Éric Vivier, Lucas REBUFFET, Janine Melsen, Daniela Basurto-Lozada, Avinash Bhandoola, Niklas K. Björkström, Yenan T. Bryceson, Roberta Castriconi, Frank Cichocki, Marco Colonna, Daniel M. Davis, Andreas Diefenbach, Bertrand Escalière, Muzlifah Haniffa, Amir Horowitz, Lewis L. Lanier, Karl"Johan Malmberg, Jeffrey S. Miller, Lorenzo Moretta, Émilie Narni-Mancinelli, Luke O'neill, Chiara Romagnani, Dylan G. Ryan, Simona Sivori, Dan Sun, Constance Vagne, Yi Ding, High-Dimensional Single-Cell Analysis of Natural Killer Cell Heterogeneity in Human Blood, 2024
Hooftman A, Peace CG, Ryan DG, Day EA, Yang M, McGettrick AF, Yin M, Montano EN, Huo L, Toller-Kawahisa JE, Zecchini V, Ryan TAJ, Bolado-Carrancio A, Casey AM, Prag HA, Costa ASH, De Los Santos G, Ishimori M, Wallace DJ, Venuturupalli S, Nikitopoulou E, Frizzell N, Johansson C, Von Kriegsheim A, Murphy MP, Jefferies C, Frezza C, O'Neill LAJ., Macrophage fumarate hydratase restrains mtRNA-mediated interferon production. , Nature, 2023, p32
Christian G. Peace, Alexander Hooftman, Dylan G. Ryan, Inflammatory mitochondrial nucleic acids as drivers of pathophysiology, Clinical and Translational Medicine, 13, (9), 2023, pe1403 - e1403, pe1403-e1403
Dylan G. Ryan, Elena V. Knatko, Alva M. Casey, Jens Hukelmann, Alejandro J. Brenes, Sharadha Dayalan Naidu, Maureen Higgins, Laura Tronci, Efterpi Nikitopoulou, Luke O'neill, Christian Frezza, Angus I. Lamond, Andrey Y. Abramov, Doreen A. Cantrell, Michael P. Murphy, Albena T. Dinkova"Kostova, Nrf2 is a central regulator of the metabolic landscape in macrophages and finetunes their inflammatory response, 2021
Non-Peer-Reviewed Publications
Hughes, O'Neill, Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling, Proceedings of the National Academy of Sciences of the United States of America, 2017
Research Expertise
Description
Mitochondrial (Immuno)metabolism group. Interests: Metabolic reprogramming and mitochondrial signalling as regulators of inflammatory disease & primary mitochondrial disorders. Macrophages are key cells of the innate immune system essential for the detection and elimination of viral and bacterial pathogens, while aberrant macrophage activation can also lead to systemic inflammation and death, as observed during sepsis. The innate immune system senses microbial infection using several families of germline-encoded pattern recognition receptors (PRRs), which detect non-self, pathogen-associated molecular patterns (PAMPs). Notable examples of PRRs are the toll-like (TLR), NOD-like (NLR) and RIG-I-like (RLR) receptor families, which initiate inflammation-associated transcription factor activation and the remodelling of cellular metabolism. Metabolic reprogramming supports the functional plasticity of macrophages by promoting pathogen clearance, inter- and intra-cellular communication, and the resolution of inflammation. Mitochondria are central to pathogen sensing and metabolic reprogramming, serving as vital signalling hubs for the execution of macrophage effector functions. These effector functions include mitochondrial reactive oxygen species (mtROS)-mediated bacterial killing, the production of metabolic signals that regulate nuclear gene expression, and the activation of supramolecular inflammatory signalling complexes. Of note, mitochondrial respiration and nucleic acid signalling has recently been shown to facilitate the activation of the NLRP3 inflammasome and pro-inflammatory cytokine secretion. Insights into the metabolic instruction of immunity has transformed the field and led to the formation of a new branch of immunological research termed `immunometabolism'. Importantly, this has now opened an avenue for the development of metabolically targeted therapies to treat systemic inflammatory and autoimmune disorders, such as septic shock and multiple sclerosis (MS). My group aims to use mitochondrial DNA mutations as a tractable framework to decode this problem. By imposing threshold-dependent defects in mitochondrial gene expression or specific oxidative phosphorylation complexes, we seek to reveal how discrete mitochondrial states are translated into immune signals. This work involves a combination of molecular biology, mass spectrometry, respirometry, imaging and genomic approaches to dissect mitochondrial metabolism and macrophage biology following inflammatory activation. Emerging evidence implicates mitochondrial nucleic acids as key mediators linking organelle dysfunction to type I interferon responses. A key future direction is to define how distinct mutations converge mechanistically, and to test the idea that primary mitochondrial disease represents, in part, a disorder of aberrant innate immune signalling. More broadly, resolving how mitochondria function as signalling hubs will be critical for understanding their role across metabolism, infection, inflammation, ageing and degenerative disease.Projects
- Title
- METABOMAC - Metabolic control of inflammatory macrophage function
- Summary
- Macrophages are key innate immune cells essential for the detection of invading pathogens and in promoting protective host immunity. Following infection, pattern recognition receptor (PRR) activation is triggered by pathogen-associated molecular patterns (PAMPs). Notable examples of PRRs are the toll-like (TLR), RIG-like (RLR) and NOD-like (NLR) receptor families, which initiate remodelling of cellular metabolism in macrophages. Mitochondria are central to pathogen sensing and metabolic rewiring, serving as vital signalling hubs for the execution of macrophage effector functions. These effector functions range from mitochondrial reactive oxygen species (mtROS)-mediated bacterial killing to the activation of the NLRP3 inflammasome signalling complex, which triggers pyroptosis to limit bacterial dissemination. However, aberrant activation of the NLRP3 inflammasome can also exacerbate systemic immune responses and promote sepsis progression. NLRP3 activation is dependent on the release of newly synthesised and oxidised mitochondrial DNA (mtDNA), a process supported by the pyrimidine salvage enzyme cytidine/uridine monophosphate kinase 2 (CMPK2). My recent unpublished data has uncovered an unappreciated increase in de novo pyrimidine biosynthesis in macrophages, a pathway reliant on the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). In parallel, pyrimidine salvage is promoted via induction of the cytosolic enzyme, uridine phosphorylase 1 (UPP1), which is also significantly increased in critically ill sepsis patients. How these pathways regulate macrophage function and septic shock is currently unknown. The main aim of this research is to understand how pyrimidine synthesis and salvage pathways regulate macrophage function, with a focus on mtDNA, NLRP3 inflammasome activation and sepsis.
- Funding Agency
- Wellcome Trust-Academy of Medical Sciences
- Date From
- 04-JAN-2024
- Date To
- 31-MAR-2026
- Title
- Decoding how pathogenic mtDNA mutations influence innate immunity and susceptibility to infection
- Summary
- This project will explore why people with inherited mitochondrial disease are often more vulnerable to severe infections. Mitochondria are widely known as the structures that generate energy inside our cells, but they also play an important role in controlling the immune system. The research will focus on harmful mutations in mitochondrial DNA, a major cause of primary mitochondrial disease, and investigate how these mutations alter the behaviour of immune cells. Although patients with these disorders frequently experience recurrent infections and inflammatory complications, the reasons for this remain poorly understood. This project aims to uncover the biological link between mitochondrial dysfunction and impaired host defence. The study will centre on macrophages, frontline immune cells that help the body detect and eliminate pathogens, such as bacteria and viruses. By combining advanced metabolic profiling, infection models and preclinical studies, the research will test whether mitochondrial DNA mutations drive these immune cells into a persistent `false alarm" state that weakens antibacterial defence and promotes damaging inflammation. It will also assess whether these abnormalities can be reversed using targeted therapeutic strategies. The findings are expected to provide new insight into infection risk in mitochondrial disease and may have wider relevance for understanding immune dysfunction in conditions such as sepsis, autoimmunity and ageing.
- Funding Agency
- Wellcome Trust
- Date From
- 01/07/2026
- Date To
- 01/07/2034
Recognition
Memberships
European Society for Mitochondrial Research and Medicine
European Immunometabolism Network