Peer-reviewedCC BYNature Metabolism
Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer
14 affiliations
- 1Johnston Cancer Research Centre, Queen's University Belfast, Belfast, Northern Ireland, UK
- 2Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- 3Cellular and Molecular Imaging Core, Royal College of Surgeons in Ireland, Dublin, Ireland
- 4Agilent Technologies, Cheadle, UK
- 5Institute for Global Food Security, Queen's University Belfast, Belfast, Northern Ireland, UK
- 6Agri-Food and Biosciences Institute, Chemical Surveillance Branch, Veterinary Sciences Division, Belfast, Northern Ireland, UK
- 7International Joint Research Centre on Food Security (IJC-FOODSEC), Khong Luang, Thailand
- 8School of Food Science and Technology, Faculty of Science and Technology, Thammasat University, Khong Luang, Thailand
- 9Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland
- 10CRUK Scotland Institute, Glasgow, UK
- 11Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
- 12School of Cancer Sciences, University of Glasgow, Glasgow, UK
- 13Department of Metabolism and Systems Science, College of Medicine and Health, University of Birmingham, Birmingham, UK
- 14Johnston Cancer Research Centre, Queen's University Belfast, Belfast, Northern Ireland, UK. [email protected]
Abstract
Therapy resistance is attributed to over 80% of cancer deaths per year, emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. As an antimetabolite, 5FU imposes substantial metabolic stress, forcing cells that survive treatment to rapidly adapt. We explored acute 5FU-driven changes in mitochondria, the organelle critical for coordinating metabolic stress responses. Here we demonstrate in a range of CRC models that 5FU treatment promotes mitochondrial biogenesis and increases mitochondrial function in surviving cells. Furthermore, we show that targeting mitochondrial metabolism, particularly by inhibiting Complex I, sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes.
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BibTeX
@article{moss2026mitochondrial,
title = {{Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer}},
author = {Deborah Y. Moss and Connor N. Brown and Andrew M. Shaw and Chris McCann and Nikita Lewis and Matilda Downs and Rebecca Wurelly and Ciara Cunningham and Aaron Philips and Niamh Doherty and Sarah Gallagher and William J. McDaid and Andrew J. Roe and Aisling Y. Coughlan and Brenton Cavanagh and Callum Ormsby and Fiammetta Falcone and Rachel McCole and Scott Monteith and Emily Rogan and Sudhir B. Malla and Alexandra J Emerson and Letitia Mohamed-Smith and Shaun Sharkey and Aoife Leonard and Peter F. Gallagher and Arindam Banerjee and Sandra Van Schaeybroeck and Sufyan Pandor and Brian Quinn and Brett Greer and Christopher Elliott and Sarah Maguire and Aideen E. Ryan and Philip D. Dunne and Mary G. Mallon and Stephanie G. Craig and Omar Aftab and Laura C. Greaves and Bryan P. Marzullo and Daniel A. Tennant and Vicky M. Coyle and Ian Geoffrey Mills and Owen James Sansom and Tríona Ní Chonghaile and DB Longley and Simon S. McDade and Melissa J. LaBonte and Emma M. Kerr},
journal = {Nature Metabolism},
year = {2026},
month = jul,
doi = {10.1038/s42255-026-01578-w},
url = {https://doi.org/10.1038/s42255-026-01578-w},
note = {CC BY},
}
RIS
TY - JOUR
TI - Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer
AU - Deborah Y. Moss
AU - Connor N. Brown
AU - Andrew M. Shaw
AU - Chris McCann
AU - Nikita Lewis
AU - Matilda Downs
AU - Rebecca Wurelly
AU - Ciara Cunningham
AU - Aaron Philips
AU - Niamh Doherty
AU - Sarah Gallagher
AU - William J. McDaid
AU - Andrew J. Roe
AU - Aisling Y. Coughlan
AU - Brenton Cavanagh
AU - Callum Ormsby
AU - Fiammetta Falcone
AU - Rachel McCole
AU - Scott Monteith
AU - Emily Rogan
AU - Sudhir B. Malla
AU - Alexandra J Emerson
AU - Letitia Mohamed-Smith
AU - Shaun Sharkey
AU - Aoife Leonard
AU - Peter F. Gallagher
AU - Arindam Banerjee
AU - Sandra Van Schaeybroeck
AU - Sufyan Pandor
AU - Brian Quinn
AU - Brett Greer
AU - Christopher Elliott
AU - Sarah Maguire
AU - Aideen E. Ryan
AU - Philip D. Dunne
AU - Mary G. Mallon
AU - Stephanie G. Craig
AU - Omar Aftab
AU - Laura C. Greaves
AU - Bryan P. Marzullo
AU - Daniel A. Tennant
AU - Vicky M. Coyle
AU - Ian Geoffrey Mills
AU - Owen James Sansom
AU - Tríona Ní Chonghaile
AU - DB Longley
AU - Simon S. McDade
AU - Melissa J. LaBonte
AU - Emma M. Kerr
PY - 2026
DA - 2026/07/23
JO - Nature Metabolism
DO - 10.1038/s42255-026-01578-w
UR - https://doi.org/10.1038/s42255-026-01578-w
AB - Therapy resistance is attributed to over 80% of cancer deaths per year, emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. As an antimetabolite, 5FU imposes substantial metabolic stress, forcing cells that survive treatment to rapidly adapt. We explored acute 5FU-driven changes in mitochondria, the organelle critical for coordinating metabolic stress responses. Here we demonstrate in a range of CRC models that 5FU treatment promotes mitochondrial biogenesis and increases mitochondrial function in surviving cells. Furthermore, we show that targeting mitochondrial metabolism, particularly by inhibiting Complex I, sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes.
SN - 2522-5812
ER -