Whole-cell energy modeling reveals quantitative changes of predicted energy flows in RAS mutant cancer cell lines
Thomas Sevrin,
Lisa Strasser,
Camille Ternet,
Philipp Junk,
Miriam Caffarini,
Stella Prins,
Cian D’Arcy,
Simona Catozzi,
Giorgio Oliviero,
Kieran Wynne,
Christina Kiel,
Philip J. Luthert
Affiliations
Thomas Sevrin
Systems Biology Ireland, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland; UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland
Lisa Strasser
Systems Biology Ireland, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland; UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland
Camille Ternet
Systems Biology Ireland, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland; UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland
Philipp Junk
Systems Biology Ireland, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland; UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland
Miriam Caffarini
Systems Biology Ireland, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland; UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland
Stella Prins
UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK
Cian D’Arcy
Systems Biology Ireland, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland; UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland
Simona Catozzi
Systems Biology Ireland, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland; UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland
Giorgio Oliviero
Systems Biology Ireland, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland
Kieran Wynne
Systems Biology Ireland, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland; Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland
Christina Kiel
Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy; Systems Biology Ireland, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland; UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland; Corresponding author
Philip J. Luthert
UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK; NIHR Moorfields Biomedical Research Centre, University College London, 11-43 Bath Street, London EC1V 9EL, UK; Corresponding author
Summary: Cellular utilization of available energy flows to drive a multitude of forms of cellular “work” is a major biological constraint. Cells steer metabolism to address changing phenotypic states but little is known as to how bioenergetics couples to the richness of processes in a cell as a whole. Here, we outline a whole-cell energy framework that is informed by proteomic analysis and an energetics-based gene ontology. We separate analysis of metabolic supply and the capacity to generate high-energy phosphates from a representation of demand that is built on the relative abundance of ATPases and GTPases that deliver cellular work. We employed mouse embryonic fibroblast cell lines that express wild-type KRAS or oncogenic mutations and with distinct phenotypes. We observe shifts between energy-requiring processes. Calibrating against Seahorse analysis, we have created a whole-cell energy budget with apparent predictive power, for instance in relation to protein synthesis.
