Investigating how mitochondrial metabolism of surrounding cells affects activation of macrophages.

Katiuscia Bianchi (primary)
Centre for Cancer Cell and Molecular Biology
Barts Cancer Institute - Queen Mary University of London
Gyorgy Szabadkai (secondary)
Department of Cell Developmental Biology
University College London


Macrophages play a vital role in the innate immune system responding to a host of signals from the microenvironment. We hypothesise that macrophage differentiation and activation will be different if the surrounding cells have an altered mitochondrial metabolism, considering that alterations of mitochondrial metabolism effect the secretome of cells, with respect of both cytokines and metabolites.
This hypothesis will be examined in patient-derived cellular models using experimental and computational metabolic flux analysis. We aim to model the correlation between altered metabolism and cytokine secretion and/or metabolite signalling, which in turn can be used to explain macrophage activation.


1. Hoffmann, E. J. & Ponik, S. M. Biomechanical Contributions to Macrophage Activation in the Tumor Microenvironment. Front. Oncol. 10, 1–11 (2020).
2. Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).
3. Coats, B. R. et al. Metabolically Activated Adipose Tissue Macrophages Perform Detrimental and Beneficial Functions during Diet-Induced Obesity. Cell Rep. 20, 3149–3161 (2017).
4. Okamoto, T. et al. Reduced substrate stiffness promotes M2-like macrophage activation and enhances peroxisome proliferator-activated receptor γ expression. Exp. Cell Res. 367, 264–273 (2018).
5. Pek, N. M. Q. et al. Mitochondrial 3243A > G mutation confers pro-atherogenic and pro-inflammatory properties in MELAS iPS derived endothelial cells. Cell Death Dis. 10, (2019).
6. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).
7. Gaude, E. et al. NADH Shuttling Couples Cytosolic Reductive Carboxylation of Glutamine with Glycolysis in Cells with Mitochondrial Dysfunction. Mol. Cell 69, 581-593.e7 (2018).
8. Wilcz-Villega, E. et al. Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway. EMBO Mol. Med. 12, (2020).
9. Rodriguez, A. E. et al. Short Article Serine Metabolism Supports Macrophage IL-1 b Short Article Serine Metabolism Supports Macrophage IL-1 b Production. Cell Metab. 1–9 (2019). doi:10.1016/j.cmet.2019.01.014
10. Yu, W. et al. One-Carbon Metabolism Supports S-Adenosylmethionine and Histone Methylation to Drive Inflammatory Macrophages. Mol. Cell 1–14 (2019). doi:10.1016/j.molcel.2019.06.039
11. Pacold, M. E. et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat. Chem. Biol. 12, (2016).
12. Wang, Q. et al. Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity. Cell Chem. Biol. 24, 55–65 (2017).

Molecules, cells and industrial biotechnology
Area of Biology
Cell BiologyImmunology
Techniques & Approaches
BiochemistryBioinformaticsMicroscopy / ElectrophysiologySimulation / Modelling