Metabolic Reprogramming in Mitochondrial Disease

The tricarboxylic acid (TCA) cycle is implicated in nearly every aspect of mitochondrial function. Building on the paradigm that everything in metabolism depends on everything, we study how TCA cycle defects alter metabolic and extra-metabolic mechanisms driving mitochondrial disease.

Our research focuses on mitochondrial RNA (mtRNA) homeostasis and its crosstalk with immunometabolism. Using bottom-up approaches, we integrate metabolic fluxes, RNA regulation and protein–RNA interactions to identify disease-modifying pathways and measurable biomarkers underlying mitochondrial dysfunction in mitochondrial disease (MtD).

Approaches and models
- Tools to explore the cell: metabolic and stable-isotope labelling, RNA metabolic labelling, transcriptomics (RNA-seq, iCLIP-seq), RNA visualization, purification of protein–RNA and enzymatic complexes, metabolic flux analysis.
- Disease modelling: genetically engineered cell lines; models of hypoxia and pseudo-hypoxia; metabolic reprogramming in cell culture.

  • 2022–2025 | La Caixa Foundation (Project ID: 116925)
    This project examined how inborn defects of the TCA cycle reprogram mitochondrial RNA networks and metabolic signalling. By integrating RNA interactomics and sequencing-based approaches, we investigated how loss of TCA enzymes reshapes RNA–protein assemblies within mitochondrial RNA granules and RNA degradation pathways.
  • 2016–2018 | Marie Skłodowska-Curie Actions (Grant ID: 701730)
    This project investigated how metabolic shifts remodel RNA–protein and RNA–RNA interactions during rapid cellular transitions. Using transcriptomics and RNA metabolic labelling, it uncovered links between mRNA methylation, RNA turnover dynamics, and post-transcriptional regulation in T cell immunity, bridging metabolism with RNA biology.

Research Articles:

  • Gameiro PA*, Foskolou IP*, Butt YA, Martens A, Kuret K, de los Mozos IR, Zandhuis ND, Hozjan Ž, Kot V, Faraway R, Vermeulen M, Wolkers M, Johnson RS, Ule J. (2026). Meta-unstable mRNAs in activated CD8+ T cells are defined by interlinked AU-rich elements and m6A mRNA methylation. | * Equal contribution. Nat Commun 17, 160 (2026). https://doi.org/10.1038/s41467-025-67762-w
  • Santos CC, Schweizer N, Cairrão F, Ramirez J, Osinalde N, Yang M, Gaspar CJ, Rasheva VI, Hensel Z, Adrain C, Cordeiro TN, Voigt F, Gameiro PA, Mayor U, Domingos PM (2025). Fbxo42 promotes the degradation of Ataxin-2 granules to trigger terminal Xbp1 signaling. Nature Communications 16(1):7523. doi: 10.1038/s41467-025-62417-2.
  • Barbieri L, Veliça P, Gameiro PA, Cunha PP, Foskolou IP, Rullman E, Bargiela D, Johnson RS, and Rundqvist, H. (2023). Lactate exposure shapes the metabolic and transcriptomic profile of CD8+ T cells. Frontiers in Immunology, 14. doi: 10.3389/fimmu.2023.1101433
  • Gameiro PA, Encheva V, Dos Santos MS, MacRae JI, and Ule J. (2021). Metabolic turnover and dynamics of modified ribonucleosides by 13C labelling. Journal of Biological Chemistry 297(5):101294. | Corresponding author. doi: 10.1016/j.jbc.2021.101294
  • Rundqvist H, Veliça P, Barbieri L, Gameiro PA, Bargiela D, Gojkovic M, Mijwel S, Reitzner SM, Wulliman D, Ahlstedt E, Ule J, Östman A, and Johnson RS. (2020). Cytotoxic T-cells mediate exercise-induced reductions in tumor growth. Elife 9. doi: 10.7554/eLife.59996
  • Gameiro PA and Struhl K. (2018). Nutrient deprivation elicits a transcriptional and translational inflammatory response coupled to decreased protein synthesis. Cell Reports 24(6):1415-1424. doi: 10.1016/j.celrep.2018.07.021 | Comment in Trends Biochem Sci 43 (11), 849-852 ‘Translation Links Nutrient Availability with Inflammation’. doi: 10.1016/j.tibs.2018.08.010
  • Okazaki A, Gameiro PA, Christodoulou D, Laviollette L, Schneider M, Chaves F, Stemmer-Rachamimov A, Yazinski SA, Lee R, Stephanopoulos G, Zou L, and Iliopoulos O. (2017). Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers. Journal of Clinical Investigation. 127(5): 1631–1645. doi: 10.1172/JCI87800 | Comment in Nat Rev Nephrol 13 (6), 320 ‘Kidney Cancer: Targeting Metabolism in RCC’. doi: 10.1038/nrneph.2017.57
  • Gameiro PA, Yang J, Metelo AM, Pérez-Carro R, Baker R, Wang Z, Arreola A, Rathmell WK, Olumi A, López-Larrubia P, Stephanopoulos G, and Iliopoulos O. (2013). In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation. Cell Metabolism 17(3):372-85. doi: 10.1016/j.cmet.2013.02.002 | Comment in Nat Rev Cancer 13 (5), 293 ‘Metabolism: Glutamine connections’. doi: 10.1038/nrc3515
  • Gameiro PA, Laviolette LA, Kelleher JK, Iliopoulos O, and Stephanopoulos G. (2013). Cofactor balance by nicotinamide nucleotide transhydrogenase (NNT) coordinates reductive carboxylation and glucose catabolism in the TCA cycle. Journal of Biological Chemistry 288(18):12967-77. doi: 10.1074/jbc.M112.396796 | Paper of the week
  • Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, and Stephanopoulos G. (2012). Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481 (7381):380-4. doi: 10.1038/nature1060

Book Chapters:

  • Patrício JS*, Mendes*, and Gameiro PA. Mitochondrial energy metabolism in cancer, immunoregulation and anti-tumour response. Springer Nature 2025. In press. *Equal contribution
  • Patrício JS, Guerreiro ACL*, Gameiro PA*, and Morello J*. Mass spectrometry as a tool for metabolomics in cancer. Springer Nature 2025. In press. *Equal contribution
  • 2014 | InnoCentive Award: “Real Time Monitoring of Steroid Metabolites and Metabolic Flux”
  • 2008 | BSc top3% merit prize, University of Coimbra, Portugal
  • 2007 | BSc top3% merit prize, University of Coimbra, Portugal
  • 2006 | BSc merit prize, BPI bank, Portugal
  • 2018 | Metabolic Gene, Enzyme, and Flux Targets for Cancer Therapy (US Patent No. US10064885B2).
    Inventors: Stephanopoulos G, Metallo CM, Kelleher JK, Iliopoulos O, and Gameiro PA.
  • Iosifina Foskolou  - Sanquin Research, Amsterdam, The Netherlands | RNA and immune regulation
  • Cristina Santos - Hospital D. Estefânia (ULS São José), Lisboa | Hereditary retinopathies
  • Sandra Jacinto - Hospital Dona Estefânia (ULS São José), Lisboa | Mitochondrial disorders
  • Jernej Ule - King’s College London (KCL), London, UK | CLIP resources and bioinformatics
  • Othon Iliopoulos - Harvard Medical School (HMS), Boston MA, US | Hypoxia cell models

Principal Investigator

Paulo Gameiro
Principal Investigator

Team

André Minderico
MSc Student
Leonor Pestana
Visiting Researcher