Metabolic reprogramming in hereditary diseases

The Krebs cycle is implicated in nearly every aspect of mitochondrial homeostasis. Our research builds upon the ‘everything depends on everything’ view to investigate how the Krebs cycle functions in homeostasis and disease, with emphasis on mitochondrial disorders (MtD).

We apply experimental and computational approaches to investigate the critical interconnections between the Krebs cycle’s activity, the OxPhos system and mitochondrial biogenesis. Our goal is to identify disease-modifying target pathways and biomarkers linked to the metabolic manifestations of MtD.

  • Tools to explore the cell: Metabolic and isotopic labelling analyses, metabolic labelling of RNA, transcriptomics (RNA-seq, iCLIP-seq), molecular tools to visualize RNA, purification of protein-RNA complexes, metabolic flux analyses.
  • Disease modelling: genetically-engineered cell lines; cell models of hypoxia and pseudo-hypoxic states; metabolic reprogramming in cell culture.
Graphical Abstract

2022-2025    “Unraveling RNA networks in inborn errors of the Krebs cycle”, “la Caixa” Foundation (Catalonia, ES). Grant number: 116925
2022-2028    “Metabolic regulation of RNA networks in immunity and inborn errors of metabolism”, Fundação para a Ciência e a Tecnologia (Lisboa, PT), Grant number: 2021.01737.CEECIND
2016-2018    “Metabolic control of RNA-protein and RNA-RNA interactions in cellular transformation”, Marie Sklodowska-Curie Actions (Brussels, BE), Grant number: 701730

ARTIGOS:

  • 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.
  • 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.
  • 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.
  • 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 | Commented in Trends Biochem Sci 43 (11), 849-852 ‘Translation Links Nutrient Availability with Inflammation’.
  • Li BB, Qian C, Gameiro PA, Liu C-C, Jiang T, Roberts TM, Struhl K, and Zhao JJ. (2018). Targeted profiling of RNA translation reveals mTOR-4EBP1/2-independent translation regulation of mRNAs encoding ribosomal proteins. Proc. Natl. Acad. Sci. U. S. A. 115, E9325–E9332.
  • 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. | Commented in Nat Rev Nephrol 13 (6), 320 ‘Kidney Cancer: Targeting Metabolism in RCC’
  • 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. | Commented in Nat Rev Cancer 13 (5), 293 ‘Metabolism: Glutamine connections’
  • Nicolay BN, Gameiro PA, Tschöp K, Korenjak M, Heilmann AM, Asara JM, Stephanopoulos G, Iliopoulos O, and Dyson NJ. (2013). Loss of RBF1 changes glutamine catabolism. Genes and Development. 27, 182–196.
  • 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. | 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.
  • Gaglio D, Metallo CM, Gameiro PA, Hiller K, Danna LS, Balestrieri C, Alberghina L, Stephanopoulos G, and Chiaradonna F. (2011). Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Molecular Systems Biology 7, 523.

 

CAPÍTULOS DE LIVROS:

  • Zhang J*, Ahn WS*, Gameiro PA*, Keibler MA, Zhang Z, and Stephanopoulos G. (2014). 13C isotope assisted methods for quantifying glutamine metabolism in cancer cells. Methods in Enzymology (542):269-89 (Chapter 19). | * Equal contribution
  • Gameiro PA, Metallo CM, and Stephanopoulos G. Systems-level analysis of cancer metabolism. Systems Metabolic Engineering pp 349–381 (Chapter 11). Springer (2012)

 

PREPRINTS:

  • Gameiro PA*, Foskolou IP*, Martens A, Kuret K, de los Mozos IR, Hozjan Ž, Kot V, Faraway R, Vermeulen M, Wolkers M, Johnson RS, Ule J. (2024). Meta-unstable mRNAs in activated CD8+ T cells are defined by interlinked AU-rich elements and m6A mRNA methylation. | * equal contribution. doi.org/10.21203/rs.3.rs-4768725/v1. Under Review
  • 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 Student 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.

PhD and Post-Doc Opportunities @ Paulo Gameiro's Lab
Grants

Contact: paulo.gameiro@nms.unl.pt 
Deadline for contact: 17th March 2023

  • Iosifina Foskolou • Sanquin Research, Amsterdam, The Netherlands • RNA and immune regulation
  • Sandra Tenreiro • chair of the “Retina & Vision”, NMS •  RPE models and retinal organoids
  • Cristina Santos • Hospital D. Estefânia (ULS São José), Lisboa •  Hereditary retinopathies
  • Sandra Jacinto • Hospital Dona Estefânia (ULS São José), Lisboa •  Mitochondrial diseases
  • Jernej Ule • King’s College London (KCL), London, UK • CLIP resources
  • Othon Iliopoulos • Harvard Medical School (HMS), Boston MA, US • hypoxia cell models

Principal Investigator

Paulo Gameiro