Metabolic reprogramming in hereditary diseases

Metabolic pathways are intertwined systems that act on nearly every aspect of cellular behaviour. Our research builds upon the view that ‘everything depends on everything’ to understand the mechanisms of disease in inborn errors of metabolism (IEM), with emphasis on IEM that cause tumorigenic and neurological pathologies.

IEM present complex phenotypes that are poorly explained by linear genetic-metabolic models. Our group’s goal is to address how the pathological accumulation (or deficiency) of metabolites alter biochemical processes that also rely on these substrates, such as RNA-protein interactions and modifications, and how this ultimately contributes to cell dysfunction in IEM.

To this end, we take on a multidisciplinary framework, combining mass spectrometry, next-generation sequencing (NGS) and biochemical approaches, to assess the pleiotropic effects of otherwise dead-end metabolites (DEM) in IEM cell models, focused on inborn errors of the Krebs cycle and amino acid catabolism.

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:

  • 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:

  • Barbieri L, Veliça P, Gameiro PA, Cunha PP, Foskolou IP, Bargiela D, Rundqvist H, and Johnson RS. (2021). Lactate regulation of activation in CD8+ T cells. BioRxiv. doi.org/10.1101/2021.12.14.472728
  • 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 • University of Cambridge, UK • RNA methylation in T lymphocytes
  • Jernej Ule • Kings College London and the Francis Crick Institute, UK • CLIP resources
  • Paulo J. Oliveira • CNC/CIBB, Coimbra, Portugal • mitochondria-targeted antioxidants
  • Júlio César Rocha • NOVA Medical School • studies on phenylketonuria (PKU)

Principal Investigator

Paulo Gameiro

Team

Joana de Almeida Borba