Constantinos Demetriades

Max Planck Institute for Biology of Aging

Curriculum Vitae

Research Areas

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Nutrient Sensing & Metabolic Signalling

The mTOR signalling network orchestrates the homeostatic adaptation of cells to nutrient availability, starvation and stress. Its activity is commonly dysregulated in cancer, metabolic disease, neurological disorders, and ageing.

Research Focus

The Demetriades group investigates how nutritional cues, cellular stresses and pharmacological inhibitors control multiple interconnected cellular functions in health, disease and ageing, via the regulation of the TSC/mTOR signalling axis.
Figure 1. The Demetriades group investigates how nutritional cues, cellular stresses and pharmacological inhibitors control multiple interconnected cellular functions in health, disease and ageing, via the regulation of the TSC/mTOR signalling axis.

Because nutrients are the building blocks for cells to grow and proliferate, nutrient sensing mechanisms ensure that cells only grow when all necessary elements are available and all conditions are optimal. Our work focuses on the intricate molecular and cellular mechanisms that govern cellular growth, metabolism and protein secretion upon starvation and stress, mainly via the regulation of the TSC/mTOR signalling hub. Given the central role of mTOR in the ageing process—and that dysregulation of the nutrient sensing machinery is a hallmark of ageing—our research investigates fundamental aspects of ageing and age-related diseases.

We seek to uncover new mechanisms and principles of nutrient sensing and metabolic signalling in cells, thus expanding our view on how nutritional cues and stress stimuli influence cellular physiological responses in health, disease, and over ageing.

Our Goals

In cells lacking components of the TSC complex, mTOR demonstrates aberrant, constitutive lysosomal localization—and thus remains hyperactive—even under conditions of nutrient deprivation. Confocal microscopy images of TSC2-null cells showing mTOR (red) localizing at lysosomes (marked by LAMP2, blue) (upper right cell). Exogenous TSC2 expression (lower left cell, marked by EGFP) in starved cells restores mTOR localization, which becomes diffusely cytoplasmic.
In cells lacking components of the TSC complex, mTOR demonstrates aberrant, constitutive lysosomal localization—and thus remains hyperactive—even under conditions of nutrient deprivation. Confocal microscopy images of TSC2-null cells showing mTOR (red) localizing at lysosomes (marked by LAMP2, blue) (upper right cell). Exogenous TSC2 expression (lower left cell, marked by EGFP) in starved cells restores mTOR localization, which becomes diffusely cytoplasmic.
  • The mTOR kinase, primarily as part of the mTOR complex 1 (mTORC1), is the master growth and metabolic regulator. It functions as a sensor and a molecular rheostat that links the information from the cellular milieu to the growth properties of cells (reviewed in Fernandes & Demetriades, 2021 Front Aging). A large number of inputs converge on mTORC1 to regulate growth. Besides cell growth, mTOR activity affects the majority of cellular functions and can therefore influence organismal health, lifespan and ageing. Importantly, mutations on upstream pathway components, such as the tumour suppressor Tuberous Sclerosis Complex (TSC) proteins, can lead to mTORC1 hyperactivation, and, thus, are clinically relevant.
     
  • Our research sheds light on existing and novel molecular mechanisms of cell growth control, mainly via the regulation of TSC/mTORC1 signalling, and aims to identify and functionally characterize novel components and regulators of these complexes, focusing on their putative implementation as new targets for drug development. Given the key role of the TSC/mTOR signalling hub in virtually all cellular processes, we investigate the intricate interplay between nutrient sensing, lysosomal function & signalling, metabolism, protein secretion, and the extracellular proteome.
  • To achieve this, we combine high-throughput omics approaches (functional genomic screens, proteomics, metabolomics, interactome/proximome analyses) with state-of-the-art molecular biology, biochemistry, cell biology, gene-editing, and high-resolution microscopy techniques. We make use of established human and mouse cell lines, cancer cell lines, patient-derived cells, as well as mouse models, to identify evolutionarily conserved processes and to address multiple fundamental questions.

    Overall, our vision is to understand
    • i) How cells sense the availability of nutrients in their environment to adjust their growth, metabolism and other functions accordingly;
    • ii) How the dysregulation of these cellular mechanisms contributes to the development of human diseases and the ageing process, and
    • iii) How we can intervene pharmacologically to target these mTOR-related conditions.

Key Publications

  1. Nicastro, Brohée et al. (2023), Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor, Nat Cell Biol PMID: 37563253
     
  2. Artoni et al. (2023), Unbiased evaluation of rapamycin's specificity as an mTOR inhibitor, Aging Cell PMID: 37222020
     
  3. Gollwitzer, Grützmacher et al. (2022), A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids, Nat Cell Biol PMID: 36097072
     
  4. Nüchel et al. (2021), An mTORC1-GRASP55 signaling axis controls unconventional secretion to reshape the extracellular proteome upon stress, Mol Cell PMID: 34245671
     
  5. Demetriades et al. (2014), Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2, Cell PMID: 24529380

Curriculum Vitae

Research Areas

1
2
3