ERC FUNDED PROJECTS

For many years, mitochondria were viewed as semiautonomous organelles, required only for cellular energetics. This view has been displaced by the concept that mitochondria are fully integrated into the life of the cell and that mitochondrial function and stress response rapidly affect other organelles, and even other tissues. A recent discovery from my lab demonstrated that mitochondrial metabolism regulates lysosomal degradation (Cell Metabolism, 2015), thus opening the way to investigate the mechanism behind communication between these organelles and its consequences for homeostasis. With this proposal, we want to assess how mitochondrial crosstalk with endolysosomal compartment controls cellular homeostasis and how mitochondrial dysfunction in certain tissues may account for systemic effects on the rest of the organism. EndoMitTalk will deliver significant breakthroughs on (1) the molecular mediators of endolysosomal-mitochondria communication, and how deregulation of this crosstalk alters cellular (2), and organism homeostasis (3). Our central goals are: 1a,b. To identify metabolic and physical connections mediating endolysosomal-mitochondria crosstalk; 2a. To decode the consequences of altered interorganelle communication in cellular homeostasis 2b. To study the therapeutic potential of improving lysosomal function in respiration-deficient cells; 3a. To assess how unresolved organelle dysfunction and metabolic stresses exclusively in immune cells affects organism homeostasis and lifespan. 3b. To decipher the molecular mediators by which organelle dysfunction in T cells contributes to age-associated diseases, with special focus in cardiorenal and metabolic syndromes. In sum, EndoMitTalk puts forward an ambitious and multidisciplinary but feasible program with the wide purpose of understanding and improving clinical interventions in mitochondrial diseases and age-related pathologies.

1 498 625 €

Start date: 2017-03-01, End date: 2022-02-28

The existence of an “erythron-related regulator” that intensifies iron absorption and its release from stores to meet the requirements for red blood cells synthesis was proposed in the 1950s. Delineating this mechanism is of high biomedical importance as the pathway could be targeted to develop novel treatments for iron-restricted anemias that are very frequent but for which current therapies are ineffective (e.g. infections, inflammatory bowel disease, cancer, or chronic kidney disease) and for iron-loading anemias (e.g. thalassemias). We have recently identified the hormone erythroferrone (ERFE) and showed that it could be the long-sought erythroid regulator of iron homeostasis. ERFE suppresses the synthesis of the iron-regulatory hormone hepcidin to facilitate the recovery from anemia but leads to secondary iron overload in β-thalassemia. The potential of ERFE in the treatment of iron disorders is tremendous but understanding its mechanism of action is a prerequisite to envision ERFE-based therapies. The identification of ERFE has opened new research areas and our project will be organized around four axes. 1) Develop an assay to measure ERFE levels in human pathologies. Its contribution is not known and needs to be confirmed. 2) Identify the receptor for ERFE, the signaling pathways triggered by ERFE, and molecules with agonist/antagonist effects, a prerequisite in the development of new therapies. 3) Search for potential other erythroid regulators. We will take advantage of the Erfe-/- mice to determine whether hepcidin could be suppressed by an ERFE-independent mechanism. 4) Study the potential of ERFE manipulation in therapy in the mouse. We will first establish a proof of principle in a mouse model of anemia (B. abortus). The benefits of ERFE antagonization will be addressed in thalassemic mice. We will also examine the role of ERFE in murine models of chronic anemia: chronic kidney disease, inflammatory bowel disease, rheumatoid arthritis and infections.

1 499 235 €

Start date: 2017-05-01, End date: 2022-04-30

Mitochondria are cell organelles that provide the energetic requirements of the body. The majority of cellular ATP is produced by the membrane protein ATP synthase through a proton gradient across the mitochondrial inner membrane. Alterations in ATP synthase biogenesis can result in severe mitochondrial diseases affecting tissues with high energy requirements as brain and muscles. Mitochondrial diseases affect approximately 20 million people in the EU, causing 35 % of deaths during the first year of life of newborns. However, the available therapeutic approaches, are still extremely limited and there is no specific treatment for ATP synthase deficiencies. To improve the treatments currently available for mitochondrial diseases, the project will focus on the realization of artificial mitochondria (AM). Based on artificial lipid vesicles, AM will be fabricated by means of microfluidics methods, a powerful tool able to produce identical replicas of a given bio-inspired membrane-object. ATP synthase will be expressed and assembled within the lipid bilayer by encapsulating cell-free protein expression systems. To test the ability of AM as in-situ energy fabrication systems, targeting-AM will be endocytosed inside cultured cells and ATP synthesis will be triggered by taking advantage of the proton gradient provided by endosomes. Finally, by enclosing other plasmids encoding for diverse proteins, AM can be used as energy-factoring pockets to elicit protein expression just when internalized within cells. This novel approach may constitute an advanced new concept in gene therapy to more effectively create breakthroughs in improving human health.

1 378 000 €

Start date: 2013-12-01, End date: 2018-11-30

Tryptophan (Trp) is an essential amino acid required for protein biosynthesis and is also a biochemical precursor of metabolites which have major effects on mammalian physiology. In the gastrointestinal tract, Trp metabolism can follow three major pathways, all of which are under the control of the gut microbiota: (i) the kynurenin pathway in immune and epithelial cells via indoleamine 2,3-Dioxygenase 1, (ii) the serotonin production pathway in enterochromaffin cells via Trp hydroxylase 1 and (iii) the direct use of Trp by the microorganisms of the gut microbiota into several molecules including ligands of the Aryl Hydrocarbon Receptor. The end products of these pathways play key roles in modulating the immune response, intestinal and metabolic functions and behaviour. Several diseases which involve the gut microbiota in their pathogenesis are also impacted by Trp metabolite. This suggests that the effect of the microbiota in these diseases could be at least partially mediated by impaired Trp metabolism. We recently observed that impaired Trp metabolism by the gut microbiota is involved in inflammatory bowel disease pathogenesis and preliminary data suggest a potential role in other major human diseases. The aims of the current proposal are (i) to identify the components of the gut microbiota, including both bacteria and fungi, involved in the control of the 3 Trp metabolism pathways in the gut, (ii) to decipher the reciprocal equilibrium between the pathways and to evaluate the potential of its modulation as a therapeutic target, and finally (iii) to assess the relevance of these phenomena in human patients. This challenging project will involve multi-disciplinary aspects, from microbiology to metabolism, inflammation and medicine, the use of multiple cutting edge technologies and translational analysis from mice to human. Beside scientific importance, it will have societal impact by identifying new therapeutic strategies in several human diseases with unmet needs.

1 495 525 €

Start date: 2017-03-01, End date: 2022-02-28