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CORDIS

Deciphering the Roles of the Salvage and De Novo Pathways of Nucleotide’s Metabolism in Mitochondrial DNA Maintenance

Project description

Mitochondrial diseases: the role of nucleotide metabolism

Mitochondria are unique organelles not only because they produce the energy required by the cell but also because they have their own mitochondrial DNA. Synthesis of both mitochondrial and nuclear DNA requires deoxynucleotides triphosphates (dNTPs) which are either produced de novo or through salvage pathways, utilising other molecules as start material. Funded by the Marie Skłodowska-Curie Actions programme, the MITO-GARAGE project seeks to understand how enzymes implicated in the metabolism and production of dNTPs may be implicated in mitochondrial diseases. Results will provide important insight into basic metabolic processes and mitochondrial pathophysiology.

Objective

Mitochondrion is a crucial integrator of various cellular metabolic pathways in the intermediary metabolism, and it has the ability to produce oxidatively-derived energy by the oxidative phosphorylation (OxPhos) system. The OxPhos complexes are composed of subunits encoded by both mtDNA and nuclear DNA (nDNA), and mutations in either class of genes can cause severe OxPhos defects, leading to mitochondrial diseases (MD). Remarkably, the mitochondrion is unique among the cell's organelles, as it contains its own DNA (mtDNA). The deoxynucleotides triphosphates (dNTPs) required for mtDNA synthesis are produced by the salvage pathway in the own mitochondrion. However, recent data suggest that de novo pathway for dNTPs synthesis is also critical for mtDNA replication. In fact, defects in enzymes involved the de novo pathway have been recently reported as causes of MD. MITO-GARAGE aims to better understand how the different pathways involved in dNTPs metabolism work in mtDNA replication and to develop therapeutic strategies when it is impaired. This will allow us to better comprehend basic metabolic processes and their integration in pathophysiological and therapeutic aspects for MD. With that purpose, we will use unique in vitro and in vivo models with defects in RRM1, GUK1 and COQ2, and a combination of modern and classical reductionist approaches. MITO-GARAGE will be carried out in international-recognized groups at Columbia University and the University of Granada. The workplan includes one key short visit to learn an specific technology; training in basic-clinic and public-private partnerships; training in academic skills; scientific and non-scientific work-packages, tasks, milestones and deliverables; a contingency plan; the landscape for results’ exploitation and the development of a career plan. Overall, MITO-GARAGE clearly define the four-way transfer of knowledge and will achieve significant advances in the progress of the hyper-personalized medicine.

Funding Scheme

MSCA-PF - MSCA-PF

Coordinator

UNIVERSIDAD DE GRANADA
Net EU contribution
€ 261 380,64
Address
CUESTA DEL HOSPICIO SN
18071 Granada
Spain

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Region
Sur Andalucía Granada
Activity type
Higher or Secondary Education Establishments
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Total cost
No data

Partners (1)