Project description
Exploiting cell endogenous degradation approaches to treat mitochondrial diseases
Mitochondria are key cellular organelles responsible for energy production. Mitochondria dysfunction can be detrimental to cell viability and lead to neuromuscular disorders known as mitochondrial myopathies. The EU-funded MTPHAGYTREAT project is working on a novel approach to treat mitochondria dysfunction by inducing mitochondria degradation through the natural mechanism of removing unwanted or damaged organelles known as autophagy. To investigate this approach, researchers will develop a mouse model that recapitulates the genetic defects of human disease. This model can also serve as a platform for testing various natural compounds for the treatment of mitochondrial diseases.
Objective
Mutations in COX15 are associated to cytochrome c oxidase (COX) deficiency (OMIM: 220110), a mitochondrial disease characterized by inefficient energy production due to the accumulation of impaired mitochondria. The phenotype of a muscle-specific Cox15 knockout (Cox15sm/sm), a model of severe mitochondrial myopathy characterized by profound COX deficiency, was previously shown to be ameliorated by the coordinated induction of autophagy and lysosomal biogenesis via TFEB activation. Stimulation of mitophagy, a selective degradation of mitochondria by autophagy, is one attractive possibility to induce the elimination of damaged mitochondria and be used as a broad-spectrum treatment for mitochondrial dysfunctions. However, the role of mitophagy in this mitochondrial dysfunction was not investigated in detail. To clarify the role of mitophagy in the amelioration of Cox15sm/sm mice phenotype and explore its therapeutic potential, a Cox15sm/sm mito-QC reporter mouse has been created in the host laboratory. Mito-QC, a pH-sensitive mitochondrial targeted probe, will allow to assess unambiguously mitophagy at single cell resolution by the quantification of the number of mitolysosomes in COX-deficient myocytes. Likewise, the investigation of the mitophagy role in muscle regeneration in the Cox15sm/sm mice can have a high impact in mitochondrial diseases. MTPHAGYTREAT will thus create a new myoblast model for the evaluation of autophagy/mitophagy role in muscle regeneration. In addition, we will take advantage of Cox15sm/sm myoblasts and advanced imaging techniques to fast track the discovery of new drugs for the treatment of mitochondrial diseases by screening a library of natural compounds previously shown to be safe for humans, thus facilitating the eventual translation to the patients.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- natural sciencesbiological sciencescell biology
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Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
35122 Padova
Italy