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Mitochondrial Medicine: developing treatments of OXPHOS-defects in recombinant mammalian models

Final Report Summary - MITCARE (Mitochondrial Medicine: developing treatments of OXPHOS-defects in recombinant mammalian models.)

Mitochondria are the major source of ATP, synthesized by the mitochondrial respiratory chain (MRC) through the process of oxidative phosphorylation. ATP deficiency leads to cellular dysfunction and ultimately death. In mammals, 13 mitochondrial DNA (mtDNA)-encoded subunits interact with over 70 nuclear-encoded subunits to form four of the five MRC complexes. Many additional factors are essential for the regulation of MRC activity, and the maintenance and expression of mtDNA. As a result, genetic defects affecting either genome can compromise ATP synthesis and cause human disease. There is no effective treatment for mitochondrial disorders. Major hurdles to this achievement include (i) the still incomplete molecular definition of mitochondrial disease; (ii) the poorly understood function of many disease gene products, (iii) the difficulty to rationally manipulate the complex biochemical and genetic systems underpinning mitochondrial bioenergetics.
The ultimate scope of MitCare was to investigate the physiopathological basis of mitochondrial diseases and to develop effective therapies. MitCare was an extremely successful project, which achieved outstanding results by: (i) elucidating new roles for disease-related genes and proteins, such as PITRM1, TTC19, APOPT1, and SURF1 to name a few (ii) unravelling new signalling pathways relevant mitochondrial diseases, such as the role of reactive oxygen species in supporting mitochondrial biogenesis and satellite cells differentiation in skeletal muscle, and the role of autophagy and lysosomal biogenesis in mitochondrial myopathies; (iii) developing a number of innovative experimental therapies, some of which will be translated into the clinics in the coming years. These include: the stimulation of mitochondrial biogenesis by using NAD precursors, the coordinated stimulation of autophagy and lysosomal biogenesis by rapamycin, the possibility to shape mitochondrial cristae by manipulating Opa1 levels to ameliorate the clinical phenotype of mitochondrial disease models, the use of different adeno-associated viral (AAV) vectors to deliver therapeutic genes to target different organs, the possibility to shift mtDNA heteroplasmy in vivo by using mitochondrially-targeted Zinc Finger Nucleases.