FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA
The aim of the research
Main researcherMASSIMO ZEVIANI
The tremendous clinical, biochemical and molecular heterogeneity of mitochondrial disorders makes virtually each member of the whole mitochondrial proteome a candidate for disease.
As a result, only 40% of adult-onset disorders are currently diagnosed at the molecular level, and much lesser so in infantile syndromes. However, new technological and biocomputational tools offer the possibility of rapid and affordable analysis of the exome, i.e. the coding regions of all genes in single individuals or small families. Mitochondrial disease proteins can then be selected by exploiting predictive softwares, dedicated databases, and ex vivo experiments. MitMed is a Telethon Consortium dedicated to (i) the identification of mitochondrial disease genes and their characterization using (ii) in vitro analysis of disease proteins and (iii) creation and investigation of in vivo disease models. MitMed activities will be grouped in three Workpackages (WP). In WP1, MitMed will carry out mitochondrial disease gene hunting using exome sequencing in a large cohort of selected mitochondrial disease patients. MitMed WP2 will address the in vitro analysis of several disease gene products identified during the Telethon GGP07019 project lifetime, of which MitMed is the logical continuation. A powerful tool for the identification of proteins, called mass-spectrometry, will be applied to dissect out the partner proteins interacting with Mpv17, responsible of hepatocerebral mtDNA depletion, of its yeast ortholog Sym1, and of TTC19, a putative assembly factor of complex III whose absence causes cIII-defective, progressive neurodegeneration. MitMed WP3 will address the creation of and investigation on in vivo models, namely, knockout mice and flies for Mpv17 and TTC19; a knockout zebrafish for Mpv17; and yeast mutant strains for Mpv17/Sym1 and for SDHAF1, a complex II (cII) assembly factor that is mutated in cII-defective severe leukoencephalopathy. Any new gene identified in WP1 will then be characterized in WP2 and WP3 during the MitMed lifetime. Whenever possible, the results of the MitMed project will directly feed the activity of MitCare, a Telethon program project dedicated to the development of experimental therapy for mitochondrial disorders.