Mitochondrial Medicine

This programme will allow us to identify new disease-genes and proteins, to investigate disease mechanisms, and to test new interventions for effective treatment of Mitochondrial Disorders, a group of genetic maladies characterized by dysfunction of oxidative phosphorylation (OXPHOS), the energy-supplying metabolic pathway carried out by the mitochondrial respiratory chain (MRC) complexes. Thirteen MRC protein subunits are encoded by mtDNA, which adds to the genetic, functional and structural complexity of OXPHOS, and of its disorders as well. The heterogeneity of mitochondrial disorders makes the identification of effective therapy an exceedingly difficult task. However, the elucidation of many of the pathophysiological features of these conditions give us now several clues for the development of therapeutic strategies, with the ultimate goal to cure mitochondrial disease.

This project is aimed at identifying new genes responsible for mitochondrial disorders, characterized by isolated or combined defects of the mitochondrial respiratory chain (MRC) complexes by exome sequencing of human DNA samples using Illumina technology. An inter-institutional agreement between the MRC-MBU in Cambridge, UK and the Fondazione Istituto Neurologico Carlo Besta, Milan, Italy, allow us to get access to genomic DNA samples from numerous patients with biochemically defined mitochondrial diseases. To the same aim, collaborations have been established with other Research Centres in the UK, such as the Mitochondrial Disease Centre at the University of Newcastle and the Institute of Neurology at Queen Square in London; and abroad, e.g. the Max Planck Institute for Aging in Cologne, and the Institute of Human Genetics in Munich, Germany. We expect that the project will lead to the genetic definition of all or most of our cohort of probands, an achievement that will contribute to define the molecular-genetic basis of this vast group of conditions. The identification of new mitochondrial disease proteins is essential to further elucidate the pathogenesis of mitochondrial disorders, is important to complete our knowledge on the composition of the human mitochondrial proteome, and will contribute to the molecular characterization of mitochondrial energy-related pathways. This goal will be implemented by creating recombinant cell models for new mutant genes, in vitro characterization by proteomics approaches, and investigating suitable animal models, including mouse and zebrafish. Examples of gene products that will be studied include TTC19, an assembly factor for complex III; Mpv17, a mitochondrial protein of unknown function whose mutations cause profound depletion of mtDNA in livers of knockout mice and patients; FBXL4 and Apopt1, two proteins of unknown function associated with mtFDNA depletion and deficiency of cytochrome c oxidase, respectively; and Pitrm1, a mitochondrial protease we recently found mutated in patients showing a neurodegenerative disease. The molecular and functional characterization of new disease genes/proteins and pathways will underpin the development of rational therapeutic strategies. Effective therapy for OXPHOS diseases is missing. We have collected a huge series of mutant cell (fibroblast) lines and created numerous mouse recombinant lines with specific defects in genes associated with human mitochondrial disease. The availability of these tools will be exploited to develop experimental therapy transferable to humans. The translational agenda that will be implemented at the MBU will include three main strategies for experimental therapy, based on (a) Activators of mitochondrial biogenesis acting on the PGC1-alpha axis; (b) Gene replacement using adeno-associated viral vectors; (c) Xenogene targeting using alternative oxidases expressed in recombinant mouse lines.