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Mitochondrial European Educational Training

Final Report Summary - MEET (Mitochondrial European Educational Training)

The overall goal of the MEET project was to train a new generation of young scientists in the field of mitochondrial medicine. After the recruitment process, 14 fellows begun their pre- or post-doctoral training in each of the four work packages, i.e. mitochondria and cancer, selection of mitochondrial DNA mutations, regulation of respiratory complexes, and therapeutic strategies. Some of them will complete the PhD program after the MEET Project is officially concluded. During the project, fellows actively attended many international scientific conferences by presenting oral papers and they have been also trained in scientific topics and in communication and management skills.
The training and experience gained in the network significantly improved future career prospects of the ESRs/ERs in industry, academia and in the health private and public sector. The top-level research in a multi-disciplinary environment as well as training in complementary skills offered in the network imparted ESRs and ERs with an excellent set of skills and helped them make effective progress in their careers. Scientific work, strictly immersed in an industrial environment, led them to a practical understanding of the research issues which are more relevant for industry. The multilayer training, offered in advanced, specific or complementary courses as well as technical workshops, made the ESRs/ERs extremely attractive for any academic institution, industrial enterprise or government organization. The scientific training program with intensive involvement of both academic and industrial partners made ESRs and ERs very valuable for highly selective positions at the frontiers of industrial and/or academic research in biomedical research.
The MEET project had a multilevel communication strategy, addressed to different audiences.
The MEET website represented the most important communication tool used by the Consortium in order to increase public awareness of mitochondrial diseases, patients voices and MEET project activities. The website is a multilingual platform and contains a specific section dedicated to Patients with a number of videos on the project and ESRs activities, targeting people with hearing disabilities. The MEET project had an obvious potential impact for the scientific community, as well as for the mito-patients, their families and international associations and for society tout court. The communication established between MEET fellows and (inter)national Mito-patients associations and foundations was an important goal to reach. Indeed, in January 2016 the Consortium organized a Symposium held in Nijmegen which focused on the most up-to-date knowledge advances regarding mitochondrial medicine in order to fill in the gap between basic/clinical research and disease. The ambition was to create a bidirectional communication: from patients to researchers and vice versa, with the crucial intermediate role of clinicians. This symposium was an important attempt not only to make the MEET fellows carefully closer to the patients, but also to make them know each other, thus creating bridges among them and a genuine direct communication. Within this frame, MEET fellows also launched a crowdfunding campaign on kapipal website for collecting money in order to support the “International Mito-Patients Network” (International Mito Patients is a network of national patient organizations involved in mitochondrial disease): the aim was to develop a standard therapy for dealing with muscular pain in mitochondrial diseases. In order to launch this campaign, fellows did a simple equation: mitochondria = energy = running, dancing, climbing, biking. Therefore, as young and motivated researchers involved in the mitochondrial field they engaged themselves in first person by running, dancing, climbing and biking to raise money in order to support mito-patients actions!The Project, that focused on ESRs training and on the increasing of the awareness of Mitochondrial diseases, allowed fellows to participate in several Partners’ technical workshops and in a Winter School managed by a SME as weel as in training courses concerning ad hoc soft skills, course which were offered by Associated Partners. This knowledge was then further disseminated in the local scientific and clinical communities, and among the general public through MEET Newsletters and Press release. Each team profited to strength and establish new scientific and clinical contacts. The project also supported the participation of fellows in international scientific conferences in which they could present their findings, learn about the progress in the field, further discuss about methods and results interpretation and find new collaborations.
Scientific WP achievements
The MEET programme was organized into 4 highly integrated WPs, whose milestones have all been achieved at the foreseen timepoints. Most scientific deliverables have also been completed and formalized into published original research articles, some of them are still in progress and about to be obtained in the form of a publication in the very near future, likely within 2017, as it is natural to occur in life science programmes. WP1 has revealed novel potential mitochondrial protein targets in the development of anti-cancer strategies, both in terms of carriers and in terms of metabolic enzymes, such as respiratory complex I subunits. Their functional role in tumor progression and in the rewiring of cancer cells’ metabolism has been investigated thoroughly in this WP, in certain cases justifying the use of mitochondrial functions inhibitors as anticancer drugs, such as the currently acclaimed metformin. Moreover, WP1 has yielded the outcome of the adjustments in dietary intervention in contrasting cancer growth, helping to define, through in vivo experiments in mice models, which type of human tumors may benefit from ketogenic diet as an approach to reduce the disease burden.
In WP2 nearly all deliverables have been achieved. This WP has focused on the pathophysiology of mitochondrial DNA mutations and has thereby investigated the modalities of transmission, which somewhat differs from the nuclear DNA and still represents several conceptual challenges. With respect to this, the WP has yielded a new platform for studying germline transmission of mtDNA and an improved understanding of the segregation of mtDNA variants during oogenesis. This is essential to reveal the mechanisms of disease transmission, in mitochondrial pathologies, some of which, however, recover spontaneously, respresenting an excellent study model to infer potential modifiers that may be used to aid cure in different mitochondriopathies. The identification of factors that potentially account for the spontaneous recovery from mitochondrial dysfunction has been carried out successfully in this WP, as has the identification of pathways and processes underpinning the selection of normal over mutant mtDNA in somatic cells, and the validation of small molecules that can induce the selection of wild-type mtDNAs. Such a translational approach has allowed to transfer the knowledge to WP4, where the involvement of the industrial partner in the development of novel drug candidates has been thorough throughout the programme. With respect to advances in diagnostics procedures, WP2 has also yielded a new method to accurately quantify rearrangements of mtDNA, which will help to predict specific types of mitochondrial DNA disorder.
Additional basic and disease mechanisms have been investigated in WP3 at the level of mitochondrial proteins, especially those of the respiratory complexes and their assembly cofactors. The relationship between mitochondrial dysfunction and complexes assembly has been assessed and determined in this WP, and one main achievement concerns the discovery of novel mutated genes responsible for previously genetically undiagnosed mitochondrial diseases, whose mechanistic role in conferring a pathological phenotype has been demonstrated. The identification of novel disease genes has overcome the deliverable expectations and these results likely represent the most immediate bench-to bedside deliverables as these info will be transferred into routinely diagnostics. Most information collected in the previous WPs, particularly WP2 and 3, have been conveyed to WP4, in which the research groups have focused on the industrial application of clinical and basic research, with the main intent to boost drug discovery for mitochondrial diseases. Besides successfully developing novel animal models based on Drosophila for the in vivo study of drugs against mitochondrial diseases, in this WP novel microscopy-based methods and protocols to evaluate the mitochondrial response to drugs have been optimized and published. Moreover, the investigation of disease models, with the aid of both animal models and patient samples, has led to the identification of targetable pathways for a specific mitochondrial disease, i.e. PKAN.

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