Personalized Mitochondrial Medicine (PerMiM)

Mitochondrial disorders affect the cellular energy metabolism of the human body. They cause a clinically and genetically highly diverse group of individually rare, but collectively frequent, severely disabling human diseases for which no causal treatment exists. However, a growing subgroup is amenable to treatment with e.g. cofactors (vitamin B1, B2, coenzyme Q). Biochemically, patient derived tissues show impaired mitochondrial energy metabolism and base functional validation of genetic findings as well as development of therapeutic compounds. Next Generation Sequencing (NGS) techniques have revolutionized the diagnostics for mitochondrial disease. However, still half of the affected individuals remain without a diagnosis after Whole Exome Sequencing (WES), investigating all human genes. Hence, improvement of genetic diagnostics by integrating multi omics techniques (Whole Genome Sequencing [WGS], RNA sequencing of all expressed genes [RNA-seq], investigation of all expressed proteins [Proteomics]) is highly sought after as it bases personalized management of disease. The Personalized Mitochondrial Medicine (PerMiM) consortium will leverage on the existing international multi-center rare-disease project GENOMIT integrating the national German/Austrian/Italian networks and National centres in France and China. The PerMiM consortium collectively identifies about 700 novel cases annually. This global collaborative leads to the largest collection of multi-omics data pertaining mitochondrial disease. We incorporate groups with unique expertise for biochemical and genetic diagnostics, the clinical management of mitochondrial disease and computational scientists who have developed multi-omics databases and statistical models for diagnostics. PerMiM translates biochemical and genetic research to patient care by establishing an integrated multi-omics pipeline to increase the diagnostic yield and by implementing a high-throughput pre- clinical screening to validate biomarkers and guide management. It will further examine clinical diagnostics and management within the consortium to establish evidence based best practice, diagnostics and care for mitochondrial disease patients. Only the joined forces of the PerMiM consortium allow reaching the critical mass of patients needed to achieve these aims.

Mitochondria are the powerhouses of our cells and generate the fuel for all cellular processes, the fuel for life. Mitochondrial diseases are a growing group of currently more than 400 different genetic disorders affecting the energy metabolism. One can imagine that a dysfunctional energy metabolism can lead to numerous signs and symptoms, that are burdensome for the affected individual and often lead to death in (early) childhood. Often the way to diagnosis is long and experienced as "diagnostic odyssey". With no causative therapies available, individual supportive management is key. With the PerMiM grant we were able to improve several aspects of our patient care from the diagnostic process to the personalised management. We evaluated the psychological experience of parents during the diagnostic process which enabled us to improve this process. Together with our collaborators we were able to identify numerous novel mitochondrial diseases and to learn about that underlying pathomechanism which is essential for future precision treatment. Most importantly this grant enabled us to explore individual treatment approaches for many patients. Especially, using quite simple interventions like diets enriched in fat or specific proteins, we were able to show improvement in several burdensome conditions like epileptic seizures, prevent liver failure or to improve muscle power and mobility. Together all these little steps make a big difference in the daily life activities and quality of life of affected individuals and their families. Our work was recognized in the international research community and the principal investigator was invited to give lectures and workshops at important European meetings and also received a regional distinction for her work in the field (Kulturförderpreis der Stadt Salzburg 2023).