| Summary: | Mitochondrial disorders comprise a large group of heterogeneous disorders which are characterized by impairments in the cellular energy production. One of the great challenges of mitochondrial disease is the variety of clinical features present in patients. Mitochondrial disorders affect more than one organ leading to complex multisystem dysfunctions. Tissues, in which the metabolic demand is higher, such as skeletal muscle, neurons, liver or heart are typically affected. Mutations in both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) often lead to mitochondrial disorders. Although mtDNA encodes key proteins for the normal function of the mitochondrial respiratory chain enzymes, the vast majority of the essential components and proteins needed for the maintenance and replication of the mitochondrial DNA are encoded by the nDNA. Exome sequencing in combination with bioinformatics tools has proven really effective in determining novel alterations in the genomic sequence. One aim of this thesis was to evaluate novel mutations from affected patients with combined respiratory deficiencies. As a result, mutations in C12orf65 and in the novel disease gene MiD49, associated with mitochondrial disorders, are thoroughly presented. Vitamin supplements, pharmacological agents and exercise therapy are common strategies used in patients suffering from mitochondrial disorders. It has been shown that in cell lines of patients suffering from two rare reversible infantile mitochondrial diseases (reversible infantile respiratory chain deficiency and reversible infantile hepatopathy due to TRMU deficiency) supplementation of L-cysteine resulted in an improvement in most respiratory chain complexes activities. During my PhD I studied and proved that L-cysteine supplementation was also beneficial in cells from patients suffering from common forms of mitochondrial disorders such as MELAS and MERRF as the supplementation resulted in improved mitochondrial respiratory chain function. Finally, direct conversion of fibroblasts to neuronal progenitor cells was used to model mitochondrial disorders and study the tissue specificity. This project was very challenging due to the complex characteristics of mitochondrial biology. In summary, this thesis reveals the description of novel genes and mutations associated with combined mitochondrial deficiencies. Furthermore, we detected a positive effect of L-cysteine on a subset of mitochondrial disorders, which can be the base of further therapy development.
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