Dottorato in BIOLOGIA CELLULARE E DELLO SVILUPPO

Titolo della tesi: Characterization of patients with mitochondrial disease: assessment of the pathological phenotype associated with genes involved in mitochondrial quality control and dynamics.

The maintenance of healthy and functional mitochondria is essential for cellular homeostasis; a first check point is provided by the organelle itself through the mitochondrial quality control and through the mitochondrial dynamics. One of the main players of the mitochondrial quality control is the Lon protease encoded by LONP1 gene, involved in mitochondrial proteostasis and in the maintenance of mitochondrial DNA. Mutations in LONP1 were associated with a multisystem disorder called CODAS (Cerebral, Ocular, Dental, Auricular, Skeletal) syndrome (Strauss et al. 2015) and, more recently, with a classical mitochondrial disease phenotype (Peter et al. 2018; Nimmo et al. 2019). Furthermore, mitochondrial dynamics involve the Drp1 protein, a large dynamin-like GTPases encoded by DNM1L gene, that is responsible for fission of mitochondria. Mutations in DNM1L gene have been associated with several neurological disorders (Schmid et al. 2019). Through the use of Next Generation Sequencing (NGS) technology, we identified new mutations in genes involved in mitochondrial quality control and dynamics. In one patient, we found three different mutations in LONP1, never described. These variants cause both energy defects and alterations in mitochondrial network. In five patients, we identified de novo dominant DNM1L variants, two of which have been never reported. Also in these cases, patients’ fibroblast displayed defects in mitochondrial morphology; interestingly, we observed, in muscle biopsies, changes in mitochondrial distribution. To date no peculiar histochemical alterations have been reported in DNM1L-mutated patients and this can represent a diagnostic tool.