A REDOX CYCLER-BASED APPROACH FOR TREATING MITOCHONDRIAL DISEASES

Mitochondrial diseases stem from impaired oxidative phosphorylation (OXPHOS), causing a range of incurable pathologies. Despite intensive research, there is currently no effective pharmacological treatment. Our objective was to explore the potential use of membrane permeant small molecules as a new approach to treat OXPHOS related diseases, offering an alternative to gene therapy. Therefore, we selected some molecules for their ability to replace the redox functions of respiratory chain complex I and complex III and identified pyocyanin (PYO) as a promising agent. PYO is a bacterial redox cycler that can shuttle electrons from NAD ( H/ubiquinol to cytochrome c, acting as an electron shunt. Sub μM dose of PYO was harmless, stimulated mild superoxide anion production, restored respiration and increases ATP production in different mouse and human cell lines harboring pathogenic mutations in three different assembly/stabilization factors of complex III (namely, TTC19, BCS1L and LYRM7) as well as in mouse fibroblasts with complex I deficiency caused by Ndufs4 ablation. In the present thesis, I focused on elucidating the in vivo effects of PYO across various mouse models. We showed that administration of low, non toxic concentration of PYO and of its newly synthesized derivative with enhanced life time improved motor endurance in Ttc19 KO mouse model. Moreover, PYO significantly ameliorated coordination proficiency in Ndufs4 KO and Ttc19 KO mouse models. Of note, other redox cyclers chosen for their ability to oxidize NA ( DH/ubiquinol and reduce cytochrome c could potentially function similarly to PYO. Our results point to exploitation of redox cyclers for therapy against diseases due to OXPHOS dysfunction.