A redox cycler-based therapeutic strategy against respiratory chain dysfunction-related mitochondrial diseases: towards the clinic

Mitochondria are central organelles within the cells as they are responsible for the production of ATP, a molecule which is the “Coin of Energy” that gives energy for many biochemical cellular processes. ATP is produced thanks to the function of the respiratory chain complexes located in the inner mitochondrial membrane. Genetic defects in these complexes result in energy failure and metabolic derangements.  The resulting mitochondrial dysfunction and lowered ATP production affects organs and tissues with high energy demand, such as the brain and muscle. Defects in the respiratory chain Complexes I and III are associated with a wide range of clinical presentations ranging from movement disorders to growth retardation and early death. We have recently identified some small molecules that are able to “replace” defective Complex I and Complex III function in intact cells derived from patients and to increase the level of ATP. Importantly, these molecules showed beneficial effects also in mouse models of complex I and complex III dysfunction-related genetic diseases and significantly ameliorated movement disorders, without inducing toxicity. Our project therefore aims to transform these findings into a therapy for some of the mitochondrial diseases. To this end, we propose the development of an appropriate strategy for drug delivery, ensuring a prolonged and steady supply within the therapeutic window. Altogether, our study identifies novel molecules with a strong potential of efficiently restoring mitochondrial function and thus ameliorating the clinical presentations associated with Complex I and III dysfunction.