Exploiting a bacterial redox cycler against mitochondrial diseases linked to respiratory complex dysfunction

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 Complex III are associated with a wide range of clinical presentations ranging from movement disorders to growth retardation and early death. Thus, identification of small molecules able to “replace” defective Complex III function, ultimately leading to increased ATP production is of huge therapeutic interest. We have recently identified some small molecules that are able to exert such function in intact cells derived from patients with Complex III disease and to increase the level of ATP. Importantly, these molecules showed beneficial effect also in two independent animal models of this genetic disease and ameliorated movement disorders. Our project therefore aims to discover how these molecules act and whether they show beneficial effect also in mouse models. In addition, we aim to investigate possible side effects of long-term administration of these drugs. Altogether, our study will identify novel molecules with a strong potential of efficiently restoring mitochondrial function and thus ameliorating the clinical presentations associated with Complex III dysfunction.