A novel therapeutic strategy against mitochondrial respiratory chain dysfunction-linked diseases.

Abstract

Mitochondrial diseases result from a decreased oxidative phosphorylation (OXPHOS) that leads to a broad spectrum of incurable pathologies. Our goal was to understand whether membrane permeant small molecule(s) can be exploited to treat OXPHOS-related diseases as an alternative to gene therapy. Therefore, we selected some molecules for their ability to replace the redox functions of complex III and among them identified pyocyanin as a promising agent. Pyocyanin is a bacterial redox cycler that can shuttle electrons from reduced coenzyme Q to cytochrome c, acting as an electron shunt. Sub-μM dose of pyocyanin is harmless, restores respiration and increases ATP production in Ttc19-/- mouse embryonic fibroblasts as well as in fibroblasts from patients harboring pathogenic mutations in three different assembly/stabilization factors of complex III (namely, TTC19, BCS1L and LYRM7). The drug normalized the mitochondrial membrane potential, mildly increased ROS production, and triggered mitochondrial biogenesis. These in vitro effects were confirmed in both Drosophila melanogasterTTC19KO, in Danio rerioTTC19KD. Here we show that pyocyanin and its newly synthesized derivative with enhanced life-time and tissue distribution exhibited a benefit in Ttc19 KO mouse model as well. Indeed, in all these models, administration of low, non-toxic concentration of pyocyanin significantly ameliorated movement proficiency, without inducing toxicity. Likewise, pyocyanin, able to receive electrons from NADH, showed a beneficial effect also in the case of cells and mice with complex I disease. Our results point to exploitation of redox cyclers for therapy against diseases due to OXPHOS dysfunction.