Abstract
Mitochondrial diseases impair oxidative phosphorylation and ATP production, while effective treatment is still lacking. Defective complex III is associated with a highly variable clinical spectrum. We show that pyocyanin, a bacterial redox cycler, can replace the redox functions of complex III, acting as an electron shunt. Sub-μM pyocyanin was harmless, restored respiration and increased ATP production in fibroblasts from five patients harboring pathogenic mutations in TTC19, BCS1L or LYRM7, involved in assembly/stabilization of complex III. Pyocyanin normalized the mitochondrial membrane potential, and mildly increased ROS production and biogenesis. These in vitro effects were confirmed in both DrosophilaTTC19KO and in Danio rerioTTC19KD, as administration of low concentrations of pyocyanin significantly ameliorated movement proficiency. Importantly, daily administration of pyocyanin for two months was not toxic in control mice. Our results point to utilization of redox cyclers for therapy of complex III disorders.
Highlights
Mitochondrial diseases impair oxidative phosphorylation and ATP production, while effective treatment is still lacking
When data were normalized to the ATP level measured in Ttc19+/− mouse embryonic fibroblasts (MEFs), a decrease of ATP of mitochondrial origin occurred in Ttc19−/− cells (Fig. 1l), as expected based on the decreased CIII activity observed in various tissues[21]; incubation of the TTC19Ttc19−/− cells with 0.8 or 1.5 μM PYO increased the levels of mitochondrial ATP by approximately two-fold
Since oxidative phosphorylation (OXPHOS) defects are often associated with ultrastructural alterations in cristae shape[40], we investigated whether mitochondrial morphology was altered in Ttc19−/− versus Ttc19+/− cells and whether PYO at the low concentrations had any effect on the structure of the organelle
Summary
Mitochondrial diseases impair oxidative phosphorylation and ATP production, while effective treatment is still lacking. 1.5 μM PYO caused a clear increase in basal (and stimulated) respiration rates in intact cells (Fig. 1c, d), as assessed by measuring the rate of mitochondrial oxygen consumption[38]. Low concentrations of PYO added to intact Ttc19−/− cells enhanced the ATP level (Figure S1d).
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