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.

Exploiting pyocyanin to treat mitochondrial disease due to respiratory complex III dysfunction / R. Peruzzo, S. Corrà, R. Costa, M. Brischigliaro, T. Varanita, L. Biasutto, C. Rampazzo, D. Ghezzi, L. Leanza, M. Zoratti, M. Zeviani, C. De Pittà, C. Viscomi, R. Costa, I. Szabo. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 12:1(2021 Apr 08), pp. 2103.1-2103.19. [10.1038/s41467-021-22062-x]

Exploiting pyocyanin to treat mitochondrial disease due to respiratory complex III dysfunction

D. Ghezzi;
2021-04-08

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.
ATPases associated with diverse cellular activities; adenosine triphosphate; animals; animals, genetically modified; cell line; drosophila melanogaster; electron transport complex III; humans; membrane potential, mitochondrial; membrane proteins; mice; mitochondrial diseases; mitochondrial proteins; molecular chaperones; oxidation-reduction; pyocyanine; reactive oxygen species; zebrafish
Settore MED/03 - Genetica Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/863426
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