Impaired autophagy bridges lysosomal storage disease and epithelial dysfunction in the kidney

Beatrice Paola Festa, Zhiyong Chen, Marine Berquez, Huguette Debaix, Natsuko Tokonami, Jenny Ann Prange, Glenn van de Hoek, Cremonesi Alessio, Andrea Raimondi, Nathalie Nevo, Rachel H. Giles, Olivier Devuyst () and Alessandro Luciani ()
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Beatrice Paola Festa: University of Zurich
Zhiyong Chen: University of Zurich
Marine Berquez: University of Zurich
Huguette Debaix: University of Zurich
Natsuko Tokonami: University of Zurich
Jenny Ann Prange: University of Zurich
Glenn van de Hoek: Hubrecht Institute and University Medical Center Utrecht
Cremonesi Alessio: University Children’s Hospital Zurich
Andrea Raimondi: San Raffaele Scientific Institute, Experimental Imaging Center
Nathalie Nevo: INSERM U1163, Université Paris Descartes, Institut Imagine, Hôpital Necker Enfants Malades
Rachel H. Giles: Hubrecht Institute and University Medical Center Utrecht
Olivier Devuyst: University of Zurich
Alessandro Luciani: University of Zurich

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract The endolysosomal system sustains the reabsorptive activity of specialized epithelial cells. Lysosomal storage diseases such as nephropathic cystinosis cause a major dysfunction of epithelial cells lining the kidney tubule, resulting in massive losses of vital solutes in the urine. The mechanisms linking lysosomal defects and epithelial dysfunction remain unknown, preventing the development of disease-modifying therapies. Here we demonstrate, by combining genetic and pharmacologic approaches, that lysosomal dysfunction in cystinosis results in defective autophagy-mediated clearance of damaged mitochondria. This promotes the generation of oxidative stress that stimulates Gα12/Src-mediated phosphorylation of tight junction ZO-1 and triggers a signaling cascade involving ZO-1-associated Y-box factor ZONAB, which leads to cell proliferation and transport defects. Correction of the primary lysosomal defect, neutralization of mitochondrial oxidative stress, and blockage of tight junction-associated ZONAB signaling rescue the epithelial function. We suggest a link between defective lysosome-autophagy degradation pathways and epithelial dysfunction, providing new therapeutic perspectives for lysosomal storage disorders.

Date: 2018
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DOI: 10.1038/s41467-017-02536-7

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