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

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.

Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis

“…We hypothesize that CTNS loss affects lysosomal function by hampering the delivery of newly synthesized lysosomal enzymes from Golgi to lysosomes and/or by inhibiting the maturation of these enzymes within (endo) lysosomal compartments. The latter hypothesis was confirmed by Festa et al where they have shown the impairment of lysosome proteolysis (both in vitro and in vivo) is a result of defective cathepsin activation 13 .…”

“…Recently, it has been shown that cystinosin loss-of-function compromises autophagy-mediated clearance of dysfunctional mitochondria, which are the potent source of ROS-producing compounds 13 . In this context, the αKG lowering effect of bicalutamide can be explained by its autophagy-activating properties, where it stimulates cellular exocytosis and restores endocytic cargo processing, leading to a decreased autophagy-mediated ROS production in cystinosis.…”

“…Next we evaluated the effect of CTNS loss on mammalian target of rapamycin complex 1 (mTORC1)-mediated autophagy 8,9,13 . Under normal conditions, mTORC1, is bound to the lysosomes and is responsible for regulating a wide range of cellular processes, including autophagy 14,15 .…”

Molecular Basis of Cystinosis: Geographic Distribution, Functional Consequences of Mutations in the <b><i>CTNS</i></b> Gene, and Potential for Repair

“…However, no podocyte damage was present [41]. The latter mouse model has been widely used by different research groups for studying the pathogenesis and treatment strategies in cystinosis [42,43].…”

Inhibition of microRNA-376b Protects Against Renal Interstitial Fibrosis via Inducing Macrophage Autophagy by Upregulating Atg5 in Mice with Chronic Kidney Disease

“…Additionally, autophagy, an evolutionarily conserved mechanism related to cell survival, is involved in CKD [14]. Abnormal autophagy function might be linked to kidney impairments to some extent [15]. A group of Chinese researchers revealed that miR-376b can mediate pathways related to autophagy, and autophagy-related gene 4 (Atg4) can be regulated by miR-376b [16].…”