Altered mTOR signalling in nephropathic cystinosis.

Abstract

Lysosomes play a central role in regulating autophagy via activation of mammalian target of rapamycin complex 1 (mTORC1). We examined mTORC1 signalling in the lysosomal storage disease nephropathic cystinosis (MIM 219800), in which accumulation of autophagy markers has been previously demonstrated. Cystinosis is caused by mutations in the lysosomal cystine transporter cystinosin and initially affects kidney proximal tubules causing renal Fanconi syndrome, followed by a gradual development of end-stage renal disease and extrarenal complications. Using proximal tubular kidney cells obtained from healthy donors and from cystinotic patients, we demonstrate that cystinosin deficiency is associated with a perturbed mTORC1 signalling, delayed reactivation of mTORC1 after starvation and abnormal lysosomal retention of mTOR during starvation. These effects could not be reversed by treatment with cystine-depleting drug cysteamine. Altered mTORC1 signalling can contribute to the development of proximal tubular dysfunction in cystinosis and points to new possibilities in therapeutic intervention through modulation of mTORC-dependent signalling cascades.

• Authors: Ekaterina A Ivanova, Lambertus P van den Heuvel, Mohamed A Elmonem, Humbert De Smedt, Ludwig Missiaen, Anna Pastore, Djalila Mekahli, Greet Bultynck, Elena N Levtchenko
• Journal: Journal of inherited metabolic disease (J Inherit Metab Dis) Vol. 39 Issue 3 Pg. 457-464 (05 2016) ISSN: 1573-2665 [Electronic] United States
• PMID: 26909499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Transport Systems, Neutral
• CTNS protein, human
• Cysteamine
• Mechanistic Target of Rapamycin Complex 1

Topics

• Amino Acid Transport Systems, Neutral (metabolism)
• Autophagy (physiology)
• Cells, Cultured
• Cysteamine (metabolism)
• Cystinosis (metabolism, pathology)
• Fanconi Syndrome (metabolism, pathology)
• Humans
• Kidney Failure, Chronic (metabolism, pathology)
• Kidney Tubules, Proximal (metabolism, pathology)
• Lysosomes (metabolism)
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Signal Transduction (physiology)