Abnormal mitochondrial autophagy in nephropathic cystinosis

Autophagy. 2010 Oct;6(7):971-3. doi: 10.4161/auto.6.7.13099. Epub 2010 Oct 21.

Abstract

Cystinosis, which is characterized by lysosomal accumulation of cystine in many tissues, was the first known storage disorder caused by defective metabolite export from the lysosome. The molecular and cellular mechanisms underlying nephropathic cystinosis, the most severe form, which exhibits generalized proximal tubular dysfunction and progressive renal failure, remain largely unknown. We used renal proximal tubular epithelial (RPTE) cells and fibroblasts from patients with three clinical variants of cystinosis: nephropathic, intermediate and ocular to explore the specific injury mechanism in nephropathic cystinosis. We demonstrate enhanced autophagy of mitochondria, increase in apoptosis and mitochondrial dysfunction in the nephropathic cystinosis phenotype. Furthermore, specific inhibition of autophagy results in significant attenuation of cell death in nephropathic cystinosis. This study provides ultrastructural and functional evidence of abnormal mitochondrial autophagy in nephropathic cystinosis, which may contribute to renal Fanconi syndrome and progressive renal injury.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Child
  • Cystinosis / pathology*
  • Cystinosis / physiopathology
  • Fanconi Syndrome / metabolism
  • Fanconi Syndrome / pathology
  • Fibroblasts / cytology
  • Fibroblasts / pathology
  • Humans
  • Kidney Diseases / pathology*
  • Kidney Diseases / physiopathology
  • Kidney Tubules, Proximal / cytology
  • Mice
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mitochondria / ultrastructure