title: Mitochondrial autophagy promotes cellular injury in nephropathic cystinosis.
abstract: The molecular and cellular mechanisms underlying nephropathic cystinosis, which exhibits generalized proximal tubular dysfunction and progressive renal failure, remain largely unknown. Renal biopsies from patients with this disorder can reveal abnormally large mitochondria, but the relevance of this and other ultrastructural abnormalities is unclear. We studied the ultrastructure of fibroblasts and renal proximal tubular epithelial cells from patients with three clinical variants of cystinosis: Nephropathic, intermediate, and ocular. Electron microscopy revealed the presence of morphologically abnormal mitochondria and abnormal patterns of mitochondrial autophagy (mitophagy) with a high number of autophagic vacuoles and fewer mitochondria (P < 0.02) in nephropathic cystinosis. In addition, we observed increased apoptosis in renal proximal tubular epithelial cells, greater expression of LC3-II/LC3-I (microtubule-associated protein 1 light chain 3), and significantly more autophagosomes in the nephropathic variant. The autophagy inhibitor 3-methyl adenine rescued cell death in cystinotic cells. Cystinotic cells had increased levels of beclin-1 and aberrant mitochondrial function with a significant decrease in ATP generation and an increase in reactive oxygen species. This study provides ultrastructural and functional evidence of abnormal mitophagy in nephropathic cystinosis, which may contribute to the renal Fanconi syndrome and progressive renal injury.
authors: Department of Pediatrics, G306, 300 Pasteur Drive, Stanford, CA 94304, USA.
authors: Poonam
authors: P
authors: Sansanwal
authors: Benedict
authors: B
authors: Yen
authors: William A
authors: WA
authors: Gahl
authors: Yewei
authors: Y
authors: Ma
authors: Lihua
authors: L
authors: Ying
authors: Lee-Jun C
authors: LJ
authors: Wong
authors: Minnie M
authors: MM
authors: Sarwal
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002478:Cells, Cultured; D003554:Cystinosis / Q000503:physiopathology*; D004847:Epithelial Cells / Q000473:pathology / Q000648:ultrastructure; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000473:pathology* / Q000648:ultrastructure
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D000255:Adenosine Triphosphate