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Mitochondrial Autophagy Promotes Cellular Injury in Nephropathic Cystinosis

Poonam Sansanwal^*, Benedict Yen, William A. Gahl, Yewei Ma, Lihua Ying^*, Lee-Jun C. Wong and Minnie M. Sarwal^*

*Department of Pediatrics, Stanford University, Stanford, California;
Department of Pathology, Veterans Affairs Medical Center, San Francisco, California;
Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland; and
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas

Correspondence: Dr. Minnie Sarwal, Department of Pediatrics, G306, 300 Pasteur Drive, Stanford, CA 94304. Phone: 650-723-7903 (nephrology), 650-498-5542 (transplant); Fax: 650-497-8614 (clinical), 650-723-4517 (Sarwal lab); E-mail: msarwal{at}stanford.edu or Dr. Poonam Sansanwal, Department of Pediatrics, G378, 300 Pasteur Drive, Stanford, CA 94304. Phone: 650-724-3320 (Sarwal lab); Fax: 650-723-4517; E-mail: poonams{at}stanford.edu

Received for publication April 9, 2009. Accepted for publication October 18, 2009.

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.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673