Mitochondrial Dynamics of Proximal Tubular Epithelial Cells in Nephropathic Cystinosis.

Abstract

Nephropathic cystinosis is a rare lysosomal storage disorder caused by mutations in CTNS gene leading to Fanconi syndrome. Independent studies reported defective clearance of damaged mitochondria and mitochondrial fragmentation in cystinosis. Proteins involved in the mitochondrial dynamics and the mitochondrial ultrastructure were analyzed in CTNS-/- cells treated with cysteamine, the only drug currently used in the therapy for cystinosis but ineffective to treat Fanconi syndrome. CTNS-/- cells showed an overexpression of parkin associated with deregulation of ubiquitination of mitofusin 2 and fission 1 proteins, an altered proteolytic processing of optic atrophy 1 (OPA1), and a decreased OPA1 oligomerization. According to molecular findings, the analysis of electron microscopy images showed a decrease of mitochondrial cristae number and an increase of cristae lumen and cristae junction width. Cysteamine treatment restored the fission 1 ubiquitination, the mitochondrial size, number and lumen of cristae, but had no effect on cristae junction width, making CTNS-/- tubular cells more susceptible to apoptotic stimuli.

• Authors: Domenico De Rasmo, Anna Signorile, Ester De Leo, Elena V Polishchuk, Anna Ferretta, Roberto Raso, Silvia Russo, Roman Polishchuk, Francesco Emma, Francesco Bellomo
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 1 (Dec 26 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 31888107 (Publication Type: Journal Article)

Chemical References

• Amino Acid Transport Systems, Neutral
• CTNS protein, human
• FIS1 protein, human
• Membrane Proteins
• Mitochondrial Proteins
• Cysteamine
• Ubiquitin-Protein Ligases
• parkin protein
• GTP Phosphohydrolases
• MFN2 protein, human
• OPA1 protein, human

Topics

• Amino Acid Transport Systems, Neutral (genetics)
• Cells, Cultured
• Cysteamine (pharmacology)
• Cystinosis (genetics, metabolism)
• Epithelial Cells (cytology, drug effects, metabolism)
• GTP Phosphohydrolases (metabolism)
• Humans
• Kidney Tubules, Proximal (cytology, drug effects, metabolism)
• Membrane Proteins (metabolism)
• Mitochondria (drug effects, metabolism)
• Mitochondrial Dynamics (drug effects)
• Mitochondrial Proteins (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination