Mitochondrial Dynamics of Proximal Tubular Epithelial Cells in Nephropathic Cystinosis

• Published in: International journal of molecular sciences Vol. 21; no. 1; p. 192
• Main Authors: De Rasmo, Domenico, Signorile, Anna, De Leo, Ester, Polishchuk, Elena V, Ferretta, Anna, Raso, Roberto, Russo, Silvia, Polishchuk, Roman, Emma, Francesco, Bellomo, Francesco
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26-12-2019; MDPI
• Subjects: Amino Acid Transport Systems, Neutral - genetics; Apoptosis; Atrophy; Cells, Cultured; Cristae; Cysteamine; Cysteamine - pharmacology; Cystinosis; Cystinosis - genetics; Cystinosis - metabolism; Deregulation; Disease; Electrolytes; Electron microscopy; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelium; Fanconi syndrome; GTP Phosphohydrolases - metabolism; Humans; Kidney Tubules, Proximal - cytology; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Membrane Proteins - metabolism; Metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; mitochondrial cristae; mitochondrial dynamics; Mitochondrial Dynamics - drug effects; mitochondrial fission; mitochondrial fusion; Mitochondrial Proteins - metabolism; Molecular weight; Mutation; nephropathic cystinosis; Oligomerization; Optic atrophy; Parkin protein; Phosphorylation; Proteins; Proteolysis; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Ultrastructure; mitochondrial cristae; nephropathic cystinosis; cysteamine; Fanconi syndrome; mitochondrial fission; mitochondrial fusion; mitochondrial dynamics
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21010192

Nephropathic cystinosis is a rare lysosomal storage disorder caused by mutations in
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
-/- cells treated with cysteamine, the only drug currently used in the therapy for cystinosis but ineffective to treat Fanconi syndrome.
-/- 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
-/- tubular cells more susceptible to apoptotic stimuli.