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.
Highlights
Nephropathic cystinosis (MIM 219800) is a rare inherited metabolic disease characterized by an impaired transport of the amino acid cystine out of lysosomes due to reduced or absent function of the specific carrier cystinosin, which is encoded by CTNS gene [1,2,3]
Recruitment of the GTPase dynamin-related protein 1 (Drp1) to mitochondria is a key step required for mitochondrial fission and its reversible phosphorylation was implicated in the regulation of this process
Our recent studies have shown in CTNS−/− conditionally immortalized proximal tubular epithelial cells (ciPTEC) a higher mitochondrial fragmentation index associated with lower mitochondrial potential and mitochondrial cyclic AMP levels, rescued by 24 h treatment with 100 μM cysteamine or with the cell-permeant analogue of cyclic AMP, 8-Br-cyclic adenosine monophosphate (cAMP) [8]. cAMP, is one of the major regulators of mitochondrial function [28,29,30] and dynamics [31]
Summary
Nephropathic cystinosis (MIM 219800) is a rare inherited metabolic disease characterized by an impaired transport of the amino acid cystine out of lysosomes due to reduced or absent function of the specific carrier cystinosin, which is encoded by CTNS gene [1,2,3]. Kidneys are affected at the initial stage of the disease, leading to early onset Fanconi syndrome, which is characterized by polyuria, glycosuria, phosphaturia, aminoaciduria, and urinary loss of electrolytes and low-molecular-weight proteins [4]. The cystine-depleting agent, cysteamine (MEA), significantly delays symptoms [5,6], but does not treat Fanconi syndrome and is ineffective to prevent the progression of kidney disease. In CTNS−/− cells derived from proximal tubules, mitochondrial fragmentation associated with respiratory chain dysfunction and low mitochondrial 3 ,5 -cyclic adenosine monophosphate (cAMP) levels [8]. Enhanced apoptosis [9,10], defect of autophagic flux [11,12], and endo-lysosomal dysfunction [13,14] were observed
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