R. Sumayao, Bernadette McEvoy, P. Newsholme
Jun 15, 2016
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21
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Journal
The Journal of Physiology
Abstract
Cystine is a disulphide amino acid that is normally generated in the lysosomes by the breakdown of cystine‐containing proteins. Previously, we demonstrated that lysosomal cystine accumulation in kidney proximal tubular epithelial cells (PTECs) dramatically reduced glutathione (GSH) levels, which may result in the disruption of cellular redox balance. In the present study, we show that lysosomal cystine accumulation following CTNS gene silencing in kidney PTECs resulted in elevated intracellular reactive oxygen species production, reduced antioxidant capacity, induction of redox‐sensitive proteins, altered mitochondrial integrity and augmented cell death. These alterations may represent different facets of a unique cascade leading to tubular dysfunction initiated by lysosomal cystine accumulation and may present a clear disadvantage for cystinotic PTECs in vivo. Cystine depletion by cysteamine afforded cytoprotection in CTNS knockdown cells by reducing oxidative stress, normalizing intracellular GSH and ATP content, and preserving cell viability.