Cystinosis is a disorder associated with lysosomal
cystine accumulation caused by defective
cystine efflux.
Cystine accumulation provokes a variable degree of symptoms depending on the involved tissues. Adult patients may present brain cortical
atrophy. However, the mechanisms by which
cystine is toxic to the tissues are not fully understood. Considering that brain damage may be developed by energy deficiency,
creatine kinase is a thiolic
enzyme crucial for energy homeostasis, and
disulfides like
cystine may alter thiolic
enzymes by
thiol/
disulfide exchange, the main objective of the present study was to investigate the effect of
cystine on
creatine kinase activity in total homogenate, cytosolic and mitochondrial fractions of the brain cortex from 21-day-old Wistar rats. We performed kinetic studies and investigated the effects of GSH, a biologically occurring
thiol group protector, and
cysteamine, the
drug used for
cystinosis treatment, to better understand the effect of
cystine on
creatine kinase activity. Results showed that
cystine inhibited the
enzyme activity non-competitively in a dose- and time-dependent way. GSH partially prevented and reversed CK inhibition caused by
cystine and
cysteamine fully prevented and reversed this inhibition, suggesting that
cystine inhibits
creatine kinase activity by interaction with the sulfhydryl groups of the
enzyme. Considering that
creatine kinase is a crucial
enzyme for brain cortex energy homeostasis, these results provide a possible mechanism for
cystine toxicity and also a new possible beneficial effect for the use of
cysteamine in cystinotic patients.