Abnormal calcium homeostasis in fibroblasts from patients with Leigh disease

Recently, we reported that in various cell lines under conditions of deener gization of the mitochondrial membrane, the release of Ca2+ from the endopl asmic reticulum (ER) does not produce the expected activation of store-oper ated calcium channels (SOCs) in the plasma membrane. In the present work, w e examined the activation of SOCs in fibroblasts derived from three patient s with Leigh disease (LS), We identified mutations in the SURF-1 gene in al l these cells, Consequently, cytochrome oxidase (COX) deficiency was found in all these (LSCOX) cell lines and, thus, the main mitochondrial mechanism of generation of the electrochemical proton gradient on the mitochondrial membrane was naturally depressed. We demonstrated that, in untreated LSCOX fibroblasts, the rate of Ca2+-inflow through SOCs was low compared to the f ibroblasts from healthy individuals even after thapsigargin-induced maximal release of Ca2+ from the ER. Moreover, the pretreatment of LSCOX fibroblas ts with a protonophore did not modify this rate. Thus, in LSCOX fibroblasts , the activation of SOCs was naturally impaired. Our findings suggest that altered calcium metabolism, apart from severe energy production failure, ma y also contribute to developing pathological conditions in patients with CO X-deficient Leigh disease related to SURF-1 gene mutation. (C) 2001 Academi c Press.