Recently, we reported that in various cell lines under conditions of deenergization of the mitochondrial membrane, the release of Ca(2+) from the endoplasmic reticulum (ER) does not produce the expected activation of store-operated calcium channels (SOCs) in the plasma membrane. In the present work, we examined the activation of SOCs in fibroblasts derived from three patients with Leigh disease (LS). We identified mutations in the SURF-1 gene in all these cells. Consequently, cytochrome oxidase (COX) deficiency was found in all these (LS(COX)) 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 LS(COX) fibroblasts, the rate of Ca(2+)-inflow through SOCs was low compared to the fibroblasts from healthy individuals even after thapsigargin-induced maximal release of Ca(2+) from the ER. Moreover, the pretreatment of LS(COX) fibroblasts with a protonophore did not modify this rate. Thus, in LS(COX) fibroblasts, the activation of SOCs was naturally impaired. Our findings suggest that altered calcium metabolism, apart from severe energy production failure, may also contribute to developing pathological conditions in patients with COX-deficient Leigh disease related to SURF-1 gene mutation.
Copyright 2001 Academic Press.