Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

•Knockdown of the mitochondrial protein Opa1 evokes enhanced mitochondrial Ca2+ uptake.•In humans defect of OPA1 gene induces autosomal dominant optic atrophy (ADOA).•We studied mitochondrial Ca2+ metabolism in fibroblasts of ADOA patients.•The symptoms of visual malfunction correlated with mitochondrial Ca2+ uptake.•Enhanced mitochondrial Ca2+ uptake may contribute to the progress of the disease. The most frequent form of hereditary blindness, autosomal dominant optic atrophy (ADOA), is caused by the mutation of the mitochondrial protein Opa1 and the ensuing degeneration of retinal ganglion cells. Previously we found that knockdown of OPA1 enhanced mitochondrial Ca2+ uptake (Fülöp et al., 2011). Therefore we studied mitochondrial Ca2+ metabolism in fibroblasts obtained from members of an ADOA family. Gene sequencing revealed heterozygosity for a splice site mutation (c. 984+1G>A) in intron 9 of the OPA1 gene. ADOA cells showed a higher rate of apoptosis than control cells and their mitochondria displayed increased fragmentation when forced to oxidative metabolism. The ophthalmological parameters critical fusion frequency and ganglion cell–inner plexiform layer thickness were inversely correlated to the evoked mitochondrial Ca2+ signals. The present data indicate that enhanced mitochondrial Ca2+ uptake is a pathogenetic factor in the progress of ADOA.