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Dominant optic atrophy (DOA) is characterized by retinal ganglion cell degeneration leading to optic neuropathy. A subset of DOA is caused by mutations in the OPA1 gene, encoding for a dynamin-related GTPase required for mitochondrial fusion. The functional consequences of OPA1 mutations in DOA patients are still poorly understood. This study investigated the effect of five different OPA1 pathogenic mutations on the energetic efficiency and mitochondrial network dynamics of skin fibroblasts from patients. Although DOA fibroblasts maintained their ATP levels and grew in galactose medium, i.e. under forced oxidative metabolism, a significant impairment in mitochondrial ATP synthesis driven by complex I substrates was found. Furthermore, balloon-like structures in the mitochondrial reticulum were observed in galactose medium and mitochondrial fusion was completely inhibited in about 50% of DOA …