[Molecular bases of diseases caused by mutations in genes encoding subunits of ATP synthase]

ATP synthase is the last enzyme of the OXPHOS system synthesizing ATP. Mutations in either mitochondrial or nuclear genes encoding subunits of this enzyme (17 polypeptides) cause neurodegenerative diseases. The ATP synthase subunits 8 (ATP8, alias A6L) and a (ATP6) are encoded by the MT-ATP8 and MT-ATP6 mitochondrial genes, respectively. 17 diseases associated mutations were identified in five nuclear genes coding for subunits of this enzyme. 58 mutations were described in the MT-ATP6 and MT-ATP8 genes, among them 36 were deposited in MITOMAP database. For most of them neither their pathogenic character nor the mechanisms are known. This review summarizes what is known about the molecular basis of the ATP synthase deficiencies. We review the mutations in the ATP synthase genes as well as biochemical data obtained from studies of patient's cells and cybrid or yeast models. We include yeast research about drugs selection and their mechanism of action. Moreover we position the mutations into a recently published structural model of the Fo complex and discuss their structural/functional consequences.