Mutations in subunit 6 of the F1F0-ATP synthase cause two entirely different diseases

A lowered efficiency of oxidative phosphorylation was recently found in a Leber hereditary optic neuropathy (LHON) proband carrying a mutation in the mtDNA gene for subunit 6 of the membrane-bound F-0 segment of the F1F0-ATP synthase [9], This phenotype was transferred to cytoplasmic hybrid cells together with the mutation, proving its functional significance, Increasing the respiratory rate in the mitochondria from this mutant raised the ATP/2e(-) ratio back to normal values, A different mutation in the same mtDNA gene has been found in patients with the NARP syndrome [10], Although the ATP/2e(-) ratio is also decreased in this mutant, in this case an increase in the respiratory rate could not compensate for it, Whilst both mutations affect submit 6 of the proton-translocating F-0 segment, the LHON mutation induces a proton leak whereas the NARP mutation blocks proton translocation, Hence, the latter will have much more destructive metabolic consequences in agreement with the large clinical differences between the two diseases. (C) 1997 Federation of European Biochemical Societies.