CATALYTIC ACTIVITY OF COMPLEX-I IN CELL-LINES THAT POSSESS REPLACEMENT MUTATIONS IN THE ND GENES IN LEBERS HEREDITARY OPTIC NEUROPATHY

Short-chain ubiquinone analogues act as electron accepters and as inhi bitors in the lymphoblast mitochondria of ND1/3460 mutants, which indi cates structural changes in the ubiquinone-binding domain of Complex I in this mutant. The ND4/11778 mutant and two secondary ND5 mutants st udied are associated with reductions of at least 50, 35 and 30% in the catalytic rate constant, respectively. However, the efficiency of oxi dative phosphorylation is unaffected in all these ND mutants. The rate of respiration is only slightly limited by Complex I in lymphoblast m itochondria. Consequently, there is a 30-35% reduction in the electron flow through Complex I compared with that through Complex II, and an increased lactate/pyruvate ratio, in the ND1 and ND4 mutants, but thes e factors were unaffected in the secondary ND5 mutants. Energy metabol ism is thus less severely affected in the secondary mutants than in th e primary mutants, which supports the division into these two categori es. An increased ubiquinone-10 content in the mitochondrial membrane o f all the mutants, and enhanced succinate dehydrogenase and citrate sy nthase activities in the ND4 mutant, are proposed to be compensatory c hanges. The efficiency of these changes and the level of kinetic limit ation of respiration by Complex I in each tissue are proposed to deter mine the clinical development of the disease.