The single-component type-II NADH dehydrogenases (NDH-2s) serve as alternatives to the multisubunit respiratory complex？I (type-I NADH dehydrogenase (NDH-1), also called NADH:ubiquinone oxidoreductase; EC 1.6.5.3) in catalysing electron transfer from NADH to ubiquinone in the mitochondrial respiratory chain1. The yeast NDH-2 (Ndi1) oxidizes NADH on the matrix side and reduces ubiquinone to maintain mitochondrial NADH/NAD+ homeostasis. Ndi1 is a potential therapeutic agent for human diseases caused by complex？I defects2, 3, 4, 5, 6, 7, 8, 9, particularly Parkinson’s disease, because its expression restores the mitochondrial activity in animals with complex？I deficiency. NDH-2s in pathogenic microorganisms are viable targets for new antibiotics10, 11. Here we solve the crystal structures of Ndi1 in its substrate-free, NADH-, ubiquinone- and NADH–ubiquinone-bound states, to help understand the catalytic mechanism of NDH-2s. We find that Ndi1 homodimerization through its carboxy-terminal domain is critical for its catalytic activity and membrane targeting. The structures reveal two ubiquinone-binding sites (UQI and UQII) in Ndi1. NADH and UQI can bind to Ndi1 simultaneously to form a substrate–protein complex. We propose that UQI interacts with FAD to act as an intermediate for electron transfer, and that NADH transfers electrons through this FAD–UQI complex to UQII. Together our data reveal the regulatory and catalytic mechanisms of Ndi1 and may facilitate the development or targeting of NDH-2s for potential therapeutic applications.

 

Related Links:http://www.nature.com/nature/journal/v491/n7424/full/nature11541.html