Sazanov and colleagues have proposed a molecular mechanism primarily based on structural data. The two-electron reduction of Q bound at site 1 results in a long range proton transfer from the central hydrophilic axis of the membrane arm of complex I . This brings the negative charge of the electron to the membrane domain, which would indeed enhance the strength of the coupling between proton pumping and electron transfer. This is followed by charge rearrangements in the central hydrophilic axis and the uptake of protons from the N side of the membrane. In their mechanism, ND2 is not considered as a proton uptake route, even though several simulation studies and structures have revealed a putative proton uptake route from the N side also in the ND2 subunit . Also, the proton flow occurs from the membrane domain towards the Q tunnel via E channel (Fig. ), which is in contrast to several other mechanisms proposed, where proton transfer via E channel is from the Q tunnel region towards the antiporter-like subunits .