The terminal membrane-bound subunit of complex I (ND5), in addition to a distinct P side path, hosts another molecular feature that may play an important role in gated proton transfer in complex I and related enzymes. We call it a histidine switch (Fig. ), based on a highly conserved histidine residue in TMH8. This histidine is not conserved in ND2/ND4 antiporterlike subunits of complex I, but is unique to the terminal ND5 subunit. An important mechanistic role of this histidine residue was first proposed by Djurabekova et al. based on MD simulations of complex I from Thermus thermophilus where it was seen to occupy two different positions . In several high-resolution structures of complex I, histidine has indeed been observed to occupy either of the two positions. In the recent high-resolution cryoEM structure of the Mrpantiporter from Bacillus pseudofirmus (79), the corresponding histidine was found to occupy two alternative locations (A and B), which were studied by MD simulation approaches. It was observed that histidine with δ-nitrogen protonated stabilized in alternative location (A) by a hydrogen bond with a conserved threonine, whereas when ε nitrogen is protonated, neutral histidine interacts with a hydrogen bond with a conserved serine, occupying alternative location B. A doubly protonated histidine occupies a third location somewhat equidistant from A and B locations. Not only does the protonation state of the histidine side chain determine the preferred conformation, but also the charge state of neighboring residues plays a role . Since, respiratory complex I and Mrp antiporter (both reversible enzymes) catalyze proton transfer in opposite directions under normal conditions, it is likely that the histidine switch functions in inverse ways in the two enzymes (Fig. ). We suggest that the histidine not only bridges a gap in the central hydrophilic axis, but also enables the uptake of protons from the N side. (Fig. ). Thus, in Mrp antiporters, it transfers protons to the cytoplasm and to the central axis that extends towards the subunits conducting sodium transport.