Crucial aminoacids in the F sector of the FF-ATP synthase address H across the inner mitochondrial membrane: molecular implications in mitochondrial dysfunctions.

The eukaryotic FF-ATP synthase/hydrolase activity is coupled to H translocation through the inner mitochondrial membrane. According to a recent model, two asymmetric H half-channels in the a subunit translate a transmembrane vertical H flux into the rotor rotation required for ATP synthesis/hydrolysis. Along the H pathway, conserved aminoacid residues, mainly glutamate, address H both in the downhill and uphill transmembrane movements to synthesize or hydrolyze ATP, respectively. Point mutations responsible for these aminoacid changes affect H transfer through the membrane and, as a cascade, result in mitochondrial dysfunctions and related pathologies. The involvement of specific aminoacid residues in driving H along their transmembrane pathway within a subunit, sustained by the literature and calculated data, leads to depict a model consistent with some mitochondrial disorders.