Mitochondrial F-type ATP synthase: multiple enzyme functions revealed by the membrane-embedded F O structure.

Of the two main sectors of the F-type ATP synthase, the membrane-intrinsic F _O domain is the one which, during evolution, has undergone the highest structural variations and changes in subunit composition. The F _O complexity in mitochondria is apparently related to additional enzyme functions that lack in bacterial and thylakoid complexes. Indeed, the F-type ATP synthase has the main bioenergetic role to synthesize ATP by exploiting the electrochemical gradient built by respiratory complexes. The F _O membrane domain, essential in the enzyme machinery, also participates in the bioenergetic cost of synthesizing ATP and in the formation of the cristae , thus contributing to mitochondrial morphology. The recent enzyme involvement in a high-conductance channel, which forms in the inner mitochondrial membrane and promotes the mitochondrial permeability transition, highlights a new F-type ATP synthase role. Point mutations which cause amino acid substitutions in F _O subunits produce mitochondrial dysfunctions and lead to severe pathologies. The F _O variability in different species, pointed out by cryo-EM analysis, mirrors the multiple enzyme functions and opens a new scenario in mitochondrial biology.