Assembly of the membrane domain of ATP synthase in human mitochondria

Significance Mitochondria generate the cellular fuel ATP to sustain complex life. Production of ATP depends on the oxidation of energy-rich compounds to produce the proton motive force (pmf), a chemical potential difference for protons, across the inner membrane. The pmf drives the ATP synthase, a molecular machine with a rotary action, to synthesize ATP. We have shown that the assembly of human ATP synthase in the inner organellar membrane involves the formation of a monomeric intermediate made from 25 nuclear-encoded proteins into which the two mitochondrially encoded subunits are inserted and then sealed by association of another nuclear-encoded protein, thereby dimerizing the complex. Association of a final nuclear protein oligomerizes the dimers back-to-face along the cristae edges.