Assembling the mitochondrial ATP synthase

Mitochondria are known as the powerhouses of the cell. The F1Fo-ATP synthase of the mitochondrial inner membrane produces the bulk of cellular ATP. The respiratory chain complexes pump protons across the inner membrane into the intermembrane space and thereby generate a proton-motive force that drives the ATP synthase. In a fascinating molecular mechanism, the ATP synthase couples the synthesis of ATP to the transport of protons into the matrix (1⇓–3). Formation of the ATP synthase depends on the association of 17 different structural subunits of dual genetic origin. Whereas a number of assembly factors and steps have been identified in the model organism baker’s yeast, little has been known about the assembly of the human ATP synthase. In PNAS, He et al. (4) report the identification of key assembly intermediates in the formation of the ATP synthase in human mitochondria. In a tour de force, they define the molecular composition of distinct vestigial ATP synthase complexes in cell lines lacking individual subunits of the enzyme and develop a model of how the membrane-bound domain of the ATP synthase is formed (Fig. 1). Fig. 1. Assembly pathways of the mitochondrial ATP synthase. ( Upper ) Assembly of human ATP synthase. The free F1 domain or an F1–c-ring intermediate binds to the peripheral stalk. The supernumerary subunits e, g, and f associate and promote the insertion of ATP6 and ATP8. Addition of 6.8PL and DAPIT stabilizes the inserted ATP6/ATP8, leading to formation of the proton-conducting channel between ATP6 and the c-ring. The inhibitory protein IF1 that blocks ATP hydrolysis of uncoupled ATP synthase is released. ( Lower ) Assembly of yeast ATP synthase. The chaperones Atp11 and Atp12 promote formation of the F1 domain. The INAC binds to the c-ring, as well as to an … [↵][1]1To whom correspondence should be addressed. Email: nikolaus.pfanner{at}biochemie.uni-freiburg.de. [1]: #xref-corresp-1-1