Assembling the mitochondrial ATP synthase

Proc Natl Acad Sci U S A.             online article

Mitochondria produce the bulk of cellular ATP and are therefore known as powerhouse of the cell. The ATP synthase uses the proton gradient across the inner membrane as driving force to produce ATP from ADP and phosphate. The ATP synthase is a multisubunit protein machinery that is composed of an inner membrane Fo domain and a matrix-exposed F1 part. The rotator domain of the Fo domain is linked via a peripheral and a central stalk to the catalytic head of the F1 region. In addition, several supernumerary subunits of the Fo region are important for assembly and dimerization of the ATP synthase. Recent studies shed light into the stepwise formation of the human ATP synthase. Strikingly, the assembly of human ATP synthase differs to the assembly of the ATP synthase in baker´s yeast Saccharomyces cerevisiae. Particularly, the formation of the proton-conducting channel by insertion of the subunits ATP6 and ATP8 is a critical step for the formation of a functional ATP synthase. In human mitochondria ATP6 and ATP8 are inserted in an assembly intermediate that contains the central rotor, supernumerary subunits, F1 domain and the peripheral stalk. In contrast, in yeast the  proton-conducting channel is formed when the rotor domain assembles with Atp6 and Atp8 that are associated with the peripheral stalk and the F1 domain. Subsequently, supernumerary subunits are added to the ATP synthase. Thus, although the overall composition of the ATP synthases of human and yeast  is largely comparable, a key step in the formation of the mature enzymes differs.