The ATP synthase in human mitochondria is a membrane bound assembly of 29 proteins of 18 kinds . All but two membrane components are encoded in nuclear genes, synthesized on cytoplasmic ribosomes and imported into the matrix of the organelle. Here, they are assembled into the complex with ATP6 and ATP8, the products of overlapping genes in mitochondrial DNA . By CRISPR-Cas9, we have disrupted individual human genes for the nuclear encoded subunits in the membrane portion of the enzyme. In each case, this leads to the formation of an intermediate vestigial ATPase complex. We have characterized these complexes . Another vestigial ATPase has been characterized from ρ0-cells, which are devoid of subunits ATP6 and ATP8 . These vestigial complexes provide a description of the pathway of assembly of the membrane domain (Fig. – Assembly summary). The key intermediate complex in this pathway, E, consists of the F1-c8 complex inhibited by the ATPase inhibitor protein, IF1, and attached to the peripheral stalk, with subunits e, f and g associated with the membrane domain of the peripheral stalk. This intermediate provides the template for insertion of ATP6 and ATP8 which are synthesized on mitochondrial ribosomes. The association of ATP6 and ATP8 with the complex is stabilized by the addition of the 6.8 proteolipid, and the complex is coupled to ATP synthesis at this point. A structure of the dimeric yeast Fo membrane domain  is consistent with this model of assembly.
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