19.11: ATP Synthase: Mechanism
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased ATP synthase numbers and functionality, further leading to severe neuromuscular diseases.
Certain mutations in the genes encoding ATP synthase subunits have been recognized in both nuclear and mitochondrial genomes. For instance, a neurodegenerative disorder, Leigh syndrome, results from severe impairment of the ATP synthase mechanism due to a mutation in its α subunit. In the neuronal disease called Kufs, specific mutations lead to the accumulation of subunit c in the lysosome, reducing its abundance for normal ATP synthase assembly. In Alzheimer's, there is a cytosolic accumulation of α subunit and low expression of β subunit, causing a deficiency in ATP synthase subunits.
Furthermore, certain inhibitory compounds may bind to the ATP synthase subunits and impair their activity. For instance, rotation of the γ subunit is blocked by the binding of stilbenes, a phytochemical found in the grapevines. Aurovertin, an antibiotic, binds to the mitochondrial ATP synthase β subunit and inhibits ATP synthesis. Venturicidin binds to the c-subunit and blocks the complex's proton translocation and ATPase activity.