Complex V of the respiratory chain, or ATP synthase, uses the energy created by the proton electrochemical gradient across the inner mitochondrial membrane to phosphorylate ADP to ATP. It consists of 2 functional domains F1 and Fo connected by a stalk domain. Complex V abnormalities make up the smallest percentage of known disorders of mitochondrial respiratory chain (Rodenburg RJ. Biochemical diagnosis of mitochondrial disorders. J Inherit Metab Dis. 2011;34:283–292). One wonders why this is-possibly because mutations in this complex are so deleterious to development that mutations are not compatible with life?
I recently encountered a patient with a homoplasmic variant of unknown significance in the ATP8 gene (encoding part of the Fo domain), and a constellation of features including GI dysmotility and myopathy. His medical issues have previously been attributed this variant. This represents a real clinical dilemma for me, since this variant has been described in mt haplotype N1 subgroups, and mutations of the ATP8 synthase gene (and complex V in general) are so rare, as described above.
Hilary Vernon MD PhD