A heterozygous variant in ATP5F1B has been identified as causing a mitochondrial disease with failure to thrive despite excessive caloric intake. The results of a study published in The New England Journal of Medicine suggest that dysfunction of the encoded protein, ATP5F1B, loosens the coupling that exists between the proton gradient across the inner mitochondrial membrane in mitochondrial respiration and the formation of ATP.

The researchers detected the de novo variant in ATP5F1B in monozygotic twins. The two boys did not gain weight despite excessive caloric intake. They showed tachypnea, intermittent hyperthermia and euthyroid hypermetabolism. Investigations performed on patient fibroblasts and CRISPR/Cas9-engineered cellular models revealed decreased mitochondrial membrane potential and elevated oxygen consumption. The authors suggest that ATP5F1B dysfunction leads to greater flux of protons through complex V and less efficient ATP production. ATP5F1B forms a subunit of mitochondrial ATP synthase. This enzyme complex, which is also called complex V, is essential in mitochondrial oxidative phosphorylation and uses the proton gradient across the membrane to produce ATP.