Congenital Hypermetabolism and Uncoupled Oxidative Phosphorylation

N Engl J Med. 2022 Oct 13;387(15):1395-1403. doi: 10.1056/NEJMoa2202949.


We describe the case of identical twin boys who presented with low body weight despite excessive caloric intake. An evaluation of their fibroblasts showed elevated oxygen consumption and decreased mitochondrial membrane potential. Exome analysis revealed a de novo heterozygous variant in ATP5F1B, which encodes the β subunit of mitochondrial ATP synthase (also called complex V). In yeast, mutations affecting the same region loosen coupling between the proton motive force and ATP synthesis, resulting in high rates of mitochondrial respiration. Expression of the mutant allele in human cell lines recapitulates this phenotype. These data support an autosomal dominant mitochondrial uncoupling syndrome with hypermetabolism. (Funded by the National Institutes of Health.).

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Diseases in Twins / genetics
  • Diseases in Twins / metabolism
  • Fibroblasts / metabolism
  • Humans
  • Male
  • Mitochondria / metabolism
  • Mitochondrial Diseases* / congenital
  • Mitochondrial Diseases* / genetics
  • Mitochondrial Diseases* / metabolism
  • Mitochondrial Proton-Translocating ATPases* / genetics
  • Mitochondrial Proton-Translocating ATPases* / metabolism
  • Mutation
  • Oxidative Phosphorylation*
  • Oxygen Consumption* / genetics
  • Oxygen Consumption* / physiology
  • Twins, Monozygotic / genetics


  • Adenosine Triphosphate
  • ATP5F1B protein, human
  • Mitochondrial Proton-Translocating ATPases

Supplementary concepts

  • Hypermetabolism due to Defect in Mitochondria