Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice

Science. 2020 May 8;368(6491):620-625. doi: 10.1126/science.aaz8899.


Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is characterized by progressive neurological injury culminating in death, typically by 3 years of age. Severe copper deficiency leads to multiple pathologies, including impaired energy generation caused by cytochrome c oxidase dysfunction in the mitochondria. Here we report that the small molecule elesclomol escorted copper to the mitochondria and increased cytochrome c oxidase levels in the brain. Through this mechanism, elesclomol prevented detrimental neurodegenerative changes and improved the survival of the mottled-brindled mouse-a murine model of severe Menkes disease. Thus, elesclomol holds promise for the treatment of Menkes and associated disorders of hereditary copper deficiency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Cell Line
  • Copper / metabolism*
  • Copper Transporter 1 / genetics
  • Disease Models, Animal
  • Electron Transport Complex IV / metabolism
  • Hydrazines / pharmacology
  • Hydrazines / therapeutic use*
  • Male
  • Menkes Kinky Hair Syndrome / drug therapy*
  • Menkes Kinky Hair Syndrome / metabolism
  • Menkes Kinky Hair Syndrome / pathology
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Neurodegenerative Diseases / prevention & control
  • Rats


  • Copper Transporter 1
  • Hydrazines
  • elesclomol
  • Copper
  • Electron Transport Complex IV