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.
Liam M Guthrie  1 ,  Shivatheja Soma  2 ,  Sai Yuan  3 ,  Andres Silva  2 ,  Mohammad Zulkifli  2 ,  Thomas C Snavely  2 ,  Hannah Faith Greene  2 ,  Elyssa Nunez  2 ,  Brogan Lynch  2 ,  Courtney De Ville  2 ,  Vinit Shanbhag  4 ,  Franklin R Lopez  5 ,  Arjun Acharya  2 ,  Michael J Petris  4 ,  Byung-Eun Kim  3 ,  Vishal M Gohil  6 ,  James C Sacchettini  6
Affiliations
  • 1. Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843, USA.
  • 2. Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
  • 3. Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA.
  • 4. Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA.
  • 5. Texas Veterinary Medicine Diagnostic Laboratory, College Station, TX 77843, USA.
  • 6. Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA. [email protected] [email protected].
PMID: 32381719 DOI: 10.1126/science.aaz8899
Abstract

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.

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