2. Academic Validation
  3. Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice

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

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. vgohil@tamu.edu sacchett@tamu.edu.
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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