Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice
Liam M. Guthrie, Shivatheja Soma, Sai Yuan, Andres Silva, Mohammad Zulkifli, Thomas Snavely, Hannah Faith Greene, Elyssa Nunez, Brogan Lynch, Courtney De Ville, Vinit Shanbhag, Franklin R. Lopez, Arjun Acharya, Michael J. Petris, Byung‐Eun Kim, Vishal M. Gohil, James C. Sacchettini
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.