New Study Reveals Unique Copper Delivery Method in Cells, Offering Hope for Menkes Disease Treatment

Reduced FDX1 releases ES-bound Cu in vitro. (A) A schematic representation of in vitro assay to determine FDX1-mediated release of Cu from ES. (B) UV/Vis spectra of 50 µM human FDX1Red /FDX1Ox ± 50 µM ES–Cu(II) in Tris buffer (10 mM Tris, 50 mM NaCl, pH 7.5). (C) UV/Vis spectra of the BCS–Cu(I) complex in the presence of increasing concentrations (0 to 55 µM) of FDX1Red or (D) FDX1Ox protein. FDX1Ox/Red proteins were mixed with 1 mM BCS in Tris buffer, and 20 µM ES–Cu(II) was added to start the reaction. The final dimethyl sulfoxide (DMSO) concentration in the solution was 20% after injection. Credit: Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2216722120

Menkes disease is a rare genetic disorder that causes copper deficiency in infants, leading to progressive neurological injury and often culminating in death by the age of three. Despite being a lethal disease, there are no FDA-approved therapies for the treatment of Menkes disease. However, a new study conducted by a Texas A&M AgriLife Research team has uncovered a unique way in which elesclomol, an anti-cancer drug, can deliver copper in cells. The findings have important implications for the treatment of copper deficiency disorders such as Menkes disease.

Background

Copper is an essential trace element that plays a crucial role in several physiological processes, and genetic mutations that prevent copper transport across cellular membranes can result in lethal human disorders such as Menkes disease. Current therapies, such as direct administration of hydrophilic copper salts, have limited efficacy in clinical trials due to inefficient copper delivery across cellular membranes. Therefore, there is an unmet need to identify compounds that can safely and effectively transport copper across biological membranes and restore cellular copper balance.

Study Details

The study, "FDX1-dependent and independent mechanisms of elesclomol-mediated intracellular copper delivery," published in the Proceedings of the National Academy of Sciences, was conducted by a team of researchers led by Vishal Gohil, Ph.D., associate professor in the Department of Biochemistry and Biophysics in Texas A&M's College of Agriculture and Life Sciences, Bryan-College Station. The team used a combination of biochemistry, cell biology, and genetics to demonstrate that the release of copper from elesclomol occurs both inside and outside mitochondria.

Vishal Gohil, Ph.D., left, and Mohammad Zulkifli, Ph.D., right, in the Gohil Laboratory at Texas A&M University. Credit: Texas A&M AgriLife photo by Michael Miller

Previous research had shown that ferredoxin 1, FDX1, a mitochondrial enzyme, was the protein target of elesclomol. The current study showed that FDX1 releases copper bound to elesclomol by reducing it to a form of copper that cells can use. The study also demonstrated that even when FDX1 was absent, elesclomol could still bring some copper into cells in other unknown ways.

Implications

The findings of this study have important implications for the treatment of copper deficiency disorders such as Menkes disease. According to Gohil, the therapeutic potential of elesclomol for treating copper deficiency disorders was first discovered by his team. Previous research by Gohil's team showed that elesclomol could be used effectively in a mouse model to treat Menkes disease.

The current study builds on previous research by demonstrating a unique mechanism of copper delivery in cells through elesclomol. The study showed that the modes of copper release by elesclomol are distinct from those of other currently used copper-transporting drugs, which may explain the high potency of elesclomol in rectifying copper deficiency. Additionally, the use of elesclomol to treat copper deficiency disorders is at the center of a licensing agreement between The Texas A&M University System and California-based Engrail Therapeutics.

Journal Information: Mohammad Zulkifli et al, FDX1-dependent and independent mechanisms of elesclomol-mediated intracellular copper delivery, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2216722120