FDX1-dependent and independent mechanisms of elesclomol-mediated intracellular copper delivery

Abstract

Recent studies have uncovered the therapeutic potential of elesclomol (ES), a copper-ionophore, for copper deficiency disorders. However, we currently do not understand the mechanism by which copper brought into cells as ES–Cu(II) is released and delivered to cuproenzymes present in different subcellular compartments. Here, we have utilized a combination of genetic, biochemical, and cell-biological approaches to demonstrate that intracellular release of copper from ES occurs inside and outside of mitochondria. The mitochondrial matrix reductase, FDX1, catalyzes the reduction of ES–Cu(II) to Cu(I), releasing it into mitochondria where it is bioavailable for the metalation of mitochondrial cuproenzyme— cytochrome c oxidase. Consistently, ES fails to rescue cytochrome c oxidase abundance and activity in copper-deficient cells lacking FDX1. In the absence of FDX1, the ES-dependent increase in cellular copper is attenuated but not abolished. Thus, ES-mediated copper delivery to nonmitochondrial cuproproteins continues even in the absence of FDX1, suggesting alternate mechanism(s) of copper release. Importantly, we demonstrate that this mechanism of copper transport by ES is distinct from other clinically used copper-transporting drugs. Our study uncovers a unique mode of intracellular copper delivery by ES and may further aid in repurposing this anticancer drug for copper deficiency disorders.

Addressing the gaps in homeostatic mechanisms of copper and copper dithiocarbamate complexes in cancer therapy: a shift from classical platinum-drug mechanisms

“…127 Cuproptosis is primarily brought on by increased copper build-up and mitochondrial proteotoxic stress, which is mediated by Ferredoxin 1 (FDX1). 128 Elesclomol, an anticancer drug that targets mitochondrial metabolism, binds and transfers copper (Cu 2+ ) from the external environment to intracellular compartments. 129 Elesclomol is a powerful copper ionophore and stimulates copperdependent cell death.…”

Copper homeostasis and cuproptosis in cancer immunity and therapy

“…FDX1 can rescue elesclomol‐induced copper‐dependent cell death 2 . In addition, elesclomol‐based copper transfer to non‐mitochondrial cuproproteins continues even in the context of FDX1 loss, demonstrating an alternative machinery of copper release 69 . The machinery of copper transport via elesclomol differs from other clinically utilized copper transport compounds.…”

“…2 In addition, elesclomol-based copper transfer to non-mitochondrial cuproproteins continues even in the context of FDX1 loss, demonstrating an alternative machinery of copper release. 69 The machinery of copper transport via elesclomol differs from other clinically utilized copper transport compounds. In human cancer cells, FDX1 expression associates with prognosis, tumor immunity, and drug sensitivity, which is attenuated by elesclomol, without activation of caspases 3 and 7.…”

From Monomers to Hexamers: A Theoretical Probability of the Neighbor Density Approach to Dissect Protein Oligomerization in Cells

“…The complex interplay of proteins coming together to form larger structuresknown as oligomerizationhas far-reaching effects on how cells function and maintain their stability. − Research has consistently shown that proteins often act in their combined or “oligomeric” forms for key cellular processes, such as regulating genes and controlling enzyme activity. − The behavior of these protein assemblies is not solely determined by their individual properties but is also shaped by the specific conditions within the cell. − While in vitro studies provide immensely valuable information, they often fail to fully capture the true essence of protein behaviors in a cellular context. For example, they might miss the effects of changes in cellular components or neglect variables like protein concentration and post-translational modifications.…”