Labile cellular copper pool (LCP)

The labile cellular copper pool refers to the fraction of intracellular copper that is loosely bound to low-molecular-weight ligands, such as glutathione and small peptides, making it readily available for biochemical reactions and signaling (Ge et al., 2022, Nature Reviews Cancer). Unlike the majority of cellular copper, which is sequestered within metalloenzymes or storage proteins like metallothionein, the labile pool is redox-active and must be strictly regulated to prevent oxidative stress and proteotoxic stress (Lutsenko, 2010, Journal of Biological Chemistry). Dysregulation of this pool is central to the pathogenesis of Wilson disease and Menkes disease, and it plays a critical role in promoting tumor angiogenesis and progression (Blockhuys et al., 2017, Journal of Trace Elements in Medicine and Biology). Recent discoveries have highlighted its role in 'cuproptosis,' a unique form of regulated cell death where excess copper binds directly to lipoylated components of the tricarboxylic acid (TCA) cycle, leading to protein aggregation and metabolic failure (Tsvetkov et al., 2022, Science). Pharmacological intervention targets this pool through chelating agents that remove excess copper in overload states or ionophores that deliver copper to specific tissues to either induce cell death in oncology or restore enzymatic function in neurodegeneration (Kaler, 2011, Nature Reviews Neurology). Monitoring the labile pool is essential for managing copper-related toxicities and ensuring the efficacy of metallodrug therapies.

Other names

Labile copper poolExchangeable copper poolBioavailable copper poolRedox-active copperIntracellular copper pool

Therapeutic strategies involve either the depletion of the labile copper pool via chelation to prevent toxicity and angiogenesis, or the elevation of the pool using copper ionophores to induce cuproptosis in cancer cells or restore copper-dependent enzyme activity in neurodegenerative conditions.