Copper signalling: causes and consequences

Abstract

Copper-containing enzymes perform fundamental functions by activating dioxygen (O2) and therefore allowing chemical energy-transfer for aerobic metabolism. The copper-dependence of O2 transport, metabolism and production of signalling molecules are supported by molecular systems that regulate and preserve tightly-bound static and weakly-bound dynamic cellular copper pools. Disruption of the reducing intracellular environment, characterized by glutathione shortage and ambient Cu(II) abundance drives oxidative stress and interferes with the bidirectional, copper-dependent communication between neurons and astrocytes, eventually leading to various brain disease forms. A deeper understanding of of the regulatory effects of copper on neuro-glia coupling via polyamine metabolism may reveal novel copper signalling functions and new directions for therapeutic intervention in brain disorders associated with aberrant copper metabolism.

Critical Review of Exposure and Effects: Implications for Setting Regulatory Health Criteria for Ingested Copper

“…Key areas of controversy for copper and AD have been whether: (1) excess or deficient copper exposure causes AD and associated pathogenesis, or (2) AD causes copper dysregulation and thereby excess or deficient copper states and neurodegeneration. While age and likely high lipid intake are the greatest risk factors for developing the disease, AD is multifactorial and complex, likely with many genetic and environmental contributing factors, and these issues regarding copper have yet to be resolved (Kardos et al 2018).…”

“…At the same time, the disturbed bioavailability of copper resulting in deficiency is another feature of AD (Kaden et al 2011), although the mechanisms and the causal relationships of the reduced copper availability in AD are not well understood (Kessler et al 2006;Schafer et al 2007;Klevay 2010;Bost et al 2016;Bulcke et al 2017;Li et al 2017;Bagheri et al 2018;Kardos et al 2018). AD-associated alterations in metal-ion (primarily copper) homeostasis were found in all regions of AD brain tissue (Xu et al 2017), suggesting a pan-cerebral copper deficiency in AD.…”

“…Such a widespread brain-Cu deficiency may contribute to the pathogenesis by acting through the loss of enzyme functions in energy utilization and antioxidant defenses (Xu et al 2017). Reduced copper bioavailability to the brain may be further enhanced by the accumulation of copper in AD plaques , lipid rafts (Bagheri et al 2018), or astrocytes (Kardos et al 2018). Research suggesting that copper supplementation may be beneficial in AD include animal models either overexpressing amyloid precursor protein (APP) or APP in combination with other genes like presenilins and τ, or APP in APLP knockout mice.…”

Live‐Cell Copper‐Induced Fluorescence Quenching of the Flavin‐Binding Fluorescent Protein CreiLOV

“…The data fit well to this single binding site model with a K d value of 3.2±0.3 μ m (Figure E). This affinity, although too weak for physiological intracellular copper concentrations (as low as femtomolar), could fall in the range of Cu concentrations under pathological conditions . Without further modification, CreiLOV could be useful for detecting copper in varying environments, including extracellular copper in various systems.…”

Reduced Neutrophil Extracellular Trap (NET) Formation During Systemic Inflammation in Mice With Menkes Disease and Wilson Disease: Copper Requirement for NET Release

“…At the cellular level, copper serves as a cofactor in multiple proteins due to its redox ability (19,21,22). Its uptake (both dietary and peripheral distribution) occurs via membrane copper transporters, including CTR1 (23).…”