Handling of Copper and Copper Oxide Nanoparticles by Astrocytes

Abstract

Copper is an essential trace element for many important cellular functions. However, excess of copper can impair cellular functions by copper-induced oxidative stress. In brain, astrocytes are considered to play a prominent role in the copper homeostasis. In this short review we summarise the current knowledge on the molecular mechanisms which are involved in the handling of copper by astrocytes. Cultured astrocytes efficiently take up copper ions predominantly by the copper transporter Ctr1 and the divalent metal transporter DMT1. In addition, copper oxide nanoparticles are rapidly accumulated by astrocytes via endocytosis. Cultured astrocytes tolerate moderate increases in intracellular copper contents very well. However, if a given threshold of cellular copper content is exceeded after exposure to copper, accelerated production of reactive oxygen species and compromised cell viability are observed. Upon exposure to sub-toxic concentrations of copper ions or copper oxide nanoparticles, astrocytes increase their copper storage capacity by upregulating the cellular contents of glutathione and metallothioneins. In addition, cultured astrocytes have the capacity to export copper ions which is likely to involve the copper ATPase 7A. The ability of astrocytes to efficiently accumulate, store and export copper ions suggests that astrocytes have a key role in the distribution of copper in brain. Impairment of this astrocytic function may be involved in diseases which are connected with disturbances in brain copper metabolism.

The Antidiabetic Drug Metformin Stimulates Glycolytic Lactate Production in Cultured Primary Rat Astrocytes

“…As astrocytic processes cover almost completely the brain capillaries, astrocytes are rapidly exposed to any substance crossing from blood through the blood-brain barrier into the brain [21]. Astrocytes are considered to have important functions for the metabolism of the brain [22,23], in the defence of the brain against toxins and oxidative stress [24][25][26] and in the metal homeostasis of the brain [27][28][29].…”

The Proteome of Enchytraeus crypticus—Exposure to CuO Nanomaterial and CuCl2—in Pursue of a Mechanistic Interpretation

“…So far, studies on mechanisms of Cu cell uptake (see ref. 23 for a review) support evidences that CuO NM enter the cell via endocytosis and they are internalized in lysosomes where oxidation to Cu ions (Cu +/2+ ) takes place due to a low pH, allowing Cu ions to be liberated and exported into the cytosol. Excess of cytosolic Cu ions can then be stored in metallothioneins or as complex with glutathione; handled similarly to the Cu + that enters the cell from Cu salts.…”

“…In terms of numbers, CuCl 2 was more intrinsically regulated (controlled) than CuO NM, as seen from the increase in DEP for the latter with exposure time. This could be related with a different uptake mechanism of the nanoform or slower oxidation of CuO NM (i.e., release of Cu ions), hence effects of Cu ions would occur comparatively later . However, as shown by Xiao et al., the toxicity of Cu nanoparticle (NP) is mainly driven by a particle effect when organic matter is present, because of the large reduction in the Cu ions and enhanced stability of Cu NPs.…”

“…The lack of Cu exposure signals can be explained by the regulation of Cu via constitutive genes being transcribed continually. This, of course, holds true only up to a certain threshold, e.g., as studied in astrocytes—Cu accumulating brain cells—after 10 nmol Cu mg –1 protein is exceeded, substantial toxicity is observed . In contrast, CuO NM induced gene regulation, hence transcription of facultative genes seems required for equivalent effect concentrations.…”

“…This, of course, holds true only up to a certain threshold, e.g., as studied in astrocytes-Cu accumulating brain cells-after 10 nmol Cu mg -1 protein is exceeded, substantial toxicity is observed. [23] In contrast, CuO NM induced gene regulation, hence transcription of facultative genes seems required for equivalent effect concentrations. This is a clear mechanistic difference.…”