Mitochondrial pathways of copper neurotoxicity: focus on mitochondrial dynamics and mitophagy

Abstract

Copper (Cu) is essential for brain development and function, yet its overload induces neuronal damage and contributes to neurodegeneration and other neurological disorders. Multiple studies demonstrated that Cu neurotoxicity is associated with mitochondrial dysfunction, routinely assessed by reduction of mitochondrial membrane potential. Nonetheless, the role of alterations of mitochondrial dynamics in brain mitochondrial dysfunction induced by Cu exposure is still debatable. Therefore, the objective of the present narrative review was to discuss the role of mitochondrial dysfunction in Cu-induced neurotoxicity with special emphasis on its influence on brain mitochondrial fusion and fission, as well as mitochondrial clearance by mitophagy. Existing data demonstrate that, in addition to mitochondrial electron transport chain inhibition, membrane damage, and mitochondrial reactive oxygen species (ROS) overproduction, Cu overexposure inhibits mitochondrial fusion by down-regulation of Opa1, Mfn1, and Mfn2 expression, while promoting mitochondrial fission through up-regulation of Drp1. It has been also demonstrated that Cu exposure induces PINK1/Parkin-dependent mitophagy in brain cells, that is considered a compensatory response to Cu-induced mitochondrial dysfunction. However, long-term high-dose Cu exposure impairs mitophagy, resulting in accumulation of dysfunctional mitochondria. Cu-induced inhibition of mitochondrial biogenesis due to down-regulation of PGC-1α further aggravates mitochondrial dysfunction in brain. Studies from non-brain cells corroborate these findings, also offering additional evidence that dysregulation of mitochondrial dynamics and mitophagy may be involved in Cu-induced damage in brain. Finally, Cu exposure induces cuproptosis in brain cells due mitochondrial proteotoxic stress, that may also contribute to neuronal damage and pathogenesis of certain brain diseases. Based on these findings, it is assumed that development of mitoprotective agents, specifically targeting mechanisms of mitochondrial quality control, would be useful for prevention of neurotoxic effects of Cu overload.

Keywords: copper; cuproptosis; fission; mitochondrial fusion; mitophagy.

Figure 1

Interference of Cu exposure with mitochondrial dynamics and mitophagy in brain cells. Cu exposure induces mitochondrial dysfunction through ROS overproduction, membrane damage, and ETC inhibition, altogether resulting in a decline in mitochondrial membrane potential. Cu exposure also promotes mitochondrial fission through DRP1 up-regulation. In contrast, mitochondrial fusion is suppressed due to down-regulation of MFN1, MFN2, and OPA1 expression. In parallel with increased mitochondrial fission, Cu exposure promotes neuronal mitophagy through PINK1/Parkin-mediated mechanism, although data from non-neuronal cells demonstrate that receptor-mediated mechanism may be also involved in Cu-induced mitophagy. The latter is considered a stress-response to Cu-induced mitochondrial dysfunction aimed at clearance of damaged mitochondria. Despite activation of mitophagy, long-term high-dose Cu exposure may dysregulate mitophagy, resulting in accumulation of damaged mitochondria and thus aggravation of Cu-induced neurotoxicity. In addition to mitochondrial dysfunction and alterations in mitochondrial quality control mechanisms, Cu overexposure also reduces mitochondrial biogenesis through down-regulation of mitochondrial biogenesis regulator PGC-1α.

Figure 2

Mechanisms of cuproptosis, a Cu-dependent form of programmed cell death. Cu2+ accumulating in mitochondria is reduced to a more toxic Cu + by FDX1. FDX1 also promotes lipoylation of proteins including DLAT by up-regulation of LIAS. Binding Cu + to lipoylated DLAT (DLAT-LA) induces protein aggregation. The latter results in proteotoxic stress that is also associated with Cu-induced loss of Fe-S cluster proteins, altogether leading to cuproptosis.