Role of Copper on Mitochondrial Function and Metabolism

Abstract

Copper is essential for life processes like energy metabolism, reactive oxygen species detoxification, iron uptake, and signaling in eukaryotic organisms. Mitochondria gather copper for the assembly of cuproenzymes such as the respiratory complex IV, cytochrome c oxidase, and the antioxidant enzyme superoxide dismutase 1. In this regard, copper plays a role in mitochondrial function and signaling involving bioenergetics, dynamics, and mitophagy, which affect cell fate by means of metabolic reprogramming. In mammals, copper homeostasis is tightly regulated by the liver. However, cellular copper levels are tissue specific. Copper imbalances, either overload or deficiency, have been associated with many diseases, including anemia, neutropenia, and thrombocytopenia, as well as tumor development and cancer aggressivity. Consistently, new pharmacological developments have been addressed to reduce or exacerbate copper levels as potential cancer therapies. This review goes over the copper source, distribution, cellular uptake, and its role in mitochondrial function, metabolic reprograming, and cancer biology, linking copper metabolism with the field of regenerative medicine and cancer.

Evaluation of the Safety and Toxicity of the Original Copper Nanocomposite Based on Poly-N-vinylimidazole

“…Three copper atoms included in the catalytic subunits not only provide the enzyme functioning but they are also necessary for the assembly and stability of these subunits since in the absence of copper, proteins are rapidly degraded, which prevents the formation of CcO. In addition, it is known that copper deficiency can lead to a decrease in the expression of both nuclear and mitochondrial subunits of CcO [ 6 , 82 , 83 , 84 ], while an excessive non-cytotoxic content of copper in cells causes the opposite effect, namely a CcO expression level increase [ 6 , 85 ]. In this regard, the literature discusses the possibility to regulate the mitochondrial CcO functioning and the oxidative phosphorylation activity in general by introducing chelators or, conversely, additional amounts of copper into the cells, modulating the intensity of cellular metabolism and intracellular processes dependent on energy metabolism.…”

“…In addition, the liver provides the excretion of this trace element in the bile, which is the main way of copper excretion from the body. It accounts for up to 80% of the copper removed by the liver [ 2 , 4 , 6 ].…”

“…In particular, copper is a cofactor for such key enzymes as superoxide dismutase, cytochrome c oxidase (CcO), and tyrosinase [ 8 ]. However, the most important function of copper is the one associated with energy metabolism and based on the activity of mitochondrial CcO, which is a heme-copper terminal oxidase playing the role of the final acceptor in the electron transfer chain and necessary for ATP production and molecular oxygen reduction [ 6 , 9 ].…”

“…Despite the importance of copper for the cell energy metabolism and antioxidant protection, excess amounts of metal ions are extremely toxic since they can serve as a source of reactive oxygen and nitrogen species (ROS and RNS, respectively), the generation of which leads to the development of oxidative stress accompanied by membrane lipid peroxidation, damage to proteins and nucleic acids, and finally results in cell death by apoptotic or necrotic pathways [ 6 , 10 ]. In this regard, under normal physiological conditions in the cellular content, the amount of this trace element in a free state is counted as less than one free ion per cell.…”

Glyceryl Trinitrate: History, Mystery, and Alcohol Intolerance

“…This, clearly, brings into question whether there would be a sufficient amount of transition metal to fulfil this role. However, the well-known significance of copper in the NO story, through its already proven ability to catalyze the release of NO from S-nitrosothiols, via Cu + and not Cu 2+ , as established back in the 1990s (Equation ( 1)) [25], would surely make this a realistic candidate in this thionitrate chemistry, especially given its many mitochondrial roles through various copper-dependent proteins, including those linked to superoxide dismutase and cytochrome c oxidase [71].…”