Copper is an essential transition metal that is the cofactor for the cytochrome c oxidase (CcO, complex IV) — the terminal enzyme of the mitochondrial electron transport chain that catalyses the transfer of the electrons from the cytochrome c to the molecular oxygen, forming the water and generating the proton gradient that drives the ATP synthesis. The cytochrome c oxidase is a large transmembrane protein complex that contains two copper atoms (CuA and CuB) and two heme groups (heme a and heme a3) — the CuB site is the site where the oxygen binds and is reduced to water, and the CuA site is the site where the electrons are received from the cytochrome c. Without adequate copper and functional cytochrome c oxidase, the electron transport chain cannot transfer the electrons to the oxygen, the mitochondrial ATP synthesis is impaired, the reactive oxygen species are generated (because the electron carriers upstream of the block become over-reduced and leak electrons to the oxygen), and the cell undergoes the energy failure and the oxidative stress that are the hallmarks of the copper deficiency. Beyond its role in the electron transport chain, copper is also the cofactor for the ceruloplasmin (which is the major copper-carrying protein in the blood and which is essential for the iron metabolism), for the lysyl oxidase (which is required for the cross-linking of the collagen and the elastin fibres in the blood vessels and in the skin), for the dopamine beta-hydroxylase (which converts the dopamine to the norepinephrine), and for the tyrosinase (which converts the tyrosine to the melanin). The typical dietary copper intake is 1-2mg daily (from the liver, the shellfish, the nuts, the seeds, and the dark chocolate), and the RDA is 900mcg daily for adults — but the copper deficiency is more common than generally recognised, particularly in people with the malabsorption, with the chronic diarrhoea, with the celiac disease, and with the excessive zinc supplementation (which interferes with the copper absorption).
Cytochrome c Oxidase and the Electron Transport Chain
The cytochrome c oxidase (CcO, complex IV) is the terminal enzyme of the mitochondrial electron transport chain — it receives the electrons from the cytochrome c (which carries the electrons from the complex III) and transfers them to the molecular oxygen, forming the water. This electron transfer is coupled to the pumping of the protons from the mitochondrial matrix to the intermembrane space (across the inner mitochondrial membrane), creating the electrochemical gradient (the proton motive force) that drives the synthesis of the ATP by the ATP synthase. The CcO is the rate-limiting enzyme of the electron transport chain — it regulates the rate of the oxidative phosphorylation in response to the cellular energy demand, and it is subject to the allosteric regulation by the ADP/ATP ratio and by the nitric oxide (which inhibits the CcO and thereby reduces the mitochondrial oxygen consumption when the cellular energy demand is low). Without adequate copper and functional CcO, the electron transport chain cannot operate, the NADH and the FADH2 cannot be oxidised, the mitochondrial membrane potential collapses, the ATP synthesis stops, and the cell undergoes the rapid energy failure and the cell death — because the mitochondria are unable to generate the ATP that is essential for all cellular functions.
The clinical importance of the copper for the mitochondrial function is underscored by the observation that the copper deficiency produces a characteristic reduction in the cytochrome c oxidase activity in all tissues and a corresponding impairment of the mitochondrial ATP synthesis. The copper deficiency is associated with the elevations of the lactate and the pyruvate in the blood (because the impaired oxidative phosphorylation forces the cell to rely on the anaerobic glycolysis, which produces lactate as an end product), with the elevated creatine kinase (because the muscle cell damage releases the CK into the blood), and with the exercise intolerance (because the muscle cannot generate sufficient ATP for the sustained muscle contraction). The copper deficiency myelopathy (which is one of the most devastating manifestations of the copper deficiency) is characterised by the demyelination of the posterior and lateral columns of the spinal cord (similar to the subacute combined degeneration that is seen in the vitamin B12 deficiency), producing the ataxia, the spasticity, the peripheral neuropathy, and the irreversible neurological damage that is the hallmark of the copper deficiency myelopathy.
Copper and the Iron Metabolism
Copper is also essential for the iron metabolism — it is required for the function of the ceruloplasmin (which is the major copper-carrying protein in the blood and which oxidises the ferrous iron (Fe2+) to the ferric iron (Fe3+) that is required for the transferrin binding) and for the function of the hephaestin (which is the intestinal copper-iron oxidase that is required for the iron absorption in the duodenum). Without adequate copper and functional ceruloplasmin, the iron cannot be oxidised to the Fe3+ form, the iron cannot bind to the transferrin, the iron accumulates in the tissues (particularly in the liver, the pancreas, and the heart), and the anaemia develops — the anaemia of the copper deficiency is characterised as the sideroblastic anaemia (because the iron accumulates in the mitochondria of the erythroid precursors in the bone marrow) or as the normocytic anaemia (because the red blood cells are normal in size but reduced in number). This copper-dependent anaemia is one of the most common and most treatable manifestations of the copper deficiency, and it is often misdiagnosed as the iron deficiency anaemia (which it resembles but does not respond to the iron supplementation alone).
Practical Application
For general copper supplementation, the evidence-based approach is to supplement with 1-2mg of copper daily (as copper gluconate, copper citrate, or copper bisglycinate — the forms that are well absorbed and well tolerated). The RDA of copper is 900mcg daily for adults, and the tolerable upper intake level is 10mg daily for adults (above which the copper can cause the gastrointestinal symptoms and the liver toxicity). The copper should be taken with food (to reduce the gastrointestinal irritation) and should not be taken at the same time as the zinc supplements (because the zinc competes with the copper for the absorption in the gut — a ratio of at least 15:1 of zinc to copper is recommended when both are supplemented). For comprehensive mitochondrial and haematinic support, copper pairs well with the iron (which is the primary haematinic and which requires the copper-dependent oxidation for the transport by transferrin), with the zinc (which must be balanced with the copper to prevent the zinc-induced copper deficiency), with the vitamin C (which enhances the iron absorption but which should not be taken at the same time as the copper, because the vitamin C can reduce the Cu2+ to the Cu+ and thereby interfere with the copper absorption), and with the manganese (which competes with the copper for the absorption in the gut and which should be balanced with the copper).
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