What is copper, and why is it vital?

In my teachings about copper, I emphasize that it’s not just a shiny metal for pipes and wires, but a vital nutrient necessary for our well-being. Key processes in our body depend on it.

According to a 2021 paper in Frontiers, copper is paramount for energy production. It is a crucial component of our mitochondria, aiding in converting nutrients into energy. Insufficient copper can result in fatigue.

Furthermore, copper deficiency may impair iron absorption, potentially leading to anemia, particularly since iron supplements can adversely affect copper levels. Copper is integral in iron utilization, which is vital for oxygen transport in the bloodstream.

Additionally, copper is essential for developing strong connective tissues such as skin, tendons, and blood vessels. Low levels can weaken these tissues, increasing injury susceptibility.

In terms of neurological health, copper is crucial for brain and nervous system development. A deficiency can disrupt nerve signaling, causing numbness, tingling, coordination issues, and cognitive impairments.

Copper also supports immune function, helping fend off infections. Low copper levels may compromise the immune response.

While insufficient copper poses risks, excessive copper can also be harmful. It can accumulate in tissues, leading to oxidative stress and conditions such as Wilson’s disease and Alzheimer's disease.

Maintaining balanced copper levels is essential. Most people receive adequate copper through a varied diet that includes nuts, seeds, shellfish, organ meats, and whole grains. However, some individuals may require supplements under medical supervision.

Copper is often overlooked, but its importance in maintaining our health and vitality should not be underestimated.

What is cuproptosis, and why is it significant?

Cuproptosis refers to a form of cell death that depends on copper. It involves the regulated elimination of cells through copper-induced pathways, illustrating the metal's role in cellular processes and the progression of diseases, especially in cancer research.

A 2023 review highlighted that researchers identified cuproptosis as a distinct type of cell death initiated by copper, differing from previously known forms.

The review noted copper's critical involvement in various signaling pathways in tumor cells. It activates essential molecules that influence cell migration and proliferation.

For instance, copper initiates receptor tyrosine kinase pathways, phosphorylating downstream proteins that promote cell growth. It also activates the PI3K-AKT pathway, which can stimulate processes that support tumor growth.

Increased interest in programmed cell death has emerged in recent years, particularly regarding whether copper-induced cell death is a unique category. With cuproptosis's mechanisms now revealed, more research is focusing on its implications in cancer.

Summary of Cuproptosis in Cancer Biology & Therapeutics

While it is impractical to reference hundreds of studies on cuproptosis, I will summarize the key points from the latest analysis encompassing over 250 scientific papers. For those interested in more details, the paper is publicly accessible.

The paper titled “Cuproptosis: unveiling a new frontier in cancer biology and therapeutics” was published in BMC (part of Springer Nature) on May 1, 2024. Given its complexity, I will distill its essential points into simpler terms.

Reviewers noted that the discovery of cuproptosis has transformed our understanding of how copper influences cell death and its association with cancer. Copper is a vital element in cellular signaling and cancer progression.

Prior to cuproptosis, the mechanisms by which copper induced cell death were not fully understood. Now, we recognize its close ties to cellular energy utilization and specific biological pathways. Researchers are investigating the relationship between cuproptosis and various cancers, particularly those with high energy demands, like melanoma and leukemia.

They are also examining how genes associated with cuproptosis may affect tumor growth and patient responses to treatment. This review delves into copper's functionalities in our bodies, its role in cancer, and how cuproptosis might influence cancer therapies.

Copper serves a dual role as a necessary nutrient and a potential toxin, making balance crucial. It is absorbed from the diet and transported to the liver for distribution to tissues or utilization in essential enzymes.

Special proteins known as copper chaperones direct copper to where it is needed and help regulate its levels. Two crucial proteins, ATP7A and ATP7B, control copper levels by managing its cellular movement. ATP7A exports copper from cells, while ATP7B eliminates excess copper through bile.

Understanding the functions of these proteins can lead to novel treatments for diseases related to copper imbalance, such as Menkes and Wilson’s diseases. This knowledge is vital for developing therapies targeting copper regulation in cancer and other disorders.

Copper absorption occurs mainly in the small intestine, where dietary copper ions are converted to a form suitable for absorption. The STEAP family of proteins facilitates this reduction. Once reduced, copper enters intestinal cells via transport proteins like SLC31A1 and SLC31A2.

Various factors, including specific genes and cellular processes, regulate these proteins. Other proteins, such as AMPK, can influence copper transporter expression based on cellular conditions. In the intestine, mucin 2 binds copper to prevent toxicity and promote absorption.

In inflamed or cancerous tissues, copper levels often increase, with inflammatory molecules like IL-17 enhancing copper uptake. Elevated copper can activate cancer-related pathways, including the BRAF signaling pathway, potentially contributing to cancer development. Understanding these mechanisms is essential for devising targeted therapies for copper imbalance-related diseases and cancer.

Once copper enters cells, it is directed to various organelles such as the cytoplasm, mitochondria, Golgi apparatus, and nucleus by copper chaperones, which facilitate specific functions. In the cytoplasm, the chaperone CCS activates the enzyme SOD1 to mitigate oxidative stress.

Mitochondria, which are crucial for energy production, utilize copper in several enzymes, with CCS aiding in its transport. Copper is delivered to mitochondria by COX17 to assemble enzymes involved in energy generation.

In the cytoplasm, the chaperone ATOX1 directs copper to ATP7A and ATP7B in the Golgi network for regulation. ATOX1 also interacts with cisplatin, affecting drug resistance.

Inside cells, metallothioneins, small cysteine-rich proteins, regulate copper levels, detoxifying excess copper and ensuring its availability for critical processes. Thus, they play a vital role in maintaining cellular health.

As noted, ATP7A and ATP7B regulate copper levels crucial for cellular health. Mutations in these proteins can lead to conditions like Menkes and Wilson’s diseases. They are influenced by molecules such as glutathione and glutaredoxin1.

Proteins like clusterin and COMMD1 enhance ATP7B functionality, which is vital for copper management. The N-terminal region of ATP7B is essential for its activity, with ATOX1 assisting in copper transport. COMMD proteins are key regulators of cellular copper levels.

Reduced expression of COMMD10 can lead to increased intracellular copper levels, impacting tumor growth and radioresistance, particularly in hepatocellular carcinoma.

The review emphasizes that copper dysregulation promotes cancer progression through cuproptosis, a newly identified cell death pathway initiated by copper. Elevated copper levels in tumors influence crucial processes such as cell proliferation, metastasis, and treatment resistance across various cancer types.

Copper interacts with key molecules in tumor cell signaling pathways, affecting cell behavior, proliferation, and angiogenesis. It regulates autophagy, supports cancer cell survival, and influences pathways like MAPK and Notch.

Copper stabilizes HIF-1?, facilitating angiogenesis, and activates NF-?B, contributing to inflammation and tumor formation. Additionally, it modulates lipid and glucose metabolic pathways, impacting tumor growth.

The multifaceted role of copper in cancer signaling underscores its importance in cancer development and progression.

How much copper do we need, and which foods contain it?

Our copper requirements are relatively low; around 1 mg is adequate for most adults. The NIH provides detailed guidelines for health professionals.

Copper is found in both plant and animal products, with beef liver and oysters being particularly rich sources. Despite its negative reputation, beef liver is my preferred food for health benefits, so I do not require a copper supplement. Below is a table of foods rich in copper, as listed by the NIH for health professionals.

Is deficiency a concern? If so, what are the consequences?

According to the NIH, copper deficiency is uncommon in humans. Research in both animals and humans indicates that copper deficiency can lead to:

• Anemia
• Hypopigmentation
• Hypercholesterolemia
• Connective tissue disorders
• Osteoporosis and other bone issues
• Abnormal lipid metabolism
• Ataxia
• Increased infection risk

Certain populations are more susceptible to copper deficiency, including individuals with celiac disease and Menkes disease.

Caution is also warranted regarding zinc intake. Excessive zinc consumption, particularly from supplements, may hinder copper absorption, leading to potential deficiency.

Studies suggest that even moderately high zinc intakes—around 60 mg/day for up to 10 weeks—can reduce copper status, as seen in decreased erythrocyte copper-zinc superoxide dismutase levels. To mitigate this, the Food and Nutrition Board has set the tolerable upper intake level for zinc at 40 mg/day for adults.

As zinc is another essential mineral, I have documented its significance in a previous article titled "Zinc Is an Essential Mineral, and Its Deficiency Matters for Health."

Copper's Connection to Cardiovascular & Alzheimer's Diseases

While copper deficiency can influence lipid levels in the blood, contributing to atherosclerotic cardiovascular disease (CVD), the relationship between copper levels and CVD risk is complex and not fully understood.

Observational studies show conflicting results regarding copper's impact on CVD risk factors. Limited evidence suggests that copper supplementation in healthy adults may have minimal effects on these factors, indicating the need for further research to clarify the association between copper levels, supplementation, and CVD risk.

Similarly, copper's role in Alzheimer's disease (AD) is complex and not completely understood. Some studies indicate that low copper levels in the brain may contribute to AD pathology, whereas others find higher copper levels in AD patients.

Observational studies exploring the relationship between dietary copper intake and AD risk have yielded mixed outcomes. A 2014 meta-analysis indicated that AD patients often have elevated blood copper levels, yet clinical evidence on the effects of copper supplementation in AD patients remains limited.

More research is essential to clarify copper's role in AD development and progression, as well as the potential impacts of copper supplementation on AD risk and symptoms.

Conclusions and Takeaways

The identification of cuproptosis signifies a transformative advancement in our understanding of cell death mechanisms, particularly in cancer contexts. This newly recognized cell death pathway underscores the intricate relationship between copper, an essential micronutrient, and cellular signaling networks.

By elucidating the molecular foundations of cuproptosis, researchers have unveiled new prospects for innovative therapeutic approaches targeting copper-dependent pathways in cancer.

For the general public, this highlights the importance of recognizing copper's dual role as both a vital nutrient and a potential toxin, underscoring the need to maintain a careful balance.

To conclude, I offer a few practical recommendations.

To satisfy our copper needs, it is crucial to include copper-rich foods in our diet, as mentioned earlier. However, moderation is key, as excessive copper can pose health risks.

Moreover, it is vital for scientists and healthcare professionals to understand copper's role in cancer by staying informed about the implications of copper dysregulation in cancer development and progression.

Regular consultations with healthcare providers are advisable, especially if you suspect a copper imbalance or have conditions related to copper metabolism. Personalized guidance and potential supplementation can be beneficial.

Recognizing the significance of copper regulation in cellular health and disease can empower us to proactively safeguard our well-being and potentially contribute to treatment and prevention strategies.

Thank you for engaging with my insights. I wish you a vibrant and healthy life.

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