Exploring the critical role of copper for mitochondria and its dysfunction causing protein aggregation and cell death in tumor-related signaling pathways influenced by copper metabolism

This story does not include health advice. It is for information, inspiration, and awareness purposes.

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Micronutrients, including minerals, are critical for our biology and survival. Some trace minerals are essential in physiological processes in the body. One such vital mineral is copper, essential in mitochondria and cellular energy production. I have recently read a lot about the risks of cuproptosis for potential cancer issues, which I will explain in this story based on a published comprehensive review and my prior research.

Scientists believe that cuproptosis represents a paradigm shift in cell death mechanisms. It introduces a novel concept in which copper, a trace mineral essential for various cellular processes, is central in orchestrating cell death. Unlike traditional forms of cell death like apoptosis or necrosis (caused by genetic or environmental factors), cuproptosis involves the complex relationship between metal ions and cellular signaling pathways.

This discovery challenges conventional views on cell death regulation and opens up new avenues for understanding the molecular underpinnings of diseases, particularly cancer, where dysregulated cell death processes are implicated. Identifying cuproptosis as a distinct mode of cell death broadens our understanding of cellular physiology and may pave the way for innovative therapeutic strategies targeting copper-dependent pathways.

I wrote this piece inspired by a comprehensive review paper published in Nature’s Cell Communication and Signalling last week. As soon as the paper arrived in my inbox, I read it with great interest due to its importance. Then, I spent several hours reviewing the abstracts and relevant points of 256 cited references to understand mechanisms to articulate them to my students, colleagues, clients, and readers.

Before introducing the findings and key points discussed in the review paper, I want to introduce the vital role of copper in our health and well-being, especially in energy production, based on my prior research on this critical mineral for our cells, tissues, organs, and systems.

What is copper, and why is it so critical?

When teaching copper to students, I tell them that copper is not just a shiny metal used for pipes and wires, but it is a vital nutrient that our bodies need to thrive. I will summarize essential processes for the body.

As documented in a 2021 Frontiers paper, copper's foremost importance is its role in energy production. It is an indispensable element within our mitochondria’s machinery, facilitating the conversion of nutrients into energy. Inadequate copper levels can lead to fatigue and lethargy.

Regarding energy, a copper deficiency can also hinder iron absorption and potentially lead to anemia. However, iron supplements can negatively affect copper levels. Copper helps the body absorb and utilize iron, which carries oxygen throughout the bloodstream.

Copper is essential for building strong and supple connective tissues like skin, tendons, and blood vessels. Low copper levels can weaken tissues, making people more susceptible to injuries.

Copper is also critical for the brain and nervous system. It is involved in the development and maintenance of the nervous system. A lack of copper can affect nerve signaling and lead to numbness, tingling, coordination problems, and even cognitive problems.

Lastly, copper plays a role in immune function, too, helping the body fight off infections. When copper levels are low, the immune system might not be as effective in protecting us.

While too little copper can cause problems, too much copper is not ideal either. Excess copper can accumulate in tissues, causing oxidative stress (damage to cells) and contributing to conditions like Wilson’s disease and Alzheimer’s disease.

Maintaining proper copper levels is a delicate balancing act. Most people get enough copper through a balanced diet that includes nuts, seeds, shellfish, organ meats, and whole grains. However, some people might need supplements under the guidance of a healthcare professional.

Copper is an essential mineral that often flies under the radar. I want to highlight the recognition it deserves for its critical role in keeping us healthy and energized.

What is cuproptosis, and why does it matter?

At a high level, cuproptosis is a form of cell death that relies on copper. It involves the regulated destruction of cells through copper-induced pathways, depicting the role of this metal ion in cellular processes and disease progression, particularly in the context of cancer research.

For example, as documented in a 2023 review paper, researchers have discovered cuproptosis, a type of cell death triggered by copper that’s different from other known forms of cell death.

The review informed that copper plays a crucial role in various signaling pathways within tumor cells. It binds and activates vital molecules in these pathways, influencing processes like cell migration and proliferation.

For instance, copper activates receptor tyrosine kinase pathways, phosphorylating downstream proteins like extracellular regulated protein kinases, which promote cell growth. Additionally, copper activates the PI3K-AKT pathway, directly activating PI3K or binding to specific sites on PDK1 to activate AKT.

This AKT activation can trigger processes that support cancer cell proliferation and tumor growth. Copper also influences the mitogen-activated protein kinase signaling pathway by directly binding to proteins like mitogen-activated proteinkinase kinase 1, activating downstream proteins regulating tumor growth.

This knowledge has sparked increased interest in studying programmed cell death over the past decade, with debates about whether copper-induced cell death is a distinct type. Now that the mechanism of cuproptosis has been uncovered, more researchers are exploring its connection to cancer.

Summary of Cuproptosis in Cancer Biology & Therapeutics

As it is impossible to cite hundreds of papers on cuproptosis, I want to summarize the key points of the most recent analysis, which covers over 250 scientific papers. Readers interested in details might check the paper, which is publicly available.

The paper titled “Cuproptosis: unveiling a new frontier in cancer biology and therapeutics” published in BMC (Part of Sringer Nature) on 1 May 2024. As the paper is comprehensive and complex for the public, I will summarize the key points in simple words.

Reviewers mentioned that in recent years, the discovery of cuproptosis has shaken up our understanding of how copper affects cell death and its link to cancer. Copper, a vital element, plays a big role in cell signaling and cancer development.

Before cuproptosis, we didn’t fully grasp how copper caused cell death, but now we see it is closely tied to how cells use energy and certain pathways in the body. Scientists are now digging into how cuproptosis relates to different types of cancer, especially those with high energy needs like melanoma and leukemia.

They also look at how genes involved in cuproptosis might affect tumor growth and patient response to treatment. This review dives deep into how copper works in our bodies, its role in cancer, and how cuproptosis could change how we treat cancer.

Copper has a dual role as a vital nutrient and a potential toxin, so maintaining the right balance is key. Copper is absorbed from the diet and transported to the liver, where it is distributed to tissues or used in essential enzymes.

Special proteins called copper chaperones guide copper to where it is needed and help control its levels. Two important proteins, ATP7A and ATP7B, manage copper levels by moving it in and out of cells. ATP7A helps export copper from cells, while ATP7B helps eliminate excess copper by putting it into bile.

Understanding how these proteins work can lead to new treatments for diseases related to copper imbalance, like Menkes and Wilson’s diseases. This knowledge is vital for developing therapies that target copper regulation in cancer and other diseases.

Copper absorption in the body primarily occurs in the small intestine, where copper ions from food are reduced to a form that can be absorbed. This reduction process is facilitated by a group of proteins called the STEAP family. Once reduced, copper enters intestinal cells through transport proteins like SLC31A1 and SLC31A2.

These proteins are regulated by various factors, including specific genes and cellular processes. Additionally, other proteins like AMPK can influence the expression of copper transporters in response to changes in cellular conditions. In the intestine, mucin 2 binds copper, helping to prevent its toxicity and facilitating its absorption into cells.

In inflamed or cancerous tissues, copper levels are often elevated, with certain inflammatory molecules like IL-17 promoting copper uptake. Elevated copper levels can activate pathways associated with cancer development, like the BRAF signaling pathway, potentially contributing to carcinogenesis. Understanding these mechanisms can be helpful for developing targeted therapies for diseases related to copper imbalance and cancer.

Once copper enters cells, it is directed to different parts like the cytoplasm, mitochondria, Golgi apparatus, and nucleus by copper chaperones, which help in specific functions. In the cytoplasm, the copper chaperone CCS plays a key role in activating the enzyme SOD1 to combat oxidative stress.

Mitochondria (crucial for energy production) use copper for various enzymes, with CCS aiding in copper transport. Copper is transported to mitochondria by COX17 to assemble enzymes that are involved in energy production.

In the cytoplasm, the chaperone ATOX1 delivers copper to ATP7A and ATP7B in the Golgi network, facilitating copper regulation. ATOX1 also interacts with cisplatin, impacting drug resistance.

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

As mentioned before, ATP7A and ATP7B regulate cellular copper levels, essential for cell health. Mutations in these proteins lead to diseases like Menkes and Wilson’s. They’re controlled by molecules like glutathione and glutaredoxin1.

Clusterin and COMMD1 support the proper functioning of ATP7B, a protein crucial for managing cell copper levels. ATP7B’s N-terminal region is essential for its activity, with assistance from ATOX1 in transporting copper. COMMD proteins regulate cellular copper levels.

Reduced COMMD10 expression can increase intracellular copper levels, affecting tumor growth and radioresistance, notably in hepatocellular carcinoma.

The critical point in the paper is that copper dysregulation fuels cancer progression via cuproptosis, a newly identified cell death pathway initiated by copper. Elevated copper levels in tumors impact vital processes like cell proliferation, metastasis, and resistance to therapy across various cancer types.

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

Copper stabilizes HIF-1α, promoting angiogenesis, and activates NFκB, contributing to inflammation and tumorigenesis. Additionally, it modulates lipid and sugar metabolic pathways, impacting tumor growth.

The multifaceted role of copper in cancer signaling highlights its significance in cancer development and progression.

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

We don’t need lots of copper. Just around 1 mg is sufficient for most adults. Here is the breakdown provided by NIH for health professionals.

Copper exists in both plant and animal products. The richest ones are beef liver and oysters. Despite Its Poor Reputation, Beef Liver Is My Favorite Food for Health Reasons. Therefore, I don’t need to take a copper supplement. Here’s a table showing food with copper listed by NIH for health professionals.

Is deficiency real? If so, what are its ramifications?

As NIH documented, copper deficiency is uncommon in humans. Based on studies in animals and humans, the effects of copper deficiency include:

Anemia, hypopigmentation, hypercholesterolemia, connective tissue disorders, osteoporosis and other bone defects, abnormal lipid metabolism, ataxia, and increased risk of infection.

Certain groups are at a higher risk of copper deficiency. They are people with celiac disease and Menkes disease.

We need to be careful with zinc. As mentioned in the NIH document, excessive zinc intake, especially from supplements, can hinder copper absorption, potentially leading to copper deficiency.

Even moderately high zinc intakes, around 60 mg/day for up to 10 weeks, have been associated with reduced erythrocyte copper-zinc superoxide dismutase, indicating compromised copper status. To address this concern, the Food and Nutrition Board set the tolerable upper intake level for zinc at 40 mg/day for adults.

As Zinc is also a critical mineral, I documented the details in a previous article titled Zinc Is an Essential Mineral, and Its Deficiency Matters for Health.

Copper’s Association with Cardiovascular & Alzheimer’s Diseases

As NIH documented, while copper deficiency can influence blood lipid levels, contributing to atherosclerotic cardiovascular disease (CVD), the relationship between copper concentrations and CVD risk remains complex and inconclusive.

Observational studies present conflicting findings regarding the impact of copper on CVD risk factors. Limited evidence suggests that copper supplementation in healthy adults may have minimal effects on CVD risk factors. Thus, further research is needed to comprehensively explain the association between copper concentrations, supplementation, and CVD risk.

Likewise, the role of copper in Alzheimer’s disease (AD) is multifaceted and not yet fully understood. Some studies suggest that low copper levels in the brain may contribute to AD pathology, while others indicate higher copper levels in AD patients.

Observational studies examining the relationship between dietary copper intake and AD risk have produced mixed results. 2014 meta-analyses have shown that AD patients tend to have higher blood copper levels, but clinical evidence on the impact of copper supplementation in AD patients is scarce.

More research is required to clarify the role of copper in AD development and progression, as well as the potential effects of copper supplementation on AD risk and symptoms.

Conclusions and Takeaways

The discovery of cuproptosis represents a paradigm shift in our understanding of cell death mechanisms, particularly in the context of cancer. This novel form of cell demise emphasizes the complex relationship between copper, an essential micronutrient, and cellular signaling pathways.

By solving the molecular underpinnings of cuproptosis, scientists have revealed new opportunities for innovative therapeutic strategies targeting copper-dependent pathways in cancer.

For the public, this means recognizing copper's dual role as both a vital nutrient and a potential toxin, highlighting the importance of maintaining a delicate balance.

I want to end my story by offering a few practical tips.

To meet our copper needs, we must ensure our diet includes the copper-rich foods I listed above. However, moderation is key, as excessive copper intake can lead to health issues.

Besides, it is helpful for scientists and clinicians to understand copper’s role in cancer by staying informed about the role of copper dysregulation in cancer development and progression.

Therefore, we must consult healthcare professionals for timely checkups. If you suspect a copper imbalance or have a condition related to copper metabolism, you should discuss your concerns with your family physicians for personalized guidance and potential supplementation.

Recognizing the critical role of copper regulation in cellular physiology and disease formation can empower us to proactively protect our health and possibly contribute to treatment and prevention strategies.

Thank you for reading my perspectives. I wish you a healthy and happy life.

If you found this story helpful, you may also check out my other articles on NewsBreak. As a postdoctoral researcher and executive consultant, I write about important life lessons based on my decades of research and experience in cognitive, metabolic, and mental health.