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Apoptosis process in a cell
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Ferroptosis Controlling Life or Death of Cells

Cell death is indispensable to life, as it ensures the removal of damaged or unnecessary cells. Among the many ways a cell can die, ferroptosis is a unique and regulated form of cell death. This process plays a significant role in the pathogenesis of several diseases. Prof. Marcus Conrad and his team at Helmholtz Munich are pioneers in ferroptosis research. Their findings help to develop therapies combating disease conditions such as cancer and neurodegenerative diseases.

Cell death is indispensable to life, as it ensures the removal of damaged or unnecessary cells. Among the many ways a cell can die, ferroptosis is a unique and regulated form of cell death. This process plays a significant role in the pathogenesis of several diseases. Prof. Marcus Conrad and his team at Helmholtz Munich are pioneers in ferroptosis research. Their findings help to develop therapies combating disease conditions such as cancer and neurodegenerative diseases.

The cycle of life—when one life ends, it paves the way for a new beginning. This natural cycle is essential for maintaining ecosystems, where various species coexist in a fine-tuned balance. It also plays a crucial role in keeping biological systems within individual organisms functional. Aged or dysfunctional components are systematically removed to create space for fresh, efficient cellular replacements.

 

 

 

Cell Death: The Body’s Housekeeper

Through a controlled cell turnover process, old or damaged cells are replaced by new ones, keeping tissues and organs healthy and functional. During development, tissues and organs continuously evolve and transform until they reach their final form in adulthood. Additionally, our immune system can recognize and eliminate infected or potentially harmful cells. This cycle of regulated cell death and renewal continuously acts as the body's quality control system.

A series of such cell death programs exist, each characterized and triggered by different molecular mechanisms. For instance, specific receptors on cells can detect when certain cells need to be removed, initiating a process that breaks down the cell’s components. This process ensures the targeted cell is eliminated without harming surrounding cells.

 

 

 

Cell Death by Ferroptosis

Ferroptosis (from the Latin word for iron, “ferrum”, and “-ptosis”, a Greek word meaning “fall” or “death”) is a distinct form of cell death, one of the most ancient and widespread types. It is characterized by the destruction of cellular membranes, which are crucial for a cell’s survival. This process is influenced by iron; unbound, so-called labile, iron can promote the formation of highly reactive molecules known as lipid peroxides, which are key indicators of ferroptosis. When this process is initiated, lipid peroxides damage cellular membranes, making them leaky and unable to sustain their integrity. Despite its importance, scientists still do not fully understand why ferroptosis is triggered. However, its role in disease pathogenesis makes it an intriguing subject of study.

 

 

 

Ferroptosis was first named in 2012. Yet, even before its official naming, Marcus Conrad and his team at the Institute of Metabolism and Cell Death at Helmholtz Munich were pioneering the field of oxidative cell death by making major contributions to our understanding of this unique form of cell death. Notably, their 2019 landmark discovery of the ferroptosis suppressor protein-1 (FSP1) was pivotal for many significant advances and translational approaches. FSP1 is identified as a second critical factor, next to glutathione peroxidase 4 (GPX4) (see below), in protecting cells from death by ferroptosis and preventing the uncontrolled generation of (phospho)lipid hydroperoxides within the cell.

 

 

 

Our discoveries in the realm of ferroptosis have not only advanced our understanding of this form of cell death but also illuminated the roles of proteins like FSP1 and GPX4. By identifying these key players, we are paving the way for innovative strategies to protect cells from oxidative damage and to potentially translate this knowledge into new therapies.

Prof. Marcus Conrad

The team has also conducted extensive research on the main ferroptosis-suppressing enzyme GPX4, uncovering its critical role in protecting cells and organs from lipid peroxidation as early as in 2008. GPX4 is an essential enzyme in the human body and plays a unique role in scavenging (phospho)lipid peroxides, harmful byproducts of oxidative stress. This function makes GPX4 particularly important in preventing ferroptosis. By detoxifying lipid peroxides and maintaining the integrity of cellular membranes, GPX4 acts as a key defender against oxidative damage, safeguarding cells from unwanted ferroptosis-mediated demise.

 

 

 

Dual Role: Ferroptosis in Health and Disease

Ferroptosis can act both to protect against disease and to contribute to disease progression. On one hand, it helps eliminate harmful or dysfunctional cells. On the other hand, certain diseased cells develop mechanisms to evade ferroptosis, allowing them to survive and proliferate despite their harmful effects to the body. This process plays a crucial role in the development of various conditions such as cancer and neurodegenerative diseases like Alzheimer's.

"Understanding the molecular pathways that regulate ferroptosis is becoming a key focus in research, as it holds promise for new therapeutic strategies."

Dr. Toshitaka Nakamura

The research team led by Prof. Marcus Conrad is dedicated to discovering clinically effective compounds that can selectively induce ferroptosis in diseased cells. Recent breakthroughs have led to the identification of molecules that inhibit FSP1, a protein that prevents ferroptosis and allows cancer cells to evade this form of cell death.

Further research has also linked ferroptosis to a physico-chemical process called phase separation, which could lead to innovative treatments for various diseases, including cancer. Phase separation occurs when specific components within a cell, such as lipids, proteins, or RNA, self-organize forming distinct compartments or structures. This self-organization can affect cellular functions and provide new insights into treating diseases by targeting these compartmentalized processes.

Pioneers in Ferroptosis Research: Recent Key Findings by Marcus Conrad and Team

The team of scientists uncovered:

Pharmacological Impact: Ferroptosis as a Target in Cancer Therapy

Targeting ferroptosis has significant potential for tumor suppression in cancer treatment. Modulating cell death by ferroptosis shows promise as an anti-cancer strategy by exploiting the high vulnerability of certain cancer cells to this form of death. However, the landscape is complex: while some metastatic and standard therapy-resistant cancers respond well to ferroptosis-inducing drugs, others may be less responsive.

Researchers are actively developing drugs designed to either induce ferroptosis in cancer cells susceptible to it or to inhibit the mechanisms that allow other certain cancer cells to resist this process. Key regulators of ferroptosis, such as GPX4 and FSP1, have emerged as potential targets in cancer therapy. By understanding and manipulating these regulators, scientists aim to increase the susceptibility of cancer cells to ferroptosis. Thereby, they want to slow down or stop tumor growth.

"The translational implications of ferroptosis are profound. By harnessing its mechanisms, we can bridge the gap from basic research to clinical application, creating therapies that selectively target and destroy diseased cells while sparing healthy ones. This could be a game-changer in treating cancers."

Dr. Eikan Mishima

Want to know more about ferroptosis research at Helmholtz Munich?

Check out the Institute of Metabolism and Cell Death research activities at Helmholtz Munich.

About the scientists

Porträt Eikan Mishima

Dr. Eikan Mishima

Scientist
DSC_1044 original mod

Toshitaka Nakamura

PhD Student

Latest update: October 2024.