Research Suggests Unusual Form of Cell Death Causes Severe COVID-19 Lung Damage

May 30, 2024

Ferroptosis may be the driving force behind severe pulmonary manifestations of COVID-19.

SARS-CoV-2 infection may cause severe pulmonary conditions such as pneumonia, inflammation, and acute respiratory distress syndrome, but until now, researchers have not understood the driving force behind lung damage caused by COVID-19.

In a recently published paper in Nature Communications, researchers at Columbia University discovered that a relatively new form of iron-dependent cell death called ferroptosis is the underlying mechanism causing extreme and potentially fatal pulmonary conditions in COVID-19 patients.

“This finding adds crucial insight to our understanding of how COVID-19 affects the body that will significantly improve our ability to fight life-threatening cases of the disease,” Brent Stockwell, chair of the department of biological sciences at Columbia and co-lead author of the study, said in a news release.

What Is Ferroptosis?

Human cells have powerful mechanisms for maintaining survival, but when those mechanisms become impaired, lipid peroxides—generated through normal metabolic activities—can accumulate to toxic levels, damage cell membranes, and kill cells through ferroptosis.

Ferroptosis was first identified in 2012 by Mr. Stockwell and differs from apoptosis—the most common form of cell death that occurs with aging and in some disease processes. Ferroptosis is an unusual type of cell death linked to altered iron metabolism, glutathione depletion, glutathione peroxidase 4 inactivation, and increased oxidative stress.

Since proposing the concept, Mr. Stockwell’s lab has demonstrated that ferroptosis can occur in healthy contexts as part of the body’s normal processes. For example, cell death can remove cells infected with SARS-CoV-2, inhibiting the replication and spread of the virus or counteract diseases like cancer, which involves rapid cell growth.

On the other hand, ferroptosis can be destructive, attacking healthy cells in patients with neurodegenerative diseases or causing severe manifestations of COVID-19 and possibly even long COVID.

The Study

Researchers obtained lung tissue samples from the autopsies of patients who died of respiratory failure caused by severe COVID-19, including those with and without acute lung injury (ALI). Samples were also collected from patients who had mild COVID-19 and recovered.

Control samples were obtained from pre-pandemic healthy patients who showed no signs of SARS-CoV-2 infection or lung damage. Samples from autopsies with ALI and without a history of SARS-CoV-2 infection were also analyzed. Additionally, serum ferritin records were obtained, as serum ferritin is elevated in critically ill COVID-19 patients, correlates with disease severity, and supplies the iron that drives ferroptosis. Ferritin is a protein found inside cells that stores iron and allows the body to use it when needed.

The researchers analyzed cell death markers on COVID-19 lung tissue samples obtained from the autopsies and found “distinct molecular features of ferroptosis” in severe lung pathologies. Moreover, samples revealed elevated ferroptosis markers, including iron dysregulation, lipid peroxidation, elevated lysophospholipids, and depletion in polyunsaturated fatty acyl tails (PL-PUFAs).

PUFAs, or polyunsaturated fatty acids, while essential for cell membranes and immune regulation, are highly unstable and inflammatory. Due to their sensitivity to oxygen, PUFAs can be oxidized by free radicals and broken down into toxic derivatives.

In a secondary analysis, Syrian hamsters were intentionally inoculated with the same strain of SARS-CoV-2 found in patient samples. Researchers analyzed lung samples and found that ferroptosis occurred at an early stage of lung disease and accompanied disease progression.

To confirm their findings were caused by ferroptosis, the researchers measured cell death markers associated with other forms of cell death. They did not detect an increase in these markers in any lung samples, indicating that ferroptosis was the major cell death mechanism detected in fatal COVID-19 lung samples.

“Altogether, these data suggest a strong correlation between ferroptosis and COVID-19 lung pathology, and ferroptosis inhibition may serve as adjuvant therapy to reduce lung injury,” the authors wrote.

A May 2023 paper published in Frontiers supports the paper’s findings. In their review, researchers found that dysregulated cell death from ferroptosis can lead to uncontrolled cellular damage beyond the lungs and plays a role in the multi-organ complications observed in COVID-19 patients with severe disease.

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