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FERROPTOSIS

25th May, 2024

FERROPTOSIS

Source: MedicalExpress

Disclaimer: Copyright infringement not intended.

Context

  • Research shows that ferroptosis, a form of cell death, occurs in severe COVID-19 patient lungs.

Details

  • Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, leading to oxidative damage and cell death.
  • Unlike apoptosis, necrosis, or autophagy, ferroptosis involves unique biochemical pathways and morphological changes.
  • It has significant implications in various diseases, including cancer, neurodegeneration, and ischemia-reperfusion injury.

Historical Background

  • The term "ferroptosis" was coined in 2012 by Brent R. Stockwell and colleagues, who described it as an iron-dependent form of non-apoptotic cell death.
  • This discovery expanded the understanding of cell death mechanisms and opened new avenues for research into disease pathology and therapeutic interventions.

Key Features

  • Iron Dependence: Excessive iron catalyzes the formation of reactive oxygen species (ROS) through the Fenton reaction, leading to lipid peroxidation.
  • Lipid Peroxidation: Accumulation of lipid peroxides damages cell membranes, causing cell death.
  • Glutathione Peroxidase 4 (GPX4) Inactivation: Inhibition or depletion of GPX4, a key antioxidant enzyme, exacerbates lipid peroxidation and ferroptosis.

Regulation of Ferroptosis

Positive Regulators

  • Iron Overload: Increases ROS production and lipid peroxidation.
  • Inhibition of System Xc-: Reduces cystine uptake, depleting GSH and impairing GPX4 function.
  • Inhibition of GPX4: Directly induces lipid peroxidation and ferroptosis.
  • ACSL4 Activation: Enhances PUFA incorporation into phospholipids, promoting peroxidation.

Negative Regulators

  • Iron Chelators: Bind free iron, reducing its availability for ROS generation.
  • Antioxidants: Neutralize ROS and inhibit lipid peroxidation (e.g., Vitamin E, Fer-1, Liproxstatin-1).
  • Upregulation of GPX4: Enhances detoxification of lipid peroxides.

Physiological and Pathological Roles

Physiological Roles

  • Immune Response: Ferroptosis can play a role in modulating the immune system and inflammation.
  • Development: Certain developmental processes may involve ferroptosis for tissue remodeling.

Pathological Roles

  • Cancer: Ferroptosis can suppress tumor growth; however, some cancer cells develop resistance to ferroptosis.
  • Neurodegenerative Diseases: Excessive ferroptosis contributes to neuronal loss in diseases like Alzheimer's, Parkinson's, and ALS.
  • Ischemia-Reperfusion Injury: Ferroptosis exacerbates tissue damage following ischemic events in the heart, brain, and kidneys.

Sources:

MedicalExpress

PRACTICE QUESTION

Q.  Consider the following statements regarding ferroptosis:

  1. Ferroptosis involves the accumulation of reactive oxygen species (ROS) due to iron catalysis.
  2. Lipid peroxidation is a hallmark of ferroptosis.
  3. Ferroptosis can be effectively inhibited by antioxidants such as Vitamin E.

Which of the statements given above is/are correct?

A) 1 and 2 only
B) 2 and 3 only
C) 1 and 3 only
D) 1, 2, and 3

Answer: D)