DMT1 knockout abolishes ferroptosis induced mitochondrial dysfunction in C. elegans amyloid β proteotoxicity

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Iron is essential for neuronal function, but its dysregulation is linked to neurodegenerative diseases like Alzheimer's disease (AD).
• Elevated brain iron levels are observed in AD patients, yet its precise role in disease pathogenesis remains unclear.
• Ferroptosis, a form of iron-dependent cell death, is implicated in neurodegeneration.

Purpose of the Study:

• To investigate the role of ferroptosis in mediating AD-like pathologies in a C. elegans model.
• To determine the relationship between iron accumulation, mitochondrial dysfunction, and neuronal loss in the context of amyloid-beta (Aβ) overexpression.
• To assess the therapeutic potential of modulating iron uptake in AD.

Main Methods:

• Utilized C. elegans models, including wild-type and neuronal Aβ-overexpressing strains.
• Monitored iron accumulation, neuronal function, and energetic imbalance during aging.
• Assessed mitochondrial reactive oxygen species (ROS) production and oxidative damage.
• Investigated the effects of pharmacologic agents on iron accumulation and ferroptosis.
• Employed knockout of divalent metal transporter 1 (DMT1) to limit iron uptake.

Main Results:

• Iron accumulation preceded neuronal dysfunction in aging worms.
• Energetic imbalance and increased mitochondrial ROS-mediated oxidative damage contributed to iron-induced neuronal dysfunction and ferroptosis.
• Pharmacologic modulation of iron accumulation affected ferroptosis in both wild-type and Aβ worms.
• Neuronal Aβ worms exhibited increased sensitivity to ferroptosis, which was ameliorated by DMT1 knockout.
• DMT1 knockout completely suppressed age-dependent Aβ toxicity phenotypes.

Conclusions:

• Iron-induced ferroptosis exacerbates mitochondrial redox imbalance and oxidative damage, particularly in the presence of neuronal Aβ.
• Limiting neuronal iron uptake via DMT1 knockout effectively ameliorates Aβ-associated neurotoxicity and pathology.
• Targeting iron transport mechanisms presents a potential therapeutic strategy for Alzheimer's disease.