PRDX6 augments selenium utilization to limit iron toxicity and ferroptosis

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Biology

Background:

• Ferroptosis is regulated cell death driven by iron-dependent lipid hydroperoxide accumulation.
• Selenoprotein glutathione peroxidase 4 (GPX4) is critical for suppressing ferroptosis by detoxifying lipid hydroperoxides.
• Selenocysteine (Sec) is the 21st amino acid, biosynthesized from selenium donors on tRNA[Ser]Sec, requiring safe and efficient intracellular delivery.

Purpose of the Study:

• To identify novel factors involved in selenoprotein synthesis.
• To elucidate the mechanism by which PRDX6 influences selenoprotein expression and ferroptosis.
• To understand the role of PRDX6 in intracellular selenium metabolism.

Main Methods:

• Loss-of-function studies involving PRDX6.
• Analysis of selenoprotein expression levels.
• Investigation of the selenocysteyl-tRNA[Ser]Sec synthesis pathway.
• Assessment of ferroptosis induction.

Main Results:

• Peroxiredoxin 6 (PRDX6) was identified as a novel selenoprotein synthesis factor.
• Loss of PRDX6 decreased selenoprotein expression and induced ferroptosis due to reduced GPX4 levels.
• PRDX6 enhances intracellular selenium utilization by facilitating selenium transfer within the selenocysteyl-tRNA[Ser]Sec synthesis machinery, ensuring efficient tRNA synthesis.

Conclusions:

• PRDX6 plays a crucial role in selenoprotein synthesis and ferroptosis regulation.
• PRDX6 acts as a selenium transfer protein, optimizing selenium utilization for selenoprotein production.
• These findings reveal novel selenium metabolic pathways and offer new insights into ferroptosis mechanisms.