Iron retardation in lysosomes protects senescent cells from ferroptosis

Area of Science:

• Cellular Biology
• Aging Research
• Biochemistry

Background:

• Ferroptosis, an iron-dependent cell death, is linked to aging and related diseases.
• The role of ferroptosis in cellular senescence remains unclear.
• Senescent cells accumulate iron and lipids, but their ferroptosis sensitivity is unknown.

Purpose of the Study:

• To investigate the involvement of ferroptosis in doxorubicin-induced senescent human skeletal muscle cells (HSkM).
• To elucidate the mechanism behind ferroptosis resistance in senescent cells.
• To explore lysosomes as potential targets for senolytic therapies.

Main Methods:

• Established a doxorubicin-induced senescent HSkM cell model.
• Analyzed iron accumulation, lipid peroxidation, and ferroptosis-response proteins.
• Investigated iron flux and lysosomal function using chloroquine and LLOMe.
• Examined the effect of ferroitinophagy-related proteins (FTH1/FTL, NCOA4) knockdown.

Main Results:

• Senescent HSkM cells showed increased iron and lipid peroxidation but resisted ferroptosis.
• Iron was found to be arrested within lysosomes in senescent cells.
• Disrupting lysosomal function or inhibiting ferroitinophagy induced senescent cell death.
• Senescent cells are resistant to ferroptosis inducers compared to proliferating cells.

Conclusions:

• Iron accumulation in lysosomes confers ferroptosis resistance to senescent cells.
• Lysosomal function is critical for maintaining ferroptosis resistance in senescence.
• Lysosomes represent a promising therapeutic target for senolytic drugs to clear senescent cells and mitigate aging-related diseases.