ROS Fate Summary
Reactive oxygen species (ROS) determine the cell’s death pathway based on iron availability.
If iron is scarce, ROS oxidizes mitochondrial membranes, releasing cytochrome c and triggering apoptosis.
If iron is abundant, ROS reacts with Fe²⁺ to generate hydroxyl radicals that drive ferroptosis through lipid peroxidation.
ROS to H₂O₂ Pathway (Lipid Peroxidation → Cytochrome c Leakage → Apoptosis)
Chronic ROS generation leads to accumulation of hydrogen peroxide (H₂O₂) within mitochondria.
Persistent H₂O₂ exposure oxidizes cardiolipin, a phospholipid that anchors cytochrome c to the inner membrane.
Peroxidized cardiolipin releases cytochrome c into the cytoplasm, where it binds Apaf-1 and procaspase-9, forming the apoptosome.
This activates caspase-3, initiating the programmed dismantling of the cell through apoptosis.
ROS to Fe²⁺ Pathway (Lipid Peroxidation → HO-1 Activation → Ferroptosis)
ROS reacts with ferrous iron (Fe²⁺) to form hydroxyl radicals (•OH) via the Fenton reaction.
These radicals cause lipid peroxidation of mitochondrial and cellular membranes.
Peroxidized lipids trigger HO-1 activation through the Bach1–HO-1 signaling pathway, releasing more Fe²⁺ and expanding the labile iron pool.
This self-perpetuating cycle depletes GPX4 and glutathione, leading to mitochondrial collapse and ferroptotic cell death.