Summary
Chronic stress drives the same oxidative collapse seen in cardiovascular and neurodegenerative disease. Excess cortisol and glutamate signaling increase mitochondrial ROS, activating Bach1–HO-1 and disrupting iron regulation.
Two primary sources of Fe²⁺ initiate the Fenton reaction: oxidation of iron–sulfur cluster proteins and heme accumulation caused by PGRMC1 dysfunction at mitochondria associated membranes.
The resulting reaction between hydrogen peroxide and Fe²⁺ produces hydroxyl radicals that trigger lipid peroxidation and ferroptosis. Stress converts normal oxidative signaling into a self-sustaining chemical chain reaction that destroys neurons and glia.
Mechanistic Sequence
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Cortisol and HO-1 signaling
Chronic stress activates HO-1 through Bach1–HO-1 derepression, releasing Fe²⁺ from heme and increasing the labile iron pool (Liu et al., 2025). -
Mitochondrial ROS production and Fe–S cluster oxidation
Superoxide generated by the electron transport chain is converted to H₂O₂ by SOD. Continuous ROS exposure oxidizes iron–sulfur clusters in mitochondrial enzymes, releasing Fe²⁺ into mitochondria and cytoplasm and increasing Fenton reactivity. -
PGRMC1 dysfunction and heme accumulation
PGRMC1 controls heme export through mitochondria associated membranes. Loss or inhibition of PGRMC1 blocks heme trafficking, causing mitochondrial heme buildup. Oxidative cleavage of heme releases Fe²⁺, increasing Fenton chemistry and ferroptotic sensitivity (Piel et al., 2025). -
Fenton reaction and hydroxyl radical formation
Hydrogen peroxide reacts with Fe²⁺ to form hydroxyl radicals (•OH). These radicals initiate chain lipid peroxidation, damaging mitochondrial and plasma membranes. -
GPX4 depletion and antioxidant loss
Glutathione depletion disables GPX4, preventing detoxification of lipid peroxides and allowing oxidation to spread through membranes. -
Inflammatory iron retention
IL-6 driven hepcidin expression limits iron export, trapping Fe²⁺ inside neurons and glia and maintaining oxidative stress. -
Membrane failure and ferroptosis
Ongoing peroxidation causes mitochondrial collapse, lipid fragmentation, and cell rupture. This defines the ferroptotic stage of degeneration.
Mechanistic Overview
- Fe–S cluster oxidation and heme accumulation are the two main sources of excess Fe²⁺ during stress.
- PGRMC1 functions as a redox gatekeeper; its failure converts controlled oxidative metabolism into uncontrolled ferroptotic chemistry.
- Hydrogen peroxide from mitochondrial ROS starts the process, while Fe²⁺ from heme and Fe–S proteins sustains it.
- HO-1 activation, GPX4 depletion, and hepcidin retention reinforce a continuous oxidative loop that drives neurodegeneration.
Interpretation
Stress induced iron dysregulation explains why ferroptosis represents the endpoint of many idiopathic neurological diseases. The combined effects of Bach1–HO-1 activation, Fe–S cluster breakdown, and PGRMC1 dysfunction create a positive feedback loop that overwhelms antioxidant capacity.
Apoptosis marks the early and reversible stage of oxidative stress. Ferroptosis marks the irreversible chemical phase that ends in cellular destruction.