Overview
Many idiopathic neurodegenerative diseases show the core biochemical signs of ferroptosis. These include iron accumulation, loss of GPX4 and glutathione, and extensive lipid peroxidation. Early stress triggers apoptotic death, but as mitochondrial ROS and iron increase, the system transitions into ferroptosis. Chronic excitotoxicity and HO-1 upregulation link directly to this shift.
ROS Generation
The main source of hydrogen peroxide (H₂O₂) is the mitochondrial electron transport chain (ETC). During oxidative phosphorylation, small amounts of oxygen are incompletely reduced at complexes I and III, forming superoxide (O₂•⁻). This superoxide is rapidly converted by superoxide dismutase (SOD) into H₂O₂. Under normal conditions, catalase and glutathione peroxidase neutralize it, but during stress, excess ROS leaks from mitochondria, overwhelming these defenses.
Early Phase: Apoptosis under Stress
Moderate oxidative stress oxidizes cardiolipin and releases cytochrome c, initiating apoptosis. This process is controlled and ATP-dependent, limiting collateral damage. Apoptosis predominates while mitochondria remain structurally intact and antioxidant capacity is sufficient.
Transition Phase: Iron Accumulation
Prolonged stress upregulates HO-1 through Bach1–HO-1 signaling, releasing Fe²⁺ from heme. Damaged mitochondria also leak iron–sulfur clusters, further raising Fe²⁺ levels. Once H₂O₂ from the ETC meets Fe²⁺, the Fenton reaction generates hydroxyl radicals (•OH), which rapidly oxidize lipids and proteins. At this point, apoptosis loses control and ferroptotic chemistry begins.
Late Phase: Ferroptosis
When GPX4 and glutathione are depleted, lipid peroxidation becomes self-propagating. Hydroxyl radicals attack polyunsaturated fatty acids, causing mitochondrial collapse and membrane rupture. This uncontrolled oxidative death defines ferroptosis, which spreads inflammation and secondary oxidative injury to nearby neurons. High lipid content and oxidative metabolism make neurons especially susceptible.
Evidence by Disease
ALS: Elevated HO-1, ACSL4, and TFR1; reduced GPX4 and GSH; increased 4-HNE and MDA; iron chelators and ferroptosis inhibitors preserve neurons.
Parkinson’s: Iron buildup in the substantia nigra; reduced GPX4; dopamine oxidation feeds Fenton chemistry; ferroptosis inhibitors protect dopaminergic neurons.
Alzheimer’s: Iron and ferritin accumulation, HO-1 upregulation, and lipid peroxidation near plaques; GPX4 loss tracks disease severity.
Other disorders (FTD, HD, MSA, PSP): All show iron dysregulation, oxidized phospholipids, and mitochondrial decay consistent with ferroptosis.
Mechanistic Continuum
- Moderate stress: ETC leak → O₂•⁻ → H₂O₂ → cardiolipin oxidation → apoptosis.
- Chronic stress: HO-1 upregulation → Fe²⁺ release → Fenton reaction.
- Antioxidant depletion: GPX4 and GSH loss → runaway lipid peroxidation.
- Outcome: Membrane failure → ferroptotic degeneration.
Implications
Ferroptosis represents the terminal phase of stress-driven neuronal death. It occurs when mitochondrial ROS production and iron load exceed the cell’s antioxidant control. Targeting iron handling (HO-1, hepcidin, ferritinophagy), antioxidant maintenance (GPX4, GSH, selenium), and stress modulation (glutamate, cortisol) may prevent or slow disease.
Chronic stress transforms mitochondrial H₂O₂ signaling into iron-driven hydroxyl radical damage, producing the sustained ferroptotic degeneration seen in idiopathic neurological disorders.