Reactive oxygen species (ROS) + oxidative stress

Category: signaling

Overview

Reactive oxygen + nitrogen species (superoxide O2•−, hydrogen peroxide H2O2, hydroxyl •OH, peroxynitrite ONOO−). Sources: (1) mitochondrial ETC leak at Complex I + III; (2) NADPH oxidase (NOX family — NOX2 in neutrophils for respiratory burst; NOX4 widely expressed); (3) xanthine oxidase; (4) NOS uncoupling (eNOS without BH4 makes O2•− instead of NO). Defenses: superoxide dismutase (SOD1 cytosol, SOD2 mitochondria) → H2O2 → catalase + glutathione peroxidase (selenium) + peroxiredoxins (thioredoxin-dependent). Glutathione + NADPH + vitamin C + vitamin E + bilirubin = small-molecule antioxidants. Pathologic ROS underlies ischemia-reperfusion injury, neurodegeneration, atherosclerosis. NRF2-KEAP1 axis induces antioxidant gene transcription (sulforaphane activator; dimethyl fumarate for MS).

Organ Systems

• immune-hematologic
• cardiovascular
• nervous

Pathway Steps

1. electron-transport-leak → superoxide — via Complex I + III leak (1-2% of O2 reduced this way). Reactive oxygen species arise mainly as a byproduct of the mitochondrial electron transport chain: electrons leaking from complexes I and III reduce O2 to superoxide. A few percent of consumed oxygen becomes superoxide, making mitochondria the dominant ROS source and a key site of oxidative damage and signaling.
2. superoxide → hydrogen-peroxide — via SOD1 (Cu/Zn cytosol) + SOD2 (Mn mitochondria) dismutation. Superoxide is rapidly converted to hydrogen peroxide by superoxide dismutase — mitochondrial MnSOD (SOD2) and cytosolic Cu/ZnSOD (SOD1). H2O2 is more stable and membrane-permeant, so it doubles as the main redox signaling molecule (oxidizing target cysteines) and a damage agent.
3. hydrogen-peroxide → water — via catalase (peroxisomal) + GPx (selenium, glutathione-coupled). Hydrogen peroxide is detoxified to water by catalase and the glutathione/peroxiredoxin peroxidase systems. The balance between ROS production and this antioxidant removal sets the redox state — mild ROS act as signals (hormesis), while overwhelming the defenses causes the oxidative stress of aging and disease.

Known Modulators

• coq10 (activator) — electron transport chain + antioxidant. coenzyme Q10; mitochondrial complex I-III electron carrier; statin co-prescription claim
• coq10 ubiquinol (activator) — reduced CoQ10 (ubiquinol). pre-reduced active form; better bioavailability in elderly
• pqq (activator) — mitochondrial biogenesis. pyrroloquinoline quinone; antioxidant; cognitive + sleep claims
• idebenone (activator) — CoQ10 analog + ETC. synthetic CoQ; LHON (Friedreich ataxia variants) Rx in EU
• ala r (activator) — α-lipoic acid (R-enantiomer). natural R-ALA; mitochondrial + glutathione recycling; diabetic neuropathy Rx in some markets
• c60 (activator) — fullerene antioxidant (radical sponge). C60 in olive oil; rodent lifespan claim from Baati 2012 (controversial)
• emoxypine (activator) — antioxidant + GABA modulation. mexidol; Russian-Rx antioxidant + nootropic

References

• PMID 28110218
• PMID 19061483