Oxidative stress

Oxidative stress is the disruption of cellular redox balance that follows when reactive oxygen species (ROS) production outpaces the antioxidant systems that dispose of them. The chemistry runs in a defined sequence: electron leak from the mitochondrion respiratory chain, and the deliberate activity of NADPH oxidases in phagocytes and signaling compartments, produce superoxide; Superoxide Dismutase (SOD) dismutates superoxide to hydrogen peroxide; and hydrogen peroxide is then either reduced to water by Catalase (CAT), glutathione peroxidases and peroxiredoxins, or, in the presence of ferrous iron, converted by Fenton chemistry into the hydroxyl radical, which reacts with the first molecule it meets and has no enzymatic defense. The tripeptide glutathione supplies the reducing equivalents for much of this disposal, regenerated at the expense of NADPH. At controlled levels the same species are signals rather than poisons, driving the phagocyte respiratory burst and the reversible oxidation of cysteine residues that switches enzymes and transcription factors on and off; oxidative stress is better understood as the loss of that control than as the mere presence of ROS.

When disposal is outrun, ROS damage the macromolecules they encounter. Membrane lipid peroxidation, read out biochemically as malondialdehyde (MDA), is the most widely measured consequence and the same reaction that Glutathione Peroxidase 4 (GPX4) restrains to prevent ferroptosis; proteins accumulate carbonyl adducts and oxidized cysteines, and DNA acquires lesions such as 8-oxo-guanine. Cells answer through the kelch like ECH associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (Nrf2) axis, in which oxidation of KEAP1 cysteines releases Nrf2 to transcribe the antioxidant and detoxification program, while nuclear factor kappa B (NF-κB) couples the same signals to inflammatory transcription. Sustained stress engages autophagy, apoptotic cascades and cellular senescence, each of which can in turn alter ROS production.

That reciprocity is what makes oxidative stress difficult to place causally: it drives pathology in neurodegeneration, cardiovascular disease, diabetic complications, cancer and aging, and is also generated by those same processes, so in most diseases it is both cause and consequence rather than either alone. The therapeutic history reflects this. Large trials of indiscriminate dietary antioxidants such as vitamin E and β-carotene produced no benefit and occasional harm, consistent with blunting redox signaling the cell requires, and attention has moved instead to targeted approaches — Nrf2 activators, mitochondria-directed antioxidants, and iron chelation — that aim at a specific source or compartment rather than at ROS in general.