Reactive oxygen species (ROS) are produced continuously by complexes I and III of the electron transport chain when electrons leak from the respiratory chain and reduce molecular oxygen. At low concentrations, superoxide and hydrogen peroxide act as redox signals that modify cysteine residues on sensor proteins and influence proliferation, differentiation, and stress responses. The cell keeps ROS within this signaling range using a layered antioxidant defense: manganese superoxide dismutase (MnSOD/SOD2) in the matrix converts superoxide to hydrogen peroxide; glutathione peroxidases and peroxiredoxins reduce hydrogen peroxide to water using glutathione and thioredoxin; and glutathione itself is maintained in its reduced form by glutathione reductase at the expense of NADPH. When production exceeds this buffering capacity, the same molecules become damaging. They oxidize cardiolipin and other membrane lipids, carbonylate and cross-link proteins, and damage mitochondrial DNA, which has limited repair capacity because it is packaged with mitochondrial transcription factor A rather than histones. The result is a self-reinforcing loop: oxidative damage to complex I and III impairs electron transport, which increases electron leak, which produces more ROS.
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The diagram shows two curves. The lower one is the rate of ROS production from complexes I and III, and the upper one is the capacity of the antioxidant defenses, mainly MnSOD in the matrix and the glutathione and peroxiredoxin systems. As long as production stays below the defense capacity, ROS remain at signaling concentrations and reversibly modify cysteine residues on sensor proteins. When production crosses the defense line, the excess superoxide and hydrogen peroxide begin to oxidize cardiolipin, carbonylate proteins, and damage mitochondrial DNA. The critical point is that the same molecule is a signal below the line and a damaging agent above it, and the line is set by the antioxidant capacity, not by the absolute amount of ROS.
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