Figure 1.

Oxidative phosphorylation and mitochondrial uncoupling. Substrate-derived electrons from glucose and fatty acid metabolism flow through complexes I–IV of the electron transport chain embedded in the mitochondrial inner membrane and the energy of this process is used for pumping protons (H⁺) from the matrix into the intermembrane space. The resulting proton gradient sustains the mitochondrial membrane potential (Δψ_m), which drives ATP synthase (oxidative phosphorylation). The ATP and ADP are exchanged between the matrix and cytoplasm via ANT. Proton conductance (proton leak) induced by uncoupling proteins (exemplified here by the ubiquitous UCP2) competes for the same proton gradient, resulting in lower values of (Δψ_m) and diminished production of ATP. Decrease in Δψ_m accelerates electron transport and mitochondrial respiration, limiting the odds for electron escape and production of superoxide, a prototype of ROS. Activation of UCP2 by ROS (purple dotted arrow) provides an important negative feedback mechanism for the regulation of Δψ_m and mitochondrial oxidant production. The colour reproduction of this figure is available at the British Journal of Cancer online.