Do not overcharge the system or it will explode!: how mitochondrial uncoupling protein 2 maintains endothelial function.

T he electrochemical gradient over the inner mitochon-drial membrane is the driving force for cellular ATP production. For this, electrons, which are derived from suc-cinate and NADH, are passed along the mitochondrial electron transfer chain, and the resulting energy is used to pump protons. The transport of the positively charged protons into the mitochondrial inner membrane space builds up an electric gradient mitochondrial membrane potential (ΔΨ) and a chemical gradient ΔpH. The effective proton motive force is ΔΨ −2.3·RT·ΔpH. Mitochondria are not only the central cellular producers of ATP but also a significant source of reactive oxygen species (ROS), which are formed as a consequence of electron leak from the respiratory chain. This relatively frequent event occurs when an electron, particularly at complex I, complex III, or ubiquinone, escapes from the transfer chain and reacts with oxygen. The resulting superox-ide anions (O 2 −) are to a great extent detoxified by manganese superoxide dismutase (MnSOD), and homozygous deletion of this important antioxidative enzyme is lethal. A low transfer rate of electrons through the respiratory chain increases the ratio of reduced to oxidized compounds and therefore favors electron escape onto oxygen and thus ROS production. Because a high ΔΨ hinders proton pumping over the inner mitochondrial membrane, high ΔΨ is thought to decrease the electron transport rate through the respiratory chain, and thus to increase ROS formation. Conversely, a reduction of ΔΨ reduces mitochondrial ROS formation. 1 Besides increasing the ADP-to-ATP ratio and thus the turnover of complex V, respiratory chain uncoupling compounds have been shown to lower ΔΨ. Chemical uncouplers like dinitrophenol not only massively reduce ΔΨ but also lower mitochondrial ROS formation to an extent that ROS, in the presence of an intact antioxidant defense, become virtually undetectable. Mechanistically, uncouplers, which are also abused for fat loss therapy, are lipophilic redox-cyclers that move protons over the inner mitochondrial membrane and bypass the ATP synthase. Importantly, with the protein family of uncoupling proteins (UCP1 to UCP5), such a function is also achieved physiologically. 1 UCP1 is highly expressed in brown adipose tissue, and its uncoupling function facilitates thermogenesis. UCP4 and UCP5 are expressed tissue-specifically, whereas UCP2 and UCP3 show a different and broader expression. Because UCP2 to UCP5 uncouple less extensively than UCP1, they do not contribute to thermogenesis, and their negative impact on cellular ATP production is small. 2 Rather, these UCPs mediate a low degree of mitochondrial uncou-pling …