Mechanisms of mitochondrial redox signaling

The mitochondrial respiratory chain is a main source of reactive oxygen species (ROS) in eukaryotic cells. Mitochondrial ROS associated with a disfunction of respiratory chain complexes have been implicated in a number of degenerative diseases and the process of biological aging. However, recent findings suggest that mitochondrial ROS can also be an integral part of cellular signal transduction. Within the respiratory chain, complexes I (NADH:ubiquinone oxidoreductase) and III (ubiquinol:cytochrome c oxidoreductase; cytochrome bc₁ complex) are generally regarded as the main producers of superoxide anions. Oxidative stress can be attributed mainly to complex I since it releases superoxide completely into the mitochodrial matrix. This occurs especially when electrons flow back against the gradient of redox potentials from succinate via complex II and ubiquinone into complex I (so called ‘reverse electron transfer') which requires a high membrane potential. Several lines of evidence indicate that those mitochondrial ROS involved in cellular redox signaling are instead generated at the Q_o site of complex III which delivers superoxide into the intermembrane space. Mechanistic studies have shown that the redox state of the ubiquinone pool (Q pool) and the acitivity of complex II (succinate:ubiquinone oxidoreductase) have a major impact on this process (Dröse and Brandt, 2008; Dröse et al., 2011). Data obtained with a redox proteomic approach with isolated rat heart mitochondria supported the view that ‘signaling ROS' are rather generated at complex III and revealed putative target proteins of this redox signal.