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THE MECHANISMS OF MITOCHONDRIAL ROS PRODUCTION AND THEIR ROLE IN REDOX SIGNALING Stefan Dröse, University Hospital Frankfurt, Germany Mitochondria equipped with powerful superoxide/hydrogen peroxide generators and an effective antioxidant system play an important role in cellular redox regulation and signaling. Otherwise, an elevated mitochondrial generation of these reactive oxygen species (ROS) can have severe pathophysiological consequences. To understand how mitochondrial superoxide/ hydrogen peroxide can cause these contradicting effects it is necessary to locate the ROS generator sites under different (patho-) physiological conditions and to decipher the molecular mechanisms that support their production. Recent investigations identified other proteins besides the well-established generators complex I (NADH:ubiquinone oxidoreductase) and complex III (cytochrome bc1 complex) as important sources and modulators of mitochondrial ROS, especially complex II (succinate:ubiquinone oxidoreductase) and the 2-oxoglutarate-dehydrogenase complex. The multiple ROS generator sites enable a distinct production of hydrogen peroxide that is regulated by concentrations and the redox state of predominant electron-donating substrates. Redox signaling linked to this specific hydrogen peroxide production is realized by the selective oxidation of thiols in a generator-selective group of target proteins as revealed by redox-proteomic approaches. Major determinants of this selectivity are a differential release of hydrogen peroxide into the mitochondrial sub-compartments (matrix, intermembrane-space and ‘outside’) and probably also a certain proximity of the target protein to the ROS generator. Interestingly, the activities of some ROS generators are also regulated by thiol-modifications. While redox signaling under physiological conditions may allow a fine-tuning of mitochondrial functions, a massive ROS production (oxidative stress) will trigger pathways that lead to apoptosis or necrosis. During these processes, redox-modifications of mitochondrial proteins are besides divalent cations – especially calcium - main promotors of mitochondrial permeability transition.

Stefan Dröse

doi: 10.1016/j.freeradbiomed.2016.10.022

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HYDROGEN PEROXIDE RELEASE FROM MITOCHONDRIA IN REGULATING METABOLIC FUNCTIONS Jan Riemer, University of Cologne, Germany Mitochondria are a major source of reactive oxygen species. Superoxide anions are released from the respiratory chain towards matrix and mitochondrial intermembrane space. There, they are rapidly dismutated to hydrogen peroxide which in turn either diffuses further or is the target of a number of enzymatic pathways. The spatiotemporal dynamics of hydrogen peroxide levels, the hierarchy of enzyme systems that handle it and the targets of hydrogen peroxide are the focus of this study. I present our insights on how hydrogen peroxide is handled in the mitochondrial matrix and how this handling affects its targets, the local glutathione pool and the viability of the cell.

Jan Riemer

doi: 10.1016/j.freeradbiomed.2016.10.023

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