Mitochondrial oxygen radical formation

The recognition of the existence 02 -radicals in biological systems three decades ago has stimulated research activities in various directions. Apart from studies on the identity of generation sites metabolic pathways of reactive oxygen species (ROS) focused on their implication in pathogenetic events have met the interest of many research laboratories in the world. One major field of interest in relation to ROS is the (still pending) elucidation of their role in the biological process of aging. Only recently superoxide radical-derived (O2 ) species were found to have signaling functions completing the wide spectrum of the involvement of ROS in pathology and biology. Due to the nature of dioxygen e - -acceptance requires the interaction with one-e - donors. The reaction product is the superoxide radical which is the parent 02 -metabolite from which all further reactive 02 species can be derived. The composition of the respiratory chain with redox-cycling one-e - carriers, the high rate of the terminal oxygen reduction in combination with the presence of cooperative antioxidant activities strongly support the concept that mitochondria are of major significance in cellular ROS formation. This is considered to be valid for all of the three categories of events (physiological singaling, oxidative stress, aging) where 02 -radicals are assumed to play a role. ROS formation observed at isolated mitochondria under certain conditions is generally considered to prove the involvement of mitochondria in cellular oxygen, activation. However, transfer of these results to mitochondrial oxygen activation in living cells requires the exclusion of artefactual ROS generation possibly resulting from the isolation procedure or detection systems for 02 radicals. The present project was designed to clarify these uncertainties, to identify the underlying mechanisms which possibly convert energy-linked mitochondrial respiration to activities associated with the release of 02 radicals for signaling activities, the establishment of oxidative stress and, age-related ROS formation. Understanding of the in vivo regulation of these far reaching side effects of cell respiration will be an access to interventional strategies.