It has long been recognized that energy metabolism is linked to the production of reactive oxygen species (ROS) and critical enzymes allied to metabolic pathways can be affected by redox reactions. This interplay between energy metabolism and ROS becomes most apparent during the aging process and in the onset and progression of many age-related diseases (i.e. diabetes, metabolic syndrome, atherosclerosis, neurodegenerative diseases). As such, the capacity to identify metabolic pathways involved in ROS formation, as well as specific targets and oxidative modifications is crucial to our understanding of the molecular basis of age-related diseases and for the design of novel therapeutic strategies. Herein we review oxidant formation associated with the cell's energetic metabolism, key antioxidants involved in ROS detoxification, and the principal targets of oxidant species in metabolic routes and discuss their relevance in cell signaling and age-related diseases.

The free radical nitric oxide (^·NO) is a key mediator in different physiological processes such as vasodilation, neurotransmission, inflammation, and cellular immune responses, and thus preserving its bioavailability is essential. In several disease conditions, superoxide radical (O₂^·−) production increases and leads to the rapid “inactivation” of ^·NO by a diffusion-controlled radical termination reaction that yields a potent and short-lived oxidant, peroxynitrite. This reaction not only limits ^·NO bioavailability for physiological signal transduction but also can divert and switch the biochemistry of ^·NO toward nitrooxidative processes. Indeed, since the early 1990s peroxynitrite (and its secondary derived species) has been linked to the establishment and progression of different acute and chronic human diseases and also to the normal aging process. Here, we revisit an earlier and classical review on the role of peroxynitrite in human physiology and pathology (Pacher P, Beckman J, Liaudet L. Physiol Rev 87: 315–424, 2007) and further integrate, update, and interpret the accumulated evidence over 30 years of research. Innovative tools and approaches for the detection, quantitation, and sub- or extracellular mapping of peroxynitrite and its secondary products (e.g., protein 3-nitrotyrosine) have allowed us to unambiguously connect the complex biochemistry of peroxynitrite with numerous biological outcomes at the physiological and pathological levels. Furthermore, our current knowledge of the ^·NO/O₂^·− and peroxynitrite interplay at the cell, tissue, and organ levels is assisting in the discovery of therapeutic interventions for a variety of human diseases.