There is significant evidence that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the organism. Mitochondria have been thought to both play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction through several mechanisms, including stimulation of opening of permeability transition pores. Until recently, the functional significance of ROS sources different from mitochondria has received lesser attention. However, the most recent data, besides confirming the mitochondrial role in tissue oxidative stress and protection, show interplay between mitochondria and other ROS cellular sources, so that activation of one can lead to activation of other sources. Thus, it is currently accepted that in various conditions all cellular sources of ROS provide significant contribution to processes that oxidatively damage tissues and assure their survival, through mechanisms such as autophagy and apoptosis.

Free radicals are chemical species (atoms, molecules, or ions) containing one or more unpaired electrons in their external orbitals and generally display a remarkable reactivity. The evidence of their existence was obtained only at the beginning of the 20th century. Chemists gradually ascertained the involvement of free radicals in organic reactions and, in the middle of the 20th century, their production in biological systems. For several decades, free radicals were thought to cause exclusively damaging effects . This idea was mainly supported by the finding that oxygen free radicals readily react with all biological macromolecules inducing their oxidative modification and loss of function. Moreover, evidence was obtained that when, in the living organism, free radicals are not neutralized by systems of biochemical defences, many pathological conditions develop. However, after some time, it became clear that the living systems not only had adapted to the coexistence with free radicals but also developed methods to turn these toxic substances to their advantage by using them in critical physiological processes. Therefore, free radicals play a dual role in living systems: they are toxic by-products of aerobic metabolism, causing oxidative damage and tissue dysfunction, and serve as molecular signals activating beneficial stress responses. This discovery also changed the way we consider antioxidants. Their use is usually regarded as helpful to counteract the damaging effects of free radicals but sometimes is harmful as it can block adaptive responses induced by low levels of radicals.

Mitochondria in aerobic eukaryotic cells are both the site of energy production and the formation of harmful species, such as radicals and other reactive oxygen species, known as ROS. They contain an efficient antioxidant system, including low-molecular-mass molecules and enzymes that specialize in removing various types of ROS or repairing the oxidative damage of biological molecules. Under normal conditions, ROS production is low, and mitochondria, which are their primary target, are slightly damaged in a similar way to other cellular compartments, since the ROS released by the mitochondria into the cytosol are negligible. As the mitochondrial generation of ROS increases, they can deactivate components of the respiratory chain and enzymes of the Krebs cycle, and mitochondria release a high amount of ROS that damage cellular structures. More recently, the feature of the mitochondrial antioxidant system, which does not specifically deal with intramitochondrial ROS, was discovered. Indeed, the mitochondrial antioxidant system detoxifies exogenous ROS species at the expense of reducing the equivalents generated in mitochondria. Thus, mitochondria are also a sink of ROS. These observations highlight the importance of the mitochondrial antioxidant system, which should be considered in our understanding of ROS-regulated processes. These processes include cell signaling and the progression of metabolic and neurodegenerative disease.

Currently, it is known that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the organism. It is also known that mitochondria, because of their capacity to produce free radicals, play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction through several mechanisms, including the stimulation of permeability transition pore opening. This process leads to mitoptosis and mitophagy, two sequential processes that are a universal route of elimination of dysfunctional mitochondria and is essential to protect cells from the harm due to mitochondrial disordered metabolism. To date, there is significant evidence not only that the above processes are induced by enhanced reactive oxygen species (ROS) production, but also that such production is involved in the other phases of the mitochondrial life cycle. Accumulating evidence also suggests that these effects are mediated through the regulation of the expression and the activity of proteins that are engaged in processes such as genesis, fission, fusion, and removal of mitochondria. This review provides an account of the developments of the knowledge on the dynamics of the mitochondrial population, examining the mechanisms governing their genesis, life, and death, and elucidating the role played by free radicals in such processes.

Unaccustomed and/or exhaustive exercise generates excessive free radicals and reactive oxygen and nitrogen species leading to muscle oxidative stress-related damage and impaired contractility. Conversely, a moderate level of free radicals induces the body’s adaptive responses. Thus, a low oxidant level in resting muscle is essential for normal force production, and the production of oxidants during each session of physical training increases the body’s antioxidant defenses. Mitochondria, NADPH oxidases and xanthine oxidases have been identified as sources of free radicals during muscle contraction, but the exact mechanisms underlying exercise-induced harmful or beneficial effects yet remain elusive. However, it is clear that redox signaling influences numerous transcriptional activators, which regulate the expression of genes involved in changes in muscle phenotype. The mitogen-activated protein kinase family is one of the main links between cellular oxidant levels and skeletal muscle adaptation. The family components phosphorylate and modulate the activities of hundreds of substrates, including transcription factors involved in cell response to oxidative stress elicited by exercise in skeletal muscle. To elucidate the complex role of ROS in exercise, here we reviewed the literature dealing on sources of ROS production and concerning the most important redox signaling pathways, including MAPKs that are involved in the responses to acute and chronic exercise in the muscle, particularly those involved in the induction of antioxidant enzymes.