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.

Hypermetabolic state in hyperthyroidism is associated with tissue oxidative injury. Available data indicate that hyperthyroid tissues exhibit an increased ROS and RNS production. The increased mitochondrial ROS generation is a side effect of the enhanced level of electron carriers, by which hyperthyroid tissues increase their metabolic capacity. Investigations of antioxidant defence system have returned controversial results. Moreover, other thyroid hormone-linked biochemical changes increase tissue susceptibility to oxidative challenge, which exacerbates the injury and dysfunction they suffer under stressful conditions. Mitochondria, as a primary target for oxidative stress, might account for hyperthyroidism linked tissue dysfunction. This is consistent with the inverse relationship found between functional recovery of ischemic hyperthyroid hearts and mitochondrial oxidative damage and respiration impairment. However, thyroid hormone-activated mitochondrial mechanisms provide protection against excessive tissue dysfunction, including increased expression of uncoupling proteins, proteolytic enzymes and transcriptional coactivator PGC-1, and stimulate opening of permeability transition pores.

The effects of altered thyroid states on lipid peroxidation, antioxidant capacity, and susceptibility to oxidative stress of rat tissues were examined. Hypothyroidism was induced by administering methimazole in drinking water for 15 days. Hyperthyroidism was elicited by a 10-day treatment of hypothyroid rats with tri-iodothyronine (10 micrograms/100 g body weight). In tissues of hypothyroid rats the lipid peroxidation was not modified, whereas in hyperthyroid rats lipid peroxidation increased in liver and heart but not in skeletal muscle. The glutathione peroxidase activity increased significantly in heart and muscle of hypothyroid rats and in muscle of hyperthyroid rats. The glutathione reductase activity was not modified in tissues of hypothyroid and hyperthyroid rats. In both rat groups the whole antioxidant capacity of tissues decreased, but significantly only in liver and heart. The results obtained studying the response to oxidative stress in vitro indicated that the susceptibility to oxidative challenge was increased in all tissues of hyperthyroid rats and in heart and muscle of hypothyroid animals. These results are explainable in terms of tissue variations in haemoprotein content and/or of antioxidant capacity. Since it has been reported that hypothyroidism offers in vivo protection against free radical damage, we suggest that such an effect could be due to greater effectiveness of cellular defence systems different from antioxidant ones.

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We studied the effects of physical training on antioxidant defences and susceptibility to damage induced by exhaustive exercise in tissues of adult (12 mo) rats. Therefore, untrained animals were sacrificed either at rest (n = 8) or immediately after swimming to exhaustion (n = 8). Rats trained to swim for 10 weeks were also sacrificed, 48 hr after the last exercise, either at rest (n = 8) or after exhaustive swimming (n = 8). Integrity of mitochondria and sarcoplasmic (SR) or endoplasmic (ER) reticulum of liver, heart, and muscle was assessed by measuring mitochondrial respiratory control and latency of alkaline phosphatase activity. Lipid peroxidation was measured by determination of malondialdehyde and hydroperoxides. Additionally, the effect of training on tissue antioxidant systems was examined by determining the glutathione peroxidase (GPX) and glutathione reductase (GR) activity and the overall antioxidant capacity (CA). Membrane integrity was unaffected by training in liver and muscle, and improved in heart of at rest animals, whereas lipid peroxidation was reduced in both liver and heart. Glutathione peroxidase and glutathione reductase activity, and overall antioxidant capacity were increased (p < 0.05) by training in liver and muscle. In heart, antioxidant capacity was increased from 0.21+/-0.01 to 0.33+/-0.02 (p<0.05), but glutathione peroxidase activity remained unchanged (p>0.05), and glutathione reductase activity was decreased from 3.56+/-0.08 to 2.27+/-0.10 micromol x min(-1) x g(-1) (p < 0.05). The exhaustive exercise gave rise to tissue damage irrespective of trained state, as documented by similar loss of SR and ER integrity, and increase (p<0.05) in lipid peroxidation found in exhausted trained and untrained rats. However, the above changes were elicited by exercise of greater duration in trained than in untrained rats (340+/-17 min and 233+/-6 min, respectively). These findings support the view that free radical-induced damage in muscle could be one of the factors involved in muscle fatigue. If so, the increased endurance in trained rats should reflect lengthening of the time required for the oxidative processes to sufficiently impair cell functions so as to make further exercise impossible.

At present, obesity is one of the most important public health problems in the world because it causes several diseases and reduces life expectancy. Although it is well known that insulin resistance plays a pivotal role in the development of type 2 diabetes mellitus (the more frequent disease in obese people) the link between obesity and insulin resistance is yet a matter of debate. One of the most deleterious effects of obesity is the deposition of lipids in non-adipose tissues when the capacity of adipose tissue is overwhelmed. During the last decade, reduced mitochondrial function has been considered as an important contributor to 'toxic' lipid metabolite accumulation and consequent insulin resistance. More recent reports suggest that mitochondrial dysfunction is not an early event in the development of insulin resistance, but rather a complication of the hyperlipidemia-induced reactive oxygen species (ROS) production in skeletal muscle, which might promote mitochondrial alterations, lipid accumulation and inhibition of insulin action. Here, we review the literature dealing with the mitochondria-centered mechanisms proposed to explain the onset of obesity-linked IR in skeletal muscle. We conclude that the different pathways leading to insulin resistance may act synergistically because ROS production by mitochondria and other sources can result in mitochondrial dysfunction, which in turn can further increase ROS production leading to the establishment of a harmful positive feedback loop.

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