Abstract
BackgroundAlthough identified in several bird species, the biological role of the avian homolog of mammalian uncoupling proteins (avUCP) remains extensively debated. In the present study, the functional properties of isolated mitochondria were examined in physiological or pharmacological situations that induce large changes in avUCP expression in duckling skeletal muscle.ResultsThe abundance of avUCP mRNA, as detected by RT-PCR in gastrocnemius muscle but not in the liver, was markedly increased by cold acclimation (CA) or pharmacological hyperthyroidism but was down-regulated by hypothyroidism. Activators of UCPs, such as superoxide with low doses of fatty acids, stimulated a GDP-sensitive proton conductance across the inner membrane of muscle mitochondria from CA or hyperthyroid ducklings. The stimulation was much weaker in controls and not observed in hypothyroid ducklings or in any liver mitochondrial preparations. The production of endogenous mitochondrial reactive oxygen species (ROS) was much lower in muscle mitochondria from CA and hyperthyroid ducklings than in the control or hypothyroid groups. The addition of GDP markedly increased the mitochondrial ROS production of CA or hyperthyroid birds up to, or above, the level of control or hypothyroid ducklings. Differences in ROS production among groups could not be attributed to changes in antioxidant enzyme activities (superoxide dismutase or glutathione peroxidase).ConclusionThis work provides the first functional in vitro evidence that avian UCP regulates mitochondrial ROS production in situations of enhanced metabolic activity.
Highlights
Identified in several bird species, the biological role of the avian homolog of mammalian uncoupling proteins remains extensively debated
Fatty acids may contribute to the activation of avian homolog of mammalian uncoupling proteins (avUCP) expression by analogy with mammals in which the expression of muscle Uncoupling Protein (UCP) mainly depends on Non-Esterified Fatty Acids (NEFA) activation of Peroxysome Proliferator-Activated Receptors (PPAR) through their interaction with the UCP promoter [51]
The present results show that a Guanosine Di phosphate (GDP)-sensitive stimulation of mitochondrial proton leakage was obtained in the presence of known avian and mammals UCP in vitro coactivators, e.g., exogenous superoxide generated by the enzymatic reaction of xanthine and xanthine oxidase (XXO) and an adequate amount of NEFA [18,21]
Summary
Identified in several bird species, the biological role of the avian homolog of mammalian uncoupling proteins (avUCP) remains extensively debated. The respiratory chain function of mitochondria constitutes a major cellular source of superoxide and derived reactive oxygen species (ROS) in vivo [1,2]. It was proposed that the proton leak activity of these more ubiquitous UCPs would result in a mild uncoupling that would decrease proton motive force and stimulate oxygen consumption, reducing local oxygen tension and attenuating superoxide production [8,9,10]. A role for UCP2 and UCP3 in attenuating superoxide production by the electron transport chain to protecting against oxidative damage is supported by the increased cellular production of ROS in UCP2 knockout mice [14] and the increased mitochondrial oxidative damage in mice underexpressing UCP3 [15]. Inhibition of UCPs by nucleotides such as GDP increased both proton motive force and the mitochondrial production of ROS [16,17]
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