Induction of Endogenous Uncoupling Protein 3 Suppresses Mitochondrial Oxidant Emission during Fatty Acid-supported Respiration

Abstract

Uncoupling protein 3 (UCP3) expression increases dramatically in skeletal muscle under metabolic states associated with elevated lipid metabolism, yet the function of UCP3 in a physiological context remains controversial. Here, in situ mitochondrial H 2 O 2 emission and respiration were measured in permeabilized fiber bundles prepared from both rat and mouse (wild-type) gastrocnemius muscle after a single bout of exercise plus 18 h of recovery (Ex/R) that induced a ϳ2-4-fold increase in UCP3 protein. Elevated uncoupling activity (i.e. GDP inhibitable) was evident in Ex/R fibers only upon the addition of palmitate (known activator of UCP3) or under substrate conditions eliciting substantial rates of H 2 O 2 production (i.e. respiration supported by succinate or palmitoyl-L-carnitine/malate but not pyruvate/malate), indicative of UCP3 activation by endogenous reactive oxygen species. In mice completely lacking UCP3 (ucp3 ؊/؊ ), Ex/R failed to induce uncoupling activity. Surprisingly, when UCP3 activity was inhibited by GDP (rats) or in the absence of UCP3 (ucp3 ؊/؊ ), H 2 O 2 emission was significantly (p < 0.05) higher in Ex/R versus non-exercised control fibers.Collectively, these findings demonstrate that the oxidant emitting potential of mitochondria is increased in skeletal muscle during recovery from exercise, possibly as a consequence of prolonged reliance on lipid metabolism and/or altered mitochondrial biochemistry/morphology and that induction of UCP3 in vivo mediates an increase in uncoupling activity that restores mitochondrial H 2 O 2 emission to non-exercised, control levels.

Glutathionylation Acts as a Control Switch for Uncoupling Proteins UCP2 and UCP3

“…The absence of UCP3 in skeletal muscle increases oxidative damage and perturbs skeletal muscle metabolism (19). Increased UCP3 expression in muscle augments fatty acid metabolism and also curtails ROS production during fatty acid oxidation (20,21). Remarkably, although they have been linked to a plethora of cellular processes, the molecular control of UCP2 and UCP3 has remained elusive.…”

310 UCP-3 uncoupling protein confers hypoxia resistance in renal epithelial cells and is upregulated in renal cell carcinoma

“…Besides lowering Δ Ψ m and directly decreasing the concentration of lipid radicals in the matrix, pyruvate and fatty acids transports are thought to ensure an equilibrium between glycolysis and oxidative phosphorylation and to prevent Co-enzyme A shortage in the matrix and consecutive lipid-induced mitochondrial damage, respectively 23,24 . As matter of fact, UCP-3 upregulation increases the efficiency of fatty acid oxidation in exercising muscle 9 . Along those lines, in animal models and in human beings, fastening 25,26 , high fat diet 27 , or direct infusion of fatty acids 26 have been demonstrated to upregulate UCP-3 expression which is consistent with a specific function of UCP-3 in switching the metabolism from glucose to fatty acid respiration.…”

“…A recent meta-analysis demonstrates an association between the -55C/T polymorphism in the UCP-3 gene and obesity further suggesting such a UCP-3 function 28 . Further triggers of UCP-3 expression include (anaerobic) exercise of skeletal muscle 9,29 and ischemia/ reperfusion of the heart 20,30 . Likewise, oxidative stress following inhibition of glutathione reductase have been demonstrated to upregulate UCP-3 expression in rat myocardium 31 where UCP-3 has been demonstrated to be indispensable for ischemic preconditioning 20 .…”

Oxidative stress in adipose tissue as a primary link in pathogenesis of insulin resistance

“…Эти факты находятся в соответствии с современной концепцией биологии редокс-систем, согласно которой редокс-сигнализация осуществляется в условиях ниже того порога локальной концентрации H 2 O 2 (не превышающего 1 мкМ), за пределами которого развивается окислительный стресс [60][61][62]. Даже в норме скорость продукции H 2 O 2 митохондриями выше при окислении НЭЖК, чем углеводов [63,64]. В условиях перегрузки клетки энергетическими субстратами (метаболический стресс), что имеет место вследствие высокой концентрации глюкозы и НЭЖК в крови при ожирении, в электрон-транспортную цепь митохондрий устремляется увеличенный поток доноров электронов (NADH и FADH 2 ).…”