A function for novel uncoupling proteins: antioxidant defense of mitochondrial matrix by translocating fatty acid peroxides from the inner to the outer membrane leaflet

Goglia, Fernando; Vp, Skulachev

doi:10.1096/fj.03-0159hyp

Cited by 215 publications

(163 citation statements)

References 87 publications

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“…UCP3, a member of the mitochondrial transporter superfamily, is a protein for which several possible functions have been proposed (6,18,24,46,56). A role for UCP3 in FA metabolism has been suggested, where UCP3 expedites rates of FA oxidation by acting as a protein that facilitates mitochondrial FA anion efflux (24, 45,46).…”

Section: Discussionmentioning

confidence: 99%

Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis

Ljubicic

Adhihetty²,

Hood³

2004

Journal of Applied Physiology

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Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis. J Appl Physiol 97: 976 -983, 2004. First published May 14, 2004 10.1152/japplphysiol.00336.2004In an effort to better characterize uncoupling protein-3 (UCP3) function in skeletal muscle, we assessed basal UCP3 protein content in rat intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondrial subfractions in conjunction with measurements of state 4 respiration. UCP3 content was 1.3-fold (P Ͻ 0.05) greater in IMF compared with SS mitochondria. State 4 respiration was 2.6-fold greater (P Ͻ 0.05) in the IMF subfraction than in SS mitochondria. GDP attenuated state 4 respiration by ϳ40% (P Ͻ 0.05) in both subfractions. The UCP3 activator oleic acid (OA) significantly increased state 4 respiration in IMF mitochondria only. We used chronic electrical stimulation (3 h/day for 7 days) to investigate the relationship between changes in UCP3 protein expression and alterations in state 4 respiration during contractile activity-induced mitochondrial biogenesis. UCP3 content was increased by 1.9-and 2.3-fold in IMF and SS mitochondria, respectively, which exceeded the concurrent 40% (P Ͻ 0.05) increase in cytochrome-c oxidase activity. Chronic contractile activity increased state 4 respiration by 1.4-fold (P Ͻ 0.05) in IMF mitochondria, but no effect was observed in the SS subfraction. The uncoupling function of UCP3 accounted for 50 -57% of the OA-induced increase in state 4 respiration in IMF mitochondria, which was independent of the induced twofold difference in UCP3 content due to chronic contractile activity. Thus modifications in UCP3 function are more important than changes in UCP3 expression in modifying state 4 respiration. This effect is evident in IMF but not SS mitochondria. We conclude that UCP3 at physiological concentrations accounts for a significant portion of state 4 respiration in both IMF and SS mitochondria, with the contribution being greater in the IMF subfraction. In addition, the contradiction between human and rat training studies with respect to UCP3 protein expression may partly be explained by the greater than twofold difference in mitochondrial UCP3 content between rat and human skeletal muscle. skeletal muscle; exercise; mitochondria; uncoupling protein-3

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Section: Discussionmentioning

confidence: 99%

Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis

Ljubicic

Adhihetty²,

Hood³

2004

Journal of Applied Physiology

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“…The recent finding of Echtay et al (29), as outlined above, is well compatible with the suggested putative function of UCP3 in fatty acid metabolism. Based on a series of (human) experiments, we (32,33) and others (34,35) have previously suggested that the primary physiological function of muscle UCP3 is to export fatty acid anions from the mitochondrial matrix, rather than function as a UCP per se (36). Thus, UCP3 is upregulated under conditions of an abundance of fatty acid supply to the mitochondria, such as during fasting (37), high FFA levels (38), acute exercise (39), and high-fat feeding (36,38).…”

Section: Mitochondrial Damage: a Role For Lipid Peroxides?mentioning

confidence: 99%

“…As UCP3 is able to export fatty acid anions (and/or fatty acid peroxides) across the mitochondrial membrane away from the matrix (45), we (32,33) and others (34,35) previously postulated that UCP3 is a fatty acid anion and/or peroxide exporter that protects the mitochondrial matrix against lipid peroxidationinduced mitochondrial damage (32,35). It is important to note that the mitochondrial matrix, in contrast to the intermembrane space, is much more vulnerable to oxidative damage because the matrix contains DNA, RNA, and numerous enzymes of (among others) the Krebs cycle, which are very sensitive to ROS (35). Please also note that by exporting fatty acid anions, UCP3 also lowers the proton gradient, thus possessing uncoupling activity and further reducing ROS formation.…”

Section: Mitochondrial Damage: a Role For Lipid Peroxides?mentioning

confidence: 99%

Oxidative Capacity, Lipotoxicity, and Mitochondrial Damage in Type 2 Diabetes

2004

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Recent evidence points toward decreased oxidative capacity and mitochondrial aberrations as a major contributor to the development of insulin resistance and type 2 diabetes. In this article we will provide an integrative view on the interrelation between decreased oxidative capacity, lipotoxicity, and mitochondrial aberrations in type 2 diabetes. Type 2 diabetes is characterized by disturbances in fatty acid metabolism and is accompanied by accumulation of fatty acids in nonadipose tissues. In metabolically active tissues, such as skeletal muscle, fatty acids are prone to so-called oxidative damage. In addition to producing energy, mitochondria are also a major source of reactive oxygen species, which can lead to lipid peroxidation. In particular, the mitochondrial matrix, which contains DNA, RNA, and numerous enzymes necessary for substrate oxidation, is sensitive to peroxide-induced oxidative damage and needs to be protected against the formation and accumulation of lipids and lipid peroxides. Recent evidence reports that mitochondrial uncoupling is involved in the protection of the mitochondrial matrix against lipid-induced mitochondrial damage. Disturbances in this protection mechanism can contribute to the development of type 2 diabetes.

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“…It has been suggested that UCP-3 may export pyruvate 21 and fatty acids including lipid radicals 13,22 from the mitochondrial matrix along their electrochemical gradients. 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 .…”

Section: Discussionmentioning

confidence: 99%

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

Braun¹,

Rudner²,

Hennenlotter³

et al. 2012

European Urology Supplements

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A function for novel uncoupling proteins: antioxidant defense of mitochondrial matrix by translocating fatty acid peroxides from the inner to the outer membrane leaflet

Cited by 215 publications

References 87 publications

Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis

Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis

Oxidative Capacity, Lipotoxicity, and Mitochondrial Damage in Type 2 Diabetes

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

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