Hydroperoxy Fatty Acid Cycling Mediated by Mitochondrial Uncoupling Protein UCP2

Jabůrek, Martin; Miyamoto, Sayuri; Mascio, Paolo Di; Garlid, Keith D.; Ježek, Petr

doi:10.1074/jbc.m405339200

Cited by 90 publications

(79 citation statements)

References 59 publications

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“…An uncoupling activity of UCP2 was initially proposed because of UCP2 similarity with UCP1 but still remains controversial (39)(40)(41)(42)(43). In the present study, UCP2 overexpression did not uncouple oxidative phosphorylation as shown by the maintained membrane potential, respiratory control, and P/O ratios.…”

Section: Discussionmentioning

confidence: 42%

Mitochondrial Retrograde Signaling Mediated by UCP2 Inhibits Cancer Cell Proliferation and Tumorigenesis

et al. 2014

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Cancer cells tilt their energy production away from oxidative phosphorylation (OXPHOS) toward glycolysis during malignant progression, even when aerobic metabolism is available. Reversing this phenomenon, known as the Warburg effect, may offer a generalized anticancer strategy. In this study, we show that overexpression of the mitochondrial membrane transport protein UCP2 in cancer cells is sufficient to restore a balance toward oxidative phosphorylation and to repress malignant phenotypes. Altered expression of glycolytic and oxidative enzymes mediated the effects of this metabolic shift. Notably, UCP2 overexpression increased signaling from the master energy-regulating kinase, adenosine monophosphate-activated protein kinase, while downregulating expression of hypoxia-induced factor. In support of recent new evidence about UCP2 function, we found that UCP2 did not function in this setting as a membrane potential uncoupling protein, but instead acted to control routing of mitochondria substrates. Taken together, our results define a strategy to reorient mitochondrial function in cancer cells toward OXPHOS that restricts their malignant phenotype.

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Section: Discussionmentioning

confidence: 42%

Mitochondrial Retrograde Signaling Mediated by UCP2 Inhibits Cancer Cell Proliferation and Tumorigenesis

et al. 2014

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“…Finally, we propose that these data enhance our understanding of how the mitochondria function as a cellular rheostat balancing cellular prosurvival and cell death homeostatic programs. However, it should be noted that the roles of the various mitochondrial uncoupling protein homologues are still being investigated and have a multitude of metabolic and signaling effects, (22,37,38) that have not been investigated in this study but may contribute to their role in cellular protection.…”

Section: Discussionmentioning

confidence: 99%

Uncoupling Proteins 2 and 3 Function in Concert to Augment Tolerance to Cardiac Ischemia

McLeod

Aziz

Hoyt

et al. 2005

Journal of Biological Chemistry

139

108

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Transient cardiac ischemia activates cell survival signaling, conferring subsequent ischemia tolerance to the heart. This biological phenomenon, termed ischemic preconditioning, results in improved clinical outcome and attenuated infarct size following myocardial infarction. To explore genomic modifications underpinning this ischemia tolerance, we delineated the regulation and function of the cardiac enriched mitochondrial uncoupling proteins 2 and 3 during delayed ischemic preconditioning in the rat. Cardiac transcripts of genes encoding uncoupling proteins 2 and 3 are upregulated in parallel with infarct size reduction in preconditioned hearts. Mitochondria isolated from preconditioned hearts exhibit an augmented inducible proton leak. In parallel, following anoxiareoxygenation these mitochondria generate less hydrogen peroxide compared with non-preconditioned mitochondria. Preconditioning in rat cardiac derived myoblasts is abolished following uncoupling protein-2 depletion by RNA-interference. RNAi of uncoupling protein-3 partially attenuates the capacity to precondition these cells. Functional characterization of anoxia and reoxygenation tolerance following uncoupling protein 2 or 3 and combined 2 and 3 RNAi shows the largest reduction in viability follows depletion of both homologues. Uncoupling protein-2 depletion alone significantly attenuates anoxia-reoxygenation tolerance but uncoupling protein-3 depletion does not reduce anoxia tolerance. In parallel combined uncoupling protein depletion and isolated uncoupling protein-2 depletion augments ROS production in viable cardiomyocytes following anoxia-reoxygenation. Concurrent antioxidant administration ameliorates the uncoupling protein-depleted anoxia-susceptible phenotype. In conclusion, mitochondrial uncoupling proteins are necessary components of ischemia tolerance and function as components of the cellular antioxidant defense program. In the cytoprotective hierarchy, uncoupling protein-2 appears to play a greater role than uncoupling protein-3 in modulating ischemia/anoxia tolerance in heart-derived cells.The cell survival program, termed ischemic preconditioning, evoked by transient nonlethal tissue ischemia, is evolutionarily conserved and is evident across multiple organs/tissues. The signal transduction networks engendering this phenomenon are well described (1); however, functional cellular modifications conferring ischemia tolerance are less tangible. Interestingly, the invariable metabolic signature of preconditioned tissue is enhanced capacity to restore mitochondrial function and ATP production following an ischemic insult (2). The mechanistic links between the molecular adaptations of the mitochondrion and the preconditioning cell survival program require further characterization. Further credence to the importance of mitochondrial adaptation to preconditioning-induced cell survival has been shown by improved mitochondrial respiratory and bioenergetic recovery following anoxia and reoxygenation in mitochondria extracted from ischemic, genomi...

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“…HNE forms stable adducts with proteins so this kind of interaction with UCP would not be reversible, but specific HNE adducts of UCPs have not been detected thus far. Interestingly, in the case of hydroperoxy fatty acids, which are also lipid peroxidation products, a classical cycling mechanism of UCP action has been proposed (Jaburek et al 2004). …”

Section: Discussionmentioning

confidence: 99%

Hydroxynonenal, a lipid peroxidation end product, stimulates uncoupling protein activity in Acanthamoeba castellanii mitochondria; the sensitivity of the inducible activity to purine nucleotides depends on the membranous ubiquinone redox state

Woyda-Płoszczyca

Jarmuszkiewicz

2012

J Bioenerg Biomembr

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We studied the influence of exogenously generated superoxide and exogenous 4-hydroxy-2-nonenal (HNE), a lipid peroxidation end product, on the activity of the Acanthamoeba castellanii uncoupling protein (AcUCP). The superoxide-generating xanthine/xanthine oxidase system was insufficient to induce mitochondrial uncoupling. In contrast, exogenously added HNE induced GTP-sensitive AcUCP-mediated mitochondrial uncoupling. In nonphosphorylating mitochondria, AcUCP activation by HNE was demonstrated by increased oxygen consumption accompanied by a decreased membrane potential and ubiquinone (Q) reduction level. The HNE-induced GTP-sensitive proton conductance was similar to that observed with linoleic acid. In phosphorylating mitochondria, the HNEinduced AcUCP-mediated uncoupling decreased the yield of oxidative phosphorylation. We demonstrated that the efficiency of GTP to inhibit HNE-induced AcUCPmediated uncoupling was regulated by the endogenous Q redox state. A high Q reduction level activated AcUCP by relieving the inhibition caused by GTP while a low Q reduction level favoured the inhibition. We propose that the regulation of UCP activity involves a rapid response through the endogenous Q redox state that modulates the inhibition of UCP by purine nucleotides, followed by a late response through lipid peroxidation products resulting from an increase in the formation of reactive oxygen species that modulate the UCP activation.

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Hydroperoxy Fatty Acid Cycling Mediated by Mitochondrial Uncoupling Protein UCP2

Cited by 90 publications

References 59 publications

Mitochondrial Retrograde Signaling Mediated by UCP2 Inhibits Cancer Cell Proliferation and Tumorigenesis

Mitochondrial Retrograde Signaling Mediated by UCP2 Inhibits Cancer Cell Proliferation and Tumorigenesis

Uncoupling Proteins 2 and 3 Function in Concert to Augment Tolerance to Cardiac Ischemia

Hydroxynonenal, a lipid peroxidation end product, stimulates uncoupling protein activity in Acanthamoeba castellanii mitochondria; the sensitivity of the inducible activity to purine nucleotides depends on the membranous ubiquinone redox state

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