Uncoupling proteins and the control of mitochondrial reactive oxygen species production

Mailloux, Ryan J.; Harper, Mary‐Ellen

doi:10.1016/j.freeradbiomed.2011.06.022

Cited by 460 publications

(359 citation statements)

References 134 publications

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“…135 (3) Uncoupling proteins (UCPs) are mitochondrial anion carrier proteins that mitigate mitochondrial ROS emission, probably by regulating the mitochondrial membrane potential. 136 A recent study using UCP3 KO mice showed that UCP3 enhanced mitoHK-II binding in skeletal muscle, participating in a UCP3-mediated decrease in ROS emission. 99 (4) Another intriguing regulatory mechanism of mitoHK-II was obtained from studies of p53, a key tumor suppressor.…”

Section: Other Modulation Of Mitohk-iimentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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Accumulating evidence reveals that metabolic and cell survival pathways are closely related, sharing common signaling molecules. Hexokinase catalyzes the phosphorylation of glucose, the rate-limiting first step of glycolysis. Hexokinase II (HK-II) is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues. It is also upregulated in many types of tumors associated with enhanced aerobic glycolysis in tumor cells, the Warburg effect. In addition to the fundamental role in glycolysis, HK-II is increasingly recognized as a component of a survival signaling nexus. This review summarizes recent advances in understanding the protective role of HK-II, controlling cellular growth, preventing mitochondrial death pathway and enhancing autophagy, with a particular focus on the interaction between HK-II and Akt/mTOR pathway to integrate metabolic status with the control of cell survival.

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Section: Other Modulation Of Mitohk-iimentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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“…In unicellular organisms, as well as in non-thermogenic animal and plant tissues, UCPs can limit the production of ROS by the mitochondrial respiratory chain (Jarmuszkiewicz et al 2010;Mailloux and Harper 2011;Vercesi et al 2006;Nicholls 2006;Cannon et al 2006;Echtay 2007). Mitochondria are the main source of ROS, which are important cell signalling molecules that are the natural by-products of aerobic respiration but can severely impair cellular functions and induce cell death when they accumulate to a toxic level (Mailloux and Harper 2011;Murphy 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Mitochondria are the main source of ROS, which are important cell signalling molecules that are the natural by-products of aerobic respiration but can severely impair cellular functions and induce cell death when they accumulate to a toxic level (Mailloux and Harper 2011;Murphy 2009). High concentrations of ROS can induce the oxidation of biomolecules.…”

Section: Introductionmentioning

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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“…Whether or not this is associated with the significant up-regulation of UCP3 remains unclear since the role of this protein is still unknown. However, potential functions are related to metabolic balancing [36] as well as handling of reactive oxygen species (ROS) [37]. We also observed a significantly increased fraction of rotenone-insensitive respiration.…”

Section: Discussionmentioning

confidence: 76%

Induction of mitochondrial biogenesis and respiration is associated with mTOR regulation in hepatocytes of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA)

Hagland

Nilsson

Burri

et al. 2013

Biochemical and Biophysical Research Communications

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Word count: 4587 2 ABSTRACTThe hypolipidemic effect of peroxisome proliferator-activated receptor (PPAR) activators has been explained by increasing mitochondrial fatty acid oxidation, as observed in livers of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA). PPAR-activation does, however, not fully explain the metabolic adaptations observed in hepatocytes after treatment with TTA. We therefore characterized the mitochondrial effects, and linked this to signalling by the metabolic sensor, the mammalian target of rapamycin (mTOR). In hepatocytes isolated from TTA-treated rats, the changes in cellular content and morphology were consistent with hypertrophy. This was associated with induction of multiple mitochondrial biomarkers, including mitochondrial DNA, citrate synthase and mRNAs of mitochondrial proteins.Transcription analysis further confirmed activation of PPARα-associated genes, in addition to genes related to mitochondrial biogenesis and function. Analysis of mitochondrial respiration revealed that the capacity of both electron transport and oxidative phosphorylation were increased. These effects coincided with activation of the stress related factor, ERK1/2, and mTOR. The protein level and phosphorylation of the downstream mTOR targets eIF4G and 4E-BP1 were induced. In summary, TTA increases hepatocyte respiration by inducing hypertrophy and mitochondrial biogenesis in rat, via adaptive regulation of PPARs as well as mTOR.

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Uncoupling proteins and the control of mitochondrial reactive oxygen species production

Cited by 460 publications

References 134 publications

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

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

Induction of mitochondrial biogenesis and respiration is associated with mTOR regulation in hepatocytes of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA)

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