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Review
, 35 (5), 298-307

The On-Off Switches of the Mitochondrial Uncoupling Proteins

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Review

The On-Off Switches of the Mitochondrial Uncoupling Proteins

Vian Azzu et al. Trends Biochem Sci.

Abstract

Mitochondrial uncoupling proteins disengage substrate oxidation from ADP phosphorylation by dissipating the proton electrochemical gradient that is required for ATP synthesis. In doing this, the archetypal uncoupling protein, UCP1, mediates adaptive thermogenesis. By contrast, its paralogues UCP2 and UCP3 are not thought to mediate whole body thermogenesis in mammals. Instead, they have been implicated in a variety of physiological and pathological processes, including protection from oxidative stress, negative regulation of glucose sensing systems and the adaptation of fatty acid oxidation capacity to starving. Although much work has been devoted to how these proteins are activated, little is known of the mechanisms that reverse this activation.

Figures

Figure I
Figure I. A model for the physiological activation of uncoupling proteins by superoxide and its downstream derivatives such as HNE
A high protonmotive force set up by the respiratory chain increases the steady state concentration of reduced electron carriers that donate an electron to molecular oxygen, thereby increasing superoxide production. Formation of downstream free radicals begins a cascade of FA radical production that ultimately results in the generation of HNE, which activates uncoupling proteins, causing them to transport protons, leading to lower protonmotive force and decreased superoxide production. Abbreviations PUFA, polyunsaturated fatty acid; SOD, superoxide dismutase. HNE, 4-hydroxynonenal; PUFA, polyunsaturated fatty acid; SOD, superoxide dismutase.
Figure 1
Figure 1. Oxidative phosphorylation and proton leak pathways in mitochondria
Respiratory substrates are oxidized at mitochondrial respiratory complexes I–IV, leading to the ejection of protons (H+) into the intermembrane space (for diagramatic simplicity, the intermembrane space is depicted as being continuous with the cytosol). This proton electrochemical gradient is consumed by demand pathways via the Fo/F1 ATP synthase to produce ATP or by proton leak pathways, which release energy in the form of heat. Proton leak pathways can be mediated by UCP or by ANT.
Figure 2
Figure 2. Phylogenetic analysis of mitochondrial anion carriers and UCPs
(a) Analysis of the mitochondrial anion carriers suggests that UCP1–3 naturally fall into a subfamily that does not include UCP4 or UCP5. The figure shows the human SLC25 mitochondrial anion carrier members A1–A33 displayed using an unrooted topological algorithm. (b) Topological view of uncoupling proteins in different organisms shows that the archetypal eutherian UCP1 has undergone rapid evolution and is more distantly related to the uncoupling protein subancestor than its eutherian paralogues UCP2 and UCP3. Sequences are based on the accession IDs in Ref. (the sequences were courtesy of Dr Martin Jastroch). Full-length protein sequences were aligned using default settings on ClustalW and the tree was generated using TreeTop (http://www.genebee.msu.su/services/phtree_reduced.html). Abbreviations: AGC, aspartate/glutamate carrier; ANC, peroxisomal membrane protein; APC, ATP-Mg/Pi carrier; BMSC, bone marrow stromal cell mitochondrial carrier; CAC, carnitine/acylcarnitine carrier; CACL, carnitine/acylcarnitine-like carrier; CIC, tricarboxylate (citrate) carrier; DIC, dicarboxylate carrier; DNC, thiamine pyrophosphate carrier; GC, glutamate carrier; GDC, Graves disease carrier; KMCP, kidney mitochondrial carrier protein; MFTC, folate carrier; ODC, oxodicarboxylate carrier; OGC, oxoglutarate/malate carrier; ORN, ornithine carrier; PiC, phosphate carrier; SAMC, S-adenosylmethionine transporter. AGC, aspartate/glutamate carrier; ANC, peroxisomal membrane protein; ANT, adenine nucleotide translocase; APC, ATP-Mg/Pi carrier; BMCP, brain mitochondrial carrier protein; BMSC, bone marrow stromal cell mitochondrial carrier; CAC, carnitine/acylcarnitine carrier; CACL, carnitine/acylcarnitine-like carrier; CIC, tricarboxylate (citrate) carrier; DIC, dicarboxylate carrier; DNC, thiamine pyrophosphate carrier; GC, glutamate carrier; GDC, Graves disease carrier; KMCP, kidney mitochondrial carrier protein; MFTC, folate carrier; ODC, oxodicarboxylate carrier; OGC, oxoglutarate/malate carrier; ORN, ornithine carrier; PiC, phosphate carrier; SAMC, S-adenosylmethionine transporter; UCP, uncoupling protein.
Figure 3
Figure 3. The concerted regulation of the mitochondrial uncoupling proteins
Uncoupling proteins are likely to be controlled at multiple levels, such as transcription, translocation, ligand activation or inhibition and protein turnover. (a) (i) During adaptive thermogenesis in BAT, UCP1 synthesis is stimulated by transcription factors of the PKA and MAPK pathways. (ii) These pathways also induce lipolysis, which generates fatty acid (FA) ligands that activate UCP-mediated proton leak. (iii) Stimulation of β3-AR and insulin receptors also inhibit UCP1 and whole mitochondrial degradation by autophagic pathways. (b) UCP2 synthesis is regulated at the (i) transcriptional and (ii) translational levels. (iii) Protein activity can be further regulated by acute activators such as FA and HNE. (iv) Protein deactivation can occur by ligand inhibition and by rapid turnover of protein UCP2, probably by the ubiquitin proteasome system. (c) (i) UCP3 synthesis is regulated at the transcriptional level by starvation and muscle transcription factors. (ii) Protein activity can be further regulated by functional ligands, such as FA and HNE. The mechanism of protein deactivation can occur by ligand inhibition. In (b) and (c), UCP2 and UCP3 turnover can also theoretically occur as the result of mitochondrial turnover via the lysosomal pathway, although this pathway is slow compared with the likely degradation via the proteasomal pathway. Abbreviations: ATF, activating transcription factor; CREB, cAMP response element binding; IR, insulin receptor; NE, norepinephrine; Δ ψ, mitochondrial membrane potential; C/EBPβ, CCAAT-enhancer-binding protein-β; FA, fatty acid; HNF, hepatic nuclear factor; IL-1β, interleukin-1β; PPAR, peroxisome proliferator-activated receptor; SREBP-1c, sterol regulatory element binding protein-1c; MyoD, myogenic regulatory factor family protein.
Figure 3
Figure 3. The concerted regulation of the mitochondrial uncoupling proteins
Uncoupling proteins are likely to be controlled at multiple levels, such as transcription, translocation, ligand activation or inhibition and protein turnover. (a) (i) During adaptive thermogenesis in BAT, UCP1 synthesis is stimulated by transcription factors of the PKA and MAPK pathways. (ii) These pathways also induce lipolysis, which generates fatty acid (FA) ligands that activate UCP-mediated proton leak. (iii) Stimulation of β3-AR and insulin receptors also inhibit UCP1 and whole mitochondrial degradation by autophagic pathways. (b) UCP2 synthesis is regulated at the (i) transcriptional and (ii) translational levels. (iii) Protein activity can be further regulated by acute activators such as FA and HNE. (iv) Protein deactivation can occur by ligand inhibition and by rapid turnover of protein UCP2, probably by the ubiquitin proteasome system. (c) (i) UCP3 synthesis is regulated at the transcriptional level by starvation and muscle transcription factors. (ii) Protein activity can be further regulated by functional ligands, such as FA and HNE. The mechanism of protein deactivation can occur by ligand inhibition. In (b) and (c), UCP2 and UCP3 turnover can also theoretically occur as the result of mitochondrial turnover via the lysosomal pathway, although this pathway is slow compared with the likely degradation via the proteasomal pathway. Abbreviations: ATF, activating transcription factor; CREB, cAMP response element binding; IR, insulin receptor; NE, norepinephrine; Δ ψ, mitochondrial membrane potential; C/EBPβ, CCAAT-enhancer-binding protein-β; FA, fatty acid; HNF, hepatic nuclear factor; IL-1β, interleukin-1β; PPAR, peroxisome proliferator-activated receptor; SREBP-1c, sterol regulatory element binding protein-1c; MyoD, myogenic regulatory factor family protein.
Figure 3
Figure 3. The concerted regulation of the mitochondrial uncoupling proteins
Uncoupling proteins are likely to be controlled at multiple levels, such as transcription, translocation, ligand activation or inhibition and protein turnover. (a) (i) During adaptive thermogenesis in BAT, UCP1 synthesis is stimulated by transcription factors of the PKA and MAPK pathways. (ii) These pathways also induce lipolysis, which generates fatty acid (FA) ligands that activate UCP-mediated proton leak. (iii) Stimulation of β3-AR and insulin receptors also inhibit UCP1 and whole mitochondrial degradation by autophagic pathways. (b) UCP2 synthesis is regulated at the (i) transcriptional and (ii) translational levels. (iii) Protein activity can be further regulated by acute activators such as FA and HNE. (iv) Protein deactivation can occur by ligand inhibition and by rapid turnover of protein UCP2, probably by the ubiquitin proteasome system. (c) (i) UCP3 synthesis is regulated at the transcriptional level by starvation and muscle transcription factors. (ii) Protein activity can be further regulated by functional ligands, such as FA and HNE. The mechanism of protein deactivation can occur by ligand inhibition. In (b) and (c), UCP2 and UCP3 turnover can also theoretically occur as the result of mitochondrial turnover via the lysosomal pathway, although this pathway is slow compared with the likely degradation via the proteasomal pathway. Abbreviations: ATF, activating transcription factor; CREB, cAMP response element binding; IR, insulin receptor; NE, norepinephrine; Δ ψ, mitochondrial membrane potential; C/EBPβ, CCAAT-enhancer-binding protein-β; FA, fatty acid; HNF, hepatic nuclear factor; IL-1β, interleukin-1β; PPAR, peroxisome proliferator-activated receptor; SREBP-1c, sterol regulatory element binding protein-1c; MyoD, myogenic regulatory factor family protein.
Figure 4
Figure 4. Models of UCP (or ANT) activation and inhibition
The proton conductance activity of uncoupling proteins under different conditions. (a) In the basal state in the presence of nucleotides such as GDP, there is minimal proton conductance through UCP (or ANT). (b–d) Different models in which FA anions induce a large proton conductance through UCP by overcoming GDP inhibition. (b) In the flip-flop model, UCP exports FA anions, which become protonated and the neutral species flips back across the mitochondrial inner membrane (MIM) and deprotonates, resulting in a net flux of protons into the matrix. (c) In the co-factor model, FA anions associate with UCP and act as negative charges, which assists proton flux into the matrix. (d) In the functional competition model, FAs allosterically overcome the inhibitory effect of GDP. (e) HNE interacts with UCP, e.g. via an -SH group adduct, which activates UCP proton conductance. As appears to be the case for ANT, this pathway differs from the FA activation pathway and might be irreversible [19]. (f) Although uncoupling proteins have an anion conductance pathway in which they can translocate molecules such as halides, this pathway is functionally distinct from the proton conductance pathway [26]. Therefore, it remains unclear as to whether FAs, which are activators of the proton conductance pathway, can be exported via this anion conductance pathway. Abbreviations: IMS, intermembrane space; MIM, mitochondrial inner membrane.

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