Important Trends in UCP3 Investigation

Pohl, Elena E.; Rupprecht, Anne; Macher, Gabriel; Hilse, Karolina E.

doi:10.3389/fphys.2019.00470

Cited by 79 publications

(79 citation statements)

References 164 publications

(248 reference statements)

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“…The protonophoric ability of other uncoupling proteins is a longstanding issue in controversial debates [30]. The proton-transporting capacity of UCP2 and UCP3 was shown to be comparable with the capacity of UCP1 in lipid bilayer membranes reconstituted with recombinant proteins (2-14/s, for a review see [31]). Several studies in multiscale and biomimetic systems indicate that the function of UCP2/UCP3 is associated with the transport of different metabolic substrates [32][33][34], possibly alongside proton transport [26,[35][36][37].…”

Section: Reactive Oxygen Species and Their Derivatives Reactive Aldementioning

confidence: 99%

The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress

Pohl

Jovanović

2019

Molecules

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Reactive oxygen species (ROS) and their derivatives, reactive aldehydes (RAs), have been implicated in the pathogenesis of many diseases, including metabolic, cardiovascular, and inflammatory disease. Understanding how RAs can modify the function of membrane proteins is critical for the design of therapeutic approaches in the above-mentioned pathologies. Over the last few decades, direct interactions of RA with proteins have been extensively studied. Yet, few studies have been performed on the modifications of membrane lipids arising from the interaction of RAs with the lipid amino group that leads to the formation of adducts. It is even less well understood how various multiple adducts affect the properties of the lipid membrane and those of embedded membrane proteins. In this short review, we discuss a crucial role of phosphatidylethanolamine (PE) and PE-derived adducts as mediators of RA effects on membrane proteins. We propose potential PE-mediated mechanisms that explain the modulation of membrane properties and the functions of membrane transporters, channels, receptors, and enzymes. We aim to highlight this new area of research and to encourage a more nuanced investigation of the complex nature of the new lipid-mediated mechanism in the modification of membrane protein function under oxidative stress.

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Section: Reactive Oxygen Species and Their Derivatives Reactive Aldementioning

confidence: 99%

The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress

Pohl

Jovanović

2019

Molecules

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“…UCP3 activation is higher with increasing FA chain length and unsaturation, with arachidonic acid being the strongest activator [ 111 ]. UCP3 proton transport is believed to be activated only under particular conditions, i.e., when FFA blood levels increase; thus, its function could depend on cellular energy metabolism [ 112 ]. This transporter is inhibited by purine nucleotides (PNs) and phosphate [ 111 ].…”

Section: Drosophila Melanogaster Vs Human Mitomentioning

confidence: 99%

“…The inhibition mechanism by PNs for UCP3 is different from that for UCP1; indeed, the UCP1 maximal inhibition is decreased upon reducing PN phosphorylation, whereas all the PNs can completely inhibit UCP3. Increased FFA levels reduce the effect of all the PNs on UCP1; conversely, FFAs affect only the ATP-mediated inhibition of UCP3 [ 112 ]. When hUCP3 was moderately and ubiquitously expressed in D. melanogaster , it did not uncouple mitochondria, but its pan-neuronal overexpression led to a significant uncoupling activity in mitochondria isolated from fly heads, causing a drastically shortened lifespan [ 113 ].…”

Section: Drosophila Melanogaster Vs Human Mitomentioning

confidence: 99%

“…UCP4 has been exclusively identified in mitochondria isolated from human fetal and adult brain tissues, and it has 29%, 33% and 34% sequence identity with the human UCP1, -2, and -3, respectively, as well as being 40% and 39% identical to the human UCP5 and UCP6, respectively [ 112 ]. Further studies have confirmed that it is specifically expressed in the central nervous system, i.e., in highly differentiated neuronal and neurosensory cells needing a high glucose supply and having low proliferation potential [ 86 ].…”

Section: Drosophila Melanogaster Vs Human Mitomentioning

confidence: 99%

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Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

Curcio

Lunetti

Zara

et al. 2020

IJMS

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Mitochondrial carriers are a family of structurally related proteins responsible for the exchange of metabolites, cofactors and nucleotides between the cytoplasm and mitochondrial matrix. The in silico analysis of the Drosophila melanogaster genome has highlighted the presence of 48 genes encoding putative mitochondrial carriers, but only 20 have been functionally characterized. Despite most Drosophila mitochondrial carrier genes having human homologs and sharing with them 50% or higher sequence identity, D. melanogaster genes display peculiar differences from their human counterparts: (1) in the fruit fly, many genes encode more transcript isoforms or are duplicated, resulting in the presence of numerous subfamilies in the genome; (2) the expression of the energy-producing genes in D. melanogaster is coordinated from a motif known as Nuclear Respiratory Gene (NRG), a palindromic 8-bp sequence; (3) fruit-fly duplicated genes encoding mitochondrial carriers show a testis-biased expression pattern, probably in order to keep a duplicate copy in the genome. Here, we review the main features, biological activities and role in the metabolism of the D. melanogaster mitochondrial carriers characterized to date, highlighting similarities and differences with their human counterparts. Such knowledge is very important for obtaining an integrated view of mitochondrial function in D. melanogaster metabolism.

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“…UCP2 is a member of the mitochondrial anion transporter superfamily (19) and is highly homologous to other members of the UCP subfamily, such as UCP3 and UCP1 (20). It has been identified in rapidly proliferating cells that rely on glycolysis, such as stem cells (21,22), activated immunological cells (23), cancer cells, and immortalized cell lines (22,24,25).…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms Responsible for Pharmacological Effects of Genipin on Mitochondrial Proteins

Kreiter

Rupprecht

Zimmermann

et al. 2019

Biophysical Journal

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Genipin, a natural compound from Gardenia jasminoides, is a well-known compound in Chinese medicine that is used for the treatment of cancer, inflammation, and diabetes. The use of genipin in classical medicine is hindered because of its unknown molecular mechanisms of action apart from its strong cross-linking ability. Genipin is increasingly applied as a specific inhibitor of proton transport mediated by mitochondrial uncoupling protein 2 (UCP2). However, its specificity for UCP2 is questionable, and the underlying mechanism behind its action is unknown. Here, we investigated the effect of genipin in different systems, including neuroblastoma cells, isolated mitochondria, isolated mitochondrial proteins, and planar lipid bilayer membranes reconstituted with recombinant proteins. We revealed that genipin activated dicarboxylate carrier and decreased the activity of UCP1, UCP3, and complex III of the respiratory chain alongside with UCP2 inhibition. Based on competitive inhibition experiments, the use of amino acid blockers, and site-directed mutagenesis of UCP1, we propose a mechanism of genipin's action on UCPs. At low concentrations, genipin binds to arginine residues located in the UCP funnel, which leads to a decrease in UCP's proton transporting function in the presence of long chain fatty acids. At concentrations above 200 mM, the inhibitory action of genipin on UCPs is overlaid by increased nonspecific membrane conductance due to the formation of protein-genipin aggregates. Understanding the concentration-dependent mechanism of genipin action in cells will allow its targeted application as a drug in the above-mentioned diseases. SIGNIFICANCE Genipin is a well-known natural cross-linking agent for proteins, collagen, gelatin, and chitosan. However, the mechanism of its multiple effects on cells and mitochondria is under dispute. Mitochondrial UCP2 was previously revealed as an important target for genipin. We show that inhibition of UCP2 by genipin at submillimolar concentrations depends on the presence of three positively charged arginines in the funnel of the protein. This mechanism is similar to the UCP inhibition by purine nucleotides such as ATP/ADP and GTP/GDP. The effect of genipin is not specific to UCP2, which can be explained by the presence of arginines in homologous UCP1 and UCP3. This insight is crucial for the design of specific inhibitors of UCPs. FIGURE 9 Extracted ion chromatograms of genipin-modified UCP1 tryptic peptides. Signals at m/z 919.47 and 914.14 correspond to UCP1 tryptic peptide 184 NVIICTELVTYDLMKGALVNNK 206 carrying K198 (919.47; tR ¼ 21.4) and C188 (919.14; tR ¼ 24.2), respectively, modified with genipin adduct of 158 amu after incubation with 50 mM (A) and 1 mM (B) genipin. Corresponding CID spectra are provided in Fig. S1. (C) Positions of cysteine C188 and lysine K198 in UCP1, at which genipin modifications were detected. Three-dimensional structure of UCP1 was computed based on the crystallographic structure of ANT (PDB: 1OKC) using PyMol. To see this figure in color, go...

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Important Trends in UCP3 Investigation

Cited by 79 publications

References 164 publications

The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress

The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress

Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

Molecular Mechanisms Responsible for Pharmacological Effects of Genipin on Mitochondrial Proteins

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