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Uncoupling Proteins
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Uncoupling Proteins

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 16494

Special Issue Editors

Prof. Dr. Luigi Palmieri

E-Mail Website
Guest Editor
Laboratory of Biochemistry and Molecular Biology, Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy
Interests: mitochondrial transporters; bioenergetics; mitochondrial diseases
Dr. Giuseppe Fiermonte

E-Mail Website
Guest Editor
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy
Interests: mitochondrial transporters; uncoupling proteins; cancers metabolism

Special Issue Information

Dear colleagues,

Mitochondria couple the respiratory oxidation of nutrients to ATP synthesis through an electrochemical proton gradient. Proton leak allows partial uncoupling of oxidative phosphorylation, producing heat. Through this mechanism, uncoupling protein (UCP) 1, a member of the mitochondrial carrier family (MCF) expressed in brown adipose tissue, regulates non-shivering thermogenesis in mammals. The identification of UCP1 homologs expressed in other tissues therefore encouraged high expectations as targets for cold adaptation and enhancing energy expenditure, and even distant MCF members were named “uncoupling proteins”. Early studies on animal models and the discovery of UCP1 homologs in plants and ectothermic species soon ruled out any involvement of these UCP1 homologs in non-shivering thermogenesis. This notwithstanding, thousands of papers have been published based on the alleged (mild) protonophoric activity of UCP2–UCP6, alleged to finely tune respiratory activity and/or ROS homeostasis. In vitro studies have recently demonstrated that plant UCP1 homologs, as well as mammalian UCP2, UCP5 and UCP6, are metabolite transporters, as are most MCF members, and this activity may account for their effect on ROS production/quenching. On the other hand, FA-induced uncoupling activity has been recently demonstrated for other MCF members.

In the light of the impressive past and ongoing work regarding this intriguing subfamily of mitochondrial carriers, we believe that this Special Issue is well timed to take stock of the enormous amount of current evidence, before new efforts are made towards the elucidation of the biochemical function and the physiological role of the so-called uncoupling proteins.

Prof. Dr. Luigi Palmieri
Dr. Giuseppe Fiermonte
Guest Editors

Manuscript Submission Information

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Keywords

  • mitochondrial transporters
  • uncoupling proteins
  • bioenergetics
  • thermogenesis
  • obesity
  • cancer metabolism
  • ROS
  • OXPHOS
  • mitochondrial metabolism

Published Papers (5 papers)

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Research

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16 pages, 2925 KiB  
Article
Drosophila melanogaster Uncoupling Protein-4A (UCP4A) Catalyzes a Unidirectional Transport of Aspartate
by Paola Lunetti, Ruggiero Gorgoglione, Rosita Curcio, Federica Marra, Antonella Pignataro, Angelo Vozza, Christopher L. Riley, Loredana Capobianco, Luigi Palmieri, Vincenza Dolce and Giuseppe Fiermonte
Int. J. Mol. Sci. 2022, 23(3), 1020; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031020 - 18 Jan 2022
Cited by 12 | Viewed by 2138
Abstract
Uncoupling proteins (UCPs) form a distinct subfamily of the mitochondrial carrier family (MCF) SLC25. Four UCPs, DmUCP4A-C and DmUCP5, have been identified in Drosophila melanogaster on the basis of their sequence homology with mammalian UCP4 and UCP5. In a Parkinson’s disease [...] Read more.
Uncoupling proteins (UCPs) form a distinct subfamily of the mitochondrial carrier family (MCF) SLC25. Four UCPs, DmUCP4A-C and DmUCP5, have been identified in Drosophila melanogaster on the basis of their sequence homology with mammalian UCP4 and UCP5. In a Parkinson’s disease model, DmUCP4A showed a protective role against mitochondrial dysfunction, by increasing mitochondrial membrane potential and ATP synthesis. To date, DmUCP4A is still an orphan of a biochemical function, although its possible involvement in mitochondrial uncoupling has been ruled out. Here, we show that DmUCP4A expressed in bacteria and reconstituted in phospholipid vesicles catalyzes a unidirectional transport of aspartate, which is saturable and inhibited by mercurials and other mitochondrial carrier inhibitors to various degrees. Swelling experiments carried out in yeast mitochondria have demonstrated that the unidirectional transport of aspartate catalyzed by DmUCP4 is not proton-coupled. The biochemical function of DmUCP4A has been further confirmed in a yeast cell model, in which growth has required an efflux of aspartate from mitochondria. Notably, DmUCP4A is the first UCP4 homolog from any species to be biochemically characterized. In Drosophila melanogaster, DmUCP4A could be involved in the transport of aspartate from mitochondria to the cytosol, in which it could be used for protein and nucleotide synthesis, as well as in the biosynthesis of ß-alanine and N-acetylaspartate, which play key roles in signal transmission in the central nervous system. Full article
(This article belongs to the Special Issue Uncoupling Proteins)
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Review

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25 pages, 12862 KiB  
Review
UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control
by Angèle Luby and Marie-Clotilde Alves-Guerra
Int. J. Mol. Sci. 2022, 23(23), 15077; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315077 - 01 Dec 2022
Cited by 9 | Viewed by 4448
Abstract
Despite numerous therapies, cancer remains one of the leading causes of death worldwide due to the lack of markers for early detection and response to treatment in many patients. Technological advances in tumor screening and renewed interest in energy metabolism have allowed us [...] Read more.
Despite numerous therapies, cancer remains one of the leading causes of death worldwide due to the lack of markers for early detection and response to treatment in many patients. Technological advances in tumor screening and renewed interest in energy metabolism have allowed us to identify new cellular players in order to develop personalized treatments. Among the metabolic actors, the mitochondrial transporter uncoupling protein 2 (UCP2), whose expression is increased in many cancers, has been identified as an interesting target in tumor metabolic reprogramming. Over the past decade, a better understanding of its biochemical and physiological functions has established a role for UCP2 in (1) protecting cells from oxidative stress, (2) regulating tumor progression through changes in glycolytic, oxidative and calcium metabolism, and (3) increasing antitumor immunity in the tumor microenvironment to limit cancer development. With these pleiotropic roles, UCP2 can be considered as a potential tumor biomarker that may be interesting to target positively or negatively, depending on the type, metabolic status and stage of tumors, in combination with conventional chemotherapy or immunotherapy to control tumor development and increase response to treatment. This review provides an overview of the latest published science linking mitochondrial UCP2 activity to the tumor context. Full article
(This article belongs to the Special Issue Uncoupling Proteins)
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18 pages, 2525 KiB  
Review
Uncoupling Proteins as Therapeutic Targets for Neurodegenerative Diseases
by Colin J. Barnstable, Mingliang Zhang and Joyce Tombran-Tink
Int. J. Mol. Sci. 2022, 23(10), 5672; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105672 - 18 May 2022
Cited by 5 | Viewed by 2047
Abstract
Most of the major retinal degenerative diseases are associated with significant levels of oxidative stress. One of the major sources contributing to the overall level of stress is the reactive oxygen species (ROS) generated by mitochondria. The driving force for ROS production is [...] Read more.
Most of the major retinal degenerative diseases are associated with significant levels of oxidative stress. One of the major sources contributing to the overall level of stress is the reactive oxygen species (ROS) generated by mitochondria. The driving force for ROS production is the proton gradient across the inner mitochondrial membrane. This gradient can be modulated by members of the uncoupling protein family, particularly the widely expressed UCP2. The overexpression and knockout studies of UCP2 in mice have established the ability of this protein to provide neuroprotection in a number of animal models of neurological disease, including retinal diseases. The expression and activity of UCP2 are controlled at the transcriptional, translational and post-translational levels, making it an ideal candidate for therapeutic intervention. In addition to regulation by a number of growth factors, including the neuroprotective factors LIF and PEDF, small molecule activators of UCP2 have been found to reduce mitochondrial ROS production and protect against cell death both in culture and animal models of retinal degeneration. Such studies point to the development of new therapeutics to combat a range of blinding retinal degenerative diseases and possibly other diseases in which oxidative stress plays a key role. Full article
(This article belongs to the Special Issue Uncoupling Proteins)
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13 pages, 660 KiB  
Review
Genipin, an Inhibitor of UCP2 as a Promising New Anticancer Agent: A Review of the Literature
by Young Seok Cho
Int. J. Mol. Sci. 2022, 23(10), 5637; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105637 - 18 May 2022
Cited by 19 | Viewed by 2832
Abstract
Genipin is a protein cross-linking agent extracted from Gardenia (Gardenia jasminoides Ellis) fruits. This fruit has conventionally been used as a Chinese herbal medicine for the treatment of inflammation and jaundice and as an edible colorant in oriental countries. Uncoupling protein (UCP)-2 [...] Read more.
Genipin is a protein cross-linking agent extracted from Gardenia (Gardenia jasminoides Ellis) fruits. This fruit has conventionally been used as a Chinese herbal medicine for the treatment of inflammation and jaundice and as an edible colorant in oriental countries. Uncoupling protein (UCP)-2 is a member of the family of uncoupling proteins, which are anion transporters positioned in the mitochondrial inner membrane. Genipin has been shown to have hepatoprotective activity, acting as an effective antioxidant and inhibitor of mitochondrial UCP2, and is also reported to exert significant anticancer effects. In this review, the author presents the latest progress of genipin as an anticancer agent and concisely describes its various mechanisms of action. In brief, genipin inhibits UCP2 to attenuate generation of reactive oxygen species (ROS), leading to ROS/c-Jun N-terminal kinase-dependent apoptosis of cancer cells. Genipin also increases the tissue inhibitors of matrix metalloproteases (MMP)-2, a kind of tumor promoter in a variety of cancers, as well as induces caspase-dependent apoptosis in in vitro and in vivo models. These findings suggest that genipin can serve as a promising novel antitumor agent that could be applicable for chemotherapy and/or chemoprevention for cancers. Full article
(This article belongs to the Special Issue Uncoupling Proteins)
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14 pages, 1057 KiB  
Review
Uncoupling Protein 1 Does Not Produce Heat without Activation
by Yongguo Li and Tobias Fromme
Int. J. Mol. Sci. 2022, 23(5), 2406; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052406 - 22 Feb 2022
Cited by 12 | Viewed by 4354
Abstract
Mitochondrial uncoupling protein 1 (UCP1) is the crucial mechanistic component of heat production in classical brown fat and the newly identified beige or brite fat. Thermogenesis inevitably comes at a high energetic cost and brown fat, ultimately, is an energy-wasting organ. A constrained [...] Read more.
Mitochondrial uncoupling protein 1 (UCP1) is the crucial mechanistic component of heat production in classical brown fat and the newly identified beige or brite fat. Thermogenesis inevitably comes at a high energetic cost and brown fat, ultimately, is an energy-wasting organ. A constrained strategy that minimizes brown fat activity unless obligate will have been favored during natural selection to safeguard metabolic thriftiness. Accordingly, UCP1 is constitutively inhibited and is inherently not leaky without activation. It follows that increasing brown adipocyte number or UCP1 abundance genetically or pharmacologically does not lead to an automatic increase in thermogenesis or subsequent metabolic consequences in the absence of a plausible route of concomitant activation. Despite its apparent obviousness, this tenet is frequently ignored. Consequently, incorrect conclusions are often drawn from increased BAT or brite/beige depot mass, e.g., predicting or causally linking beneficial metabolic effects. Here, we highlight the inherently inactive nature of UCP1, with a particular emphasis on the molecular brakes and releases of UCP1 activation under physiological conditions. These controls of UCP1 activity represent potential targets of therapeutic interventions to unlock constraints and efficiently harness the energy-expending potential of brown fat to prevent and treat obesity and associated metabolic disorders. Full article
(This article belongs to the Special Issue Uncoupling Proteins)
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