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  • Review Article
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The mitochondrial uncoupling-protein homologues

Nature Reviews Molecular Cell Biology volume 6, pages 248–261 (2005)Cite this article

Key Points

  • Uncoupling proteins (UCPs) belong to the superfamily of mitochondrial-inner-membrane anion-carrier proteins.

  • UCP1, the classic uncoupling protein, is exclusively and abundantly expressed in brown adipose tissue. Its physiological role is to mediate a regulated, thermogenic proton leak across the mitochondrial inner membrane.

  • UCP2 and UCP3 were recently isolated as homologues of brown-adipose UCP1. UCP2 and UCP3 also mediate proton leak, but they do not have a thermogenic role, and their tissue distribution is more diverse compared with UCP1. The physiological function of UCP2 and UCP3 is not known, but it has been speculated that they might control the production of reactive oxygen species.

  • Recent work has shown that the UCP homologues are activated by a superoxide-dependent mechanism. This observation led to the suggestion of a feedback mechanism which controls the production of reactive oxygen species; however, the importance of the UCP homologues in cellular antioxidant defence is not clear at this point.

  • Although the physiological functions of UCP2 and UCP3 remain uncertain, it has been shown that UCP2, by virtue of its proton-leak activity, has an important role in the pathophysiology of type-2 diabetes. In particular, hyperglycaemia causes a pathological, superoxide-dependent activation of UCP2 in pancreatic islets, which, in turn, causes loss of glucose-stimulated insulin secretion.

  • Further work is required to elucidate the physiological roles and regulation of UCP2 and UCP3, and to understand, at a molecular level, how they mediate proton leak. This will have implications for many pathologies and diseases: for example, targeted inhibition of UCP2 should be a useful tool in the treatment of pancreatic-β-cell dysfunction and type-2 diabetes.

Abstract

Uncoupling protein(UCP)1 is an integral membrane protein that is located in the mitochondrial inner membrane of brown adipocytes. Its physiological role is to mediate a regulated, thermogenic proton leak. UCP2 and UCP3 are recently identified UCP1 homologues. They also mediate regulated proton leak, and might function to control the production of superoxide and other downstream reactive oxygen species. However, their role in normal physiology remains unknown. Recent studies have shown that UCP2 has an important part in the pathogenesis of type-2 diabetes. The obscure roles of the UCP homologues in normal physiology, together with their emerging role in pathophysiology, provide exciting potential for further investigation.

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Figure 1: Substrate oxidation and oxidative phosphorylation in mammalian cells.
Figure 2: Two models for free-fatty-acid-dependent proton translocation by UCP1.
Figure 3: Superoxide activation of UCP2 — a feedback loop.
Figure 4: UCP2 and pancreatic-β-cell dysfunction.

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Acknowledgements

We would like to thank E. Rial and J. St. Pierre for discussions. This work was supported by grants from the National Institutes of Health (to B.B.L.), and a Junior Faculty Award by the American Diabetes Association and an Outstanding Young Scientist Award by the National Natural Science Foundation of China (to C.-Y.Z.).

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Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston, 02215, Massachusetts, USA

    Stefan Krauss, Chen-Yu Zhang & Bradford B. Lowell

  2. Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, 02115, Massachusetts, USA

    Stefan Krauss

  3. National Pharmaceutical & Medical Key Laboratory, School of Life Science, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu, China

    Chen-Yu Zhang

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  1. Stefan Krauss
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Correspondence to Bradford B. Lowell.

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DATABASES

Swiss-Prot

UCP1

UCP2

UCP3

UCP4

UCP5

SIM - Local similarity program

Glossary

OXIDATIVE PHOSPHORYLATION

A mitochondrial process that links the oxidation of fuel substrates to the generation of high-energy phosphates (ATP) that can be used by the cell for energy-consuming pathways.

BROWN ADIPOSE TISSUE (BAT)

A tissue that consists of brown adipocytes and is specialised in mediating thermogenesis (that is, the generation of heat).

PROTON LEAK

Movement of the proton (H+) across the mitochondrial inner membrane, which either occurs spontaneously or is mediated by proteins. Proton leak can occur nonspecifically at the protein–lipid interface; alternatively, proton leak mediated by proteins such as UCPs can occur due to direct or indirect transport of protons.

REACTIVE OXYGEN SPECIES

(ROS). Reactive intermediates that are derived from oxygen. ROS can be molecules (for example, hydrogen peroxide), radicals (for example, hydroxyl radicals), or ions (for example, hydroxyl ions).

ISLETS OF LANGERHANS

Clusters of cells that comprise the endocrine portion of the pancreas. Pancreatic islets consist of three main cell types: α-cells that secrete glucagon, β-cells that secrete insulin and δ-cells that secrete somatostatin.

TYPE-2 DIABETES

Abnormal conditions such as obesity and hyperglycaemia cause disturbances in metabolism and gene expression, which lead to insulin resistance and pancreatic-β-cell dysfunction. The combination of both insulin resistance and β-cell dysfunction causes type-2 diabetes.

β-ADRENERGIC RECEPTORS

Membrane-bound G-protein-coupled receptors, the extracellular domains of which bind noradrenaline and adrenaline. In BAT, binding of noradrenaline to β-adrenergic receptors triggers the events that lead to thermogenesis.

LIPOLYSIS

The release of fatty acids and glycerol from triacylglyceride (lipid) stores, which is mediated by hormone-sensitive lipase.

WHITE ADIPOCYTES

The cells of white adipose tissue, a main site of lipid storage.

PROTEOLIPOSOMES

A model system for the study of biological membranes and membrane-bound proteins (for example, transport proteins). Proteoliposomes lack the complexity of cellular environments and are easily amenable to adjustments of lipid and protein content, as well as specific assay conditions (such as pH and ionic strength).

CRISTAE

The folds that are formed by the mitochondrial inner membrane.

RESPIRATORY QUOTIENT

(RQ). The ratio between the amount of exhaled CO2 and the amount of inhaled oxygen. The RQ is different for each of the main fuels that are usually metabolized (that is, carbohydrates, fats and proteins). This allows the identification of fuels that are metabolized under various conditions.

ISCHAEMIA/REPERFUSION INJURY

Ischaemia occurs after the disruption of blood and oxygen supply to tissues such as the heart and the brain. When blood and oxygen supply is re-established, a paradoxical progressive destruction of cells can occur that is known as reperfusion injury.

POLYMORPHISMS

The multiple allelic forms of genes.

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Krauss, S., Zhang, CY. & Lowell, B. The mitochondrial uncoupling-protein homologues. Nat Rev Mol Cell Biol 6, 248–261 (2005). https://doi.org/10.1038/nrm1592

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