Mitochondrial uncoupling proteins in the cns: in support of function and survival

Key Points

  • Neuronal uncoupling proteins (UCP2, UCP4, BMCP1/UCP5) are integral membrane proteins located in the inner mitochondrial membrane that allow controlled 'proton leak' into the mitochondrial matrix. This controlled proton leak, or uncoupling activity, reduces the mitochondrial membrane potential — the proton motive force that drives ATP synthesis and dissipates energy as heat.

  • UCP mRNA and protein are found throughout the CNS, including in the hypothalamus, hippocampus, cerebellum, limbic system, spinal cord, brainstem, cortex, substantia nigra and ventral tegmentum. The global distribution of UCP proteins in the CNS suggests that they have an important role in neuronal function.

  • Chronic mitochondrial uncoupling leads to reduced reactive oxygen species production, reduced membrane potential-dependent mitochondrial calcium influx, increased local temperature in neuronal microenvironments, and, paradoxically, promotes cellular ATP concentrations by activating mitochondrial biogenesis. Through these mechanisms, it is thought that neuronal UCPs can positively influence neuronal function, including synaptic plasticity and synaptic transmission, and retard the neuronal deterioration that is associated with neurological disorders.

  • Neuronal uncoupling activity is known to help prevent neuronal death in ageing and in many models of neurodegeneration, including Parkinson's disease, epilepsy, ischaemia, stroke and traumatic brain injury in vivo. In all of these neuropathologies, neuronal mitochondrial uncoupling reduces free radical production and oxidative stress.

  • Many other debilitating neurological conditions that have similar aetiologies to those described above, such as Alzhemier's diease and amyotrophic lateral sclerosis, are also likely to benefit from neuronal uncoupling activity. However, this hypothesis eagerly awaits future research.

  • Because mitochondrial dysfunction lies at the heart of many neurological disorders, advances in our understanding of neuronal UCP function are likely to deliver successful clinical treatment strategies against these neurological pathologies. Many of these advances will rely on improved technical approaches to clarify tissue-specific functions of UCP biology.

Abstract

Mitochondrial uncoupling mediated by uncoupling protein 1 (UCP1) is classically associated with non-shivering thermogenesis by brown fat. Recent evidence indicates that UCP family proteins are also present in selected neurons. Unlike UCP1, these proteins (UCP2, UCP4 and BMCP1/UCP5) are not constitutive uncouplers and are not crucial for non-shivering thermogenesis. However, they can be activated by free radicals and free fatty acids, and their activity has a profound influence on neuronal function. By regulating mitochondrial biogenesis, calcium flux, free radical production and local temperature, neuronal UCPs can directly influence neurotransmission, synaptic plasticity and neurodegenerative processes. Insights into the regulation and function of these proteins offer unsuspected avenues for a better understanding of synaptic transmission and neurodegeneration.

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Figure 1: The mechanism of mitochondrial uncoupling.
Figure 2: Proposed mechanism through which neuronal uncoupling proteins can regulate neuronal function.
Figure 3: Uncoupling protein 2 reduces reactive oxygen species production in vivo.
Figure 4: Superoxides activate uncoupling proteins via a mitochondrial feedback loop.
Figure 5: Fatty acid-induced uncoupling activity in UCP2-knockout mice and mice that overexpress human UCP2.
Figure 6: Uncoupling protein 2 prevents dopamine cell loss in the substantia nigra after MPTP treatment.

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Acknowledgements

Authors' research projects associated with mechanisms discussed in this paper have been supported by an OTKA grant and the following institutes of the National Institutes of Health (NIH): National Institute on Aging (NIA), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Neurological Disorders and Stroke (NINDS).

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Correspondence to Tamas L. Horvath.

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DATABASES

Entrez Gene

BMCP1

caspase 3

PGC1

PPARγ

SOD1

UCP1

UCP2

UCP3

UCP4

OMIM

Alzheimer's disease

Amyotrophic lateral sclerosis

Parkinson's disease

Glossary

ELECTRON TRANSFER CHAIN

This comprises a series of five enzyme and protein complexes associated with the inner mitochondrial membrane. It converts energy in the form of the electron transfer potential of NADH and FADH2 into the energy found in the terminal phosphate of ATP, consuming oxygen and producing water in the process.

XANTHINE PLUS XANTHINE OXIDASE SYSTEM

An exogenous system used to generate superoxide and study the molecular and cellular consequences of superoxide production.

PC12 CELLS

A cloned rat pheochromocytomal cell line that retains a number of chromaffin cell characteristics, including the synthesis and secretion of catecholamines and the expression of various neuropeptide genes. PC12 cells are often used to study the cell biology of neuronal genes after transfection.

MPTP

(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). A toxic by-product of the chemical synthesis of a meperidine analogue that induces a parkinsonian syndrome that is almost indistinguishable from Parkinson's disease. MPTP is commonly used to study cellular and molecular aspects of Parkinson's disease in mice and monkeys, as it specifically induces dopaminergic neurodegeneration in the substantia nigra.

COENZYME Q

(2,3-dimethyloxy-5-methyl-6-multiprenyl-1,4-benzoquinone; also known as ubiquinone). A mobile electron carrier from complexes 1 and 2 to complex 3 of the electron transfer chain that is located in the hydrophobic domain of the inner mitochondrial membrane. It also acts, with vitamin E, to provide anitoxidative protection.

OLIGOMYCIN-INDUCED STATE 4 RESPIRATION

A state of mitochondrial respiration that requires oligomycin to prevent ADP phosphorylation (state 3 respiration) by blocking protons from interacting with ATP synthase. State 4 respiration is a direct measure of mitochondrial uncoupling activity.

ISCHAEMIC PRECONDITIONING

A process that occurs after sublethal ischaemic insults. Neurons activate defensive mechanisms, such as cellular calcium buffering and antioxidants systems, that counteract ischaemic damage.

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Andrews, Z., Diano, S. & Horvath, T. Mitochondrial uncoupling proteins in the cns: in support of function and survival. Nat Rev Neurosci 6, 829–840 (2005). https://doi.org/10.1038/nrn1767

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