Journal Article

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

Horvath, Tamas L., Andrews, Zane B., Diano, Sabrina

2005

Overview

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. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Amino acids / Animal Genetics and Genomics / Animals / Behavioral Sciences / Biological and medical sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Body fat / Carrier Proteins - metabolism / Carrier Proteins - physiology / Cell Survival / Central Nervous System - physiology / Energy / Fatty acids / Fundamental and applied biological sciences. Psychology / General aspects. Models. Methods / Humans / Ion Channels / Medical sciences / Membrane Proteins - metabolism / Membrane Proteins - physiology / Metabolism / Mitochondria / Mitochondrial Proteins / Neurobiology / Neurodegeneration / Neurodegenerative Diseases - physiopathology / Neuronal Plasticity - physiology / Neurons - physiology / Neurosciences / Neurosurgery / Oxidation / Phosphorylation / Proteins / Protons / review-article / Skull, brain, vascular surgery / Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases / Synapses - physiology / Synaptic Transmission - physiology / Thermogenesis / Uncoupling Protein 1 / Vertebrates: nervous system and sense organs