Mitochondrial Uncoupling Proteins: Therapeutic Targets in Neurodegeneration?

Uncoupling proteins (UCPs) are mitochondrial inner membrane proteins that uncouple electron transport from ATP production by dissipating protons across the inner membrane. UCP1 was the first uncoupling protein described and is present in brown adipose tissue being involved in the non-shivering thermogenesis. Subsequent studies demonstrated that neurons express at least three UCPs isoforms including the widely expressed UCP2 and the neuron-specific UCP4 and UCP5. UCPs control the mitochondrial membrane potential, free radicals production and calcium homeostasis and thereby influence neuronal function. Given that mitochondrial energy impairment and free radicals production are thought to be central players in neurodegeneration, recent data suggest that UCPs may have an important role in neuroprotection and neuromodulation. The function of neuronal UCPs and their impact on the central nervous system are attracting an increased interest as potential therapeutic targets in several disorders including neurodegenerative diseases. Here we will discuss the uncoupling process as an intrinsic mechanism of mitochondria physiology. The role of UCPs in healthy and pathological brain conditions will be also considered. Finally, we will discuss UCPs as potential therapeutic targets in stroke and neurodegenerative diseases.