Biophysical Properties of UCP1

Brown adipose tissue (BAT) is a specialized mammalian organ that coverts body fat reserves into heat. This conversion is mediated by BAT mitochondria and is important for maintaining body temperature and reducing fat depositions. Burning fat in BAT mitochondria does not result in ATP synthesis due to unusually high conductance of the inner mitochondrial membrane (IMM). This BAT-specific conductance dissipates the mitochondrial electrochemical gradient used in other tissues for ATP production and converts the energy of fatty acid oxidation into heat. The molecule responsible for the high conductance of the IMM and uncoupling of oxidative phosphorylation in BAT mitochondria is uncoupling protein 1 (UCP1). UCP1 is a BAT-specific protein that belongs to the superfamily of mitochondrial solute carriers (SLC25). UCP1-mediated uncoupling is activated by fatty acids and inhibited by purine nucleotides. In spite of the fact that UCP1 was identified decades ago, the mechanism of UCP1 operation is unknown due to lack of direct methods to study its activity. Here, we resolve the problem by directly recording UCP1 currents across the IMM of BAT mitochondria using the patch-clamp technique. To identify UCP1 current, we compare currents recorded from the wild-type and UCP1 (-/-) mitochondria. The detailed electrophysiological analysis demonstrated that UCP1 translocates fatty acid anion in symport with H+, while the fatty acid hydrophobic tail prevents dissociation of fatty acid from UCP1, causing UCP1 to operate as H+ carrier. This work establishes the mechanism of fatty acid dependent mitochondrial uncoupling which is implicated in metabolic and age-related diseases.