Hydroxide Ion Channel Controls Uncoupling and Thermogenesis of Brown Fat Mitochondria

Abstract

Uncoupling proteins (UCP1- UCP5) are six-transmembrane-domain transport proteins of the inner mitochondrial membrane (IMM). They increase electrical conductance of the IMM, thus dissipating the electrochemical proton gradient across this membrane and uncoupling mitochondrial respiration and ATP synthesis. By controlling mitochondrial membrane potential, UCPs can affect many aspects of mitochondrial function and have been implicated in regulation of body's energy efficiency, reducing fat depositions, thermogenesis, diabetes, and protecting the cell against oxidative damage and ageing. The founding member of the family, UCP1, is specifically expressed in brown adipose tissue (BAT) and is responsible for adaptive thermogenesis mediated by this tissue. Due to its unusually high level of expression, upon activation UCP1 completely uncouples BAT mitochondria and converts the energy of the substrate oxidation into heat. Since UCP1 can dissipate large amounts of energy, it has attracted attention as a potential target to treat obesity. In spite of their physiological and therapeutic significance, the mechanism of operation of uncoupling proteins including their ionic selectivity has long remained unknown due to the lack of direct methods to study their activity in their native membrane environment. Here, by applying the patch-clamp technique to the whole inner membrane of BAT mitochondria and for the first time directly measuring transmembrane currents produced by UCP1, we show that UCP1 is a ligand-gated hydroxide (OH-) ion channel activated by fatty acids. UCP1 is the only hydroxide ion channel reported to date. Thus, BAT thermogenesis involves the outward transport of protons by the electron transport chain along with the outward transport of OH- by UCP1, thereby amounting to cycling of water across the IMM and not to futile cycling of protons as was largely considered before.