Mechanism of Fatty-Acid-Dependent UCP1 Uncoupling in Brown Fat Mitochondria

SummaryMitochondrial uncoupling protein 1 (UCP1) is responsible for nonshivering thermogenesis in brown adipose tissue (BAT). Upon activation by long-chain fatty acids (LCFAs), UCP1 increases the conductance of the inner mitochondrial membrane (IMM) to make BAT mitochondria generate heat rather than ATP. Despite being a member of the family of mitochondrial anion carriers (SLC25), UCP1 is believed to transport H+ by an unusual mechanism that has long remained unresolved. Here, we achieved direct patch-clamp measurements of UCP1 currents from the IMM of BAT mitochondria. We show that UCP1 is an LCFA anion/H+ symporter. However, the LCFA anions cannot dissociate from UCP1 due to hydrophobic interactions established by their hydrophobic tails, and UCP1 effectively operates as an H+ carrier activated by LCFA. A similar LCFA-dependent mechanism of transmembrane H+ transport may be employed by other SLC25 members and be responsible for mitochondrial uncoupling and regulation of metabolic efficiency in various tissues.

Graphical AbstractFigure optionsDownload high-quality image (328 K)Download as PowerPoint slideHighlights
► Direct patch-clamp recording of UCP1 currents from the inner mitochondrial membrane
► UCP1 is a fatty-acid anion/H+ symporter
► Due to hydrophobic interactions, long-chain fatty acids cannot dissociate from UCP1
► Long-chain fatty acids shuttle within UCP1 to achieve H+ transport