Journal
CELL
Volume 151, Issue 2, Pages 400-413Publisher
CELL PRESS
DOI: 10.1016/j.cell.2012.09.010
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Funding
- NIH [DP2OD004656]
- UCSF Program for Breakthrough Biomedical Research
- Larry L. Hillblom Foundation
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Mitochondrial 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.
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