TY - JOUR
T1 - Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria
AU - Fedorenko, Andriy
AU - Lishko, Polina V.
AU - Kirichok, Yuriy
N1 - Funding Information:
The authors are grateful to Drs. David Nicholls, Eduardo Rial, Robert Farese, Frederick Sachs, and Francesca Fieni for advice and to Dr. Leslie Kozak for the UCP1 −/− mice. This work was funded by the NIH Director's New Innovator Award DP2OD004656, the UCSF Program for Breakthrough Biomedical Research, and a Larry L. Hillblom Foundation Start-up Award. A.F. and Y.K. conceived the project and designed the experiments. A.F. performed most of the experiments. Y.K. and P.V.L. helped with pilot experiments for the project. All authors discussed the results and commented on the manuscript.
PY - 2012/10/12
Y1 - 2012/10/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84867564026&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.09.010
DO - 10.1016/j.cell.2012.09.010
M3 - Article
C2 - 23063128
AN - SCOPUS:84867564026
SN - 0092-8674
VL - 151
SP - 400
EP - 413
JO - Cell
JF - Cell
IS - 2
ER -