Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria.
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.
Department of Physiology, University of California San Francisco, UCSF Mail Code 2140, Genentech Hall Room N272F, 600 16th Street, San Francisco, CA 94158, USA.
Andriy
A
Fedorenko
Polina V
PV
Lishko
Yuriy
Y
Kirichok
D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D003593:Cytoplasm / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011522:Protons; D011687:Purines / Q000378:metabolism; D000071256:Uncoupling Protein 1
D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D011522:Protons; D011687:Purines; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1