title: UCP1: A transporter for H+and fatty acid anions.
abstract: Adaptive thermogenesis regulates core body temperature, controls fat deposition, and contributes strongly to the overall energy balance. This process occurs in brown fat and requires uncoupling protein 1 (UCP1), an integral protein of the inner mitochondrial membrane. Classic biochemical studies revealed the general principle of adaptive thermogenesis: in the presence of long-chain fatty acids (FA), UCP1 increases the permeability of the inner mitochondrial membrane for H+, which makes brown fat mitochondria produce heat rather than ATP. However, the exact mechanism by which UCP1 increases the membrane H+conductance in a FA-dependent manner has remained a fundamental unresolved question. Recently, the patch-clamp technique was successfully applied to the inner mitochondrial membrane of brown fat to directly characterize the H+currents carried by UCP1. Based on the patch-clamp data, a new model of UCP1 operation was proposed. In brief, FA anions are transport substrates of UCP1, and UCP1 operates as an unusual FA anion/H+symporter. Interestingly, in contrast to short-chain FA anions, long-chain FA anions cannot easily dissociate from UCP1 due to strong hydrophobic interactions established by their carbon tails, and a single long-chain FA participates in many H+transport cycles. Therefore, in the presence of long-chain FA, endogenous activators of brown fat thermogenesis, UCP1 effectively operates as an H+uniport. In addition to their transport function, long-chain FA competitively remove tonic inhibition of UCP1 by cytosolic purine nucleotides, thus enabling activation of the thermogenic H+leak through UCP1 under physiological conditions.
authors.affiliation: Department of Physiology, University of California San Francisco, UCSF Mail Code 2140, Genentech Hall Room N272F, 600 16th Street, San Francisco, CA 94158, USA.
authors.forename: Ambre M
authors.initials: AM
authors.lastname: Bertholet
authors.affiliation: Department of Physiology, University of California San Francisco, UCSF Mail Code 2140, Genentech Hall Room N272F, 600 16th Street, San Francisco, CA 94158, USA. Electronic address: yuriy.kirichok@ucsf.edu.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Kirichok
mesh_terms: D052437:Adipocytes, Brown / Q000166:cytology / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D004734:Energy Metabolism / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D017136:Ion Transport; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D011522:Protons; D022722:Thermogenesis / Q000502:physiology*; D000071256:Uncoupling Protein 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D011522:Protons; D000071256:Uncoupling Protein 1
keywords: Brown fat; Fatty acid; Mitochondria; Thermogenesis; UCP1; Uncoupling