Journal
BIOCHIMIE
Volume 134, Issue -, Pages 28-34Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biochi.2016.10.013
Keywords
UCP1; Mitochondria; Uncoupling; Thermogenesis; Brown fat; Fatty acid
Categories
Funding
- NIH grants [5R01GM107710]
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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. (C) 2016 Published by Elsevier B.V.
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