A history of UCP1.
Interest in the enormous thermogenic capacity of brown adipose tissue (BAT) began in the 1960s and focused on BAT mitochondria (BATM), which when prepared by conventional techniques respired rapidly but displayed no respiratory control. Two apparently distinct treatments, fatty acid removal and purine nucleotide addition, induced respiratory control. In 1972, we found that BATM were highly permeant to halides and protons, and that albumin decreased the proton conductance while purine nucleotides decreased both. Devising techniques to quantify the proton leak in respiring mitochondria we found a nucleotide-sensitive conductance pathway whose 'break-point', the protonmotive force at which conductance suddenly increased, could be subtly modulated by free fatty acids. The nucleotide-binding site on the outer face of the inner membrane was characterized and identified by photoaffinity labelling as a 32 kDa 'uncoupling protein', now UCP1. Studies with intact brown adipocytes generated the currently accepted model, namely that fatty acids liberated by beta3-adrenergic receptor activation act as both self-regulating second messengers for UCP1 and substrates for fatty acid activation and oxidation. Fatty acid concentration increases at the outset of thermogenesis, binding to UCP1 lowers the protonmotive force below that giving respiratory control and rapid thermogenesis proceeds. At the termination of receptor activation oxidation of residual fatty acid 'recouples' the mitochondria. The challenge with the novel UCPs is to demonstrate a similar coherent mechanism.
Nicholls
D G
DG
Buck Institute for Age Research, Redwood Boulevard, Novato, CA 94945, USA. dnicholls@buckinstitute.org
D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism*; D006224:Cricetinae; D004594:Electrophysiology; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins; D008954:Models, Biological; D000071256:Uncoupling Protein 1
D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D000071256:Uncoupling Protein 1