Mitochondrial Uncoupling

Uncoupling proteins (UCPs) are members of the mitochondrial transport carrier family. The crystal structure of one member of the family, the adenine nucleotide translocase, is known, and UCPs can be successfully folded into this structure to indicate their probable 3D arrangement.

The most studied member of the family, UCP1, catalyzes adaptive thermogenesis (i.e., heat generation) in mammalian brown adipose tissue. It does so by promoting a leak of protons through the mitochondrial inner membrane, which uncouples ATP production from substrate oxidation, leading to fast oxygen consumption and ultimately to heat production. The thermogenic activity of UCP1 in brown adipose tissue plays an important role when the organism needs extra heat, e.g., during cold weather conditions (for small rodents), the cold stress of birth, or arousal from hibernation. UCP1 homologs have been found in lower vertebrates such as fish, where their role is unclear.

The proton conductance of UCP1 in brown adipose tissue is tightly controlled. It is strongly inhibited by physiological concentrations of purine nucleotides. This inhibition is overcome by fatty acids released from intracellular triacylglycerol stores following adrenergic activation in response to cold or overfeeding. Other activators include superoxide, retinoic acid, the retinoid 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphtalenyl)-1-propenyl]benzoic acid (TTNPB) and reactive alkenals, such as hydroxynonenal.

There is strong evidence that the regulated uncoupling caused by these proteins attenuates mitochondrial reactive oxygen species production, protects against cellular damage, and (in beta-cells) diminishes insulin secretion. There are also untested suggestions that their transport of fatty acids may be physiologically important.

Several models have been proposed for the molecular mechanism by which fatty acids lead to increased proton conductance by UCP1 in brown adipose tissue mitochondria and presumably by the other UCPs. We have depicted the most likely model, the "fatty acid cycling" model, in this pathway.

Studies of mouse models and cultured human cells have suggested that oleoyl-phenylalanine, synthesized by extracellular PM20D1, may play a role in uncoupling independent of the action of UCPs. Its synthesis and hydrolysis are annotated here.