Fatty acid cycling mechanism and mitochondrial uncoupling proteins

Abstract

We hypothesize that fatty acid-induced uncoupling serves in bioenergetic systems to set the optimum efficiency and tune the degree of coupling of oxidative phosphorylation. Uncoupling results from fatty acid cycling, enabled by several phylogenetically specialized proteins and, to a lesser extent, by other mitochondrial carriers. It is suggested that the regulated uncoupling in mammalian mitochondria is provided by uncoupling proteins UCP-1, UCP-2 and UCP-3, whereas in plant mitochondria by PUMP and StUCP, all belonging to the gene family of mitochondrial carriers. UCP-1, and hypothetically UCP-3, serve mostly to provide nonshivering thermogenesis in brown adipose tissue and skeletal muscle, respectively. Fatty acid cycling was documented for UCP-1, PUMP and ADP/ATP carrier, and is predicted also for UCP-2 and UCP-3. UCP-1 mediates a purine nucleotide-sensitive uniport of monovalent unipolar anions, including anionic fatty acids. The return of protonated fatty acid leads to H+ uniport and uncoupling. UCP-2 is probably involved in the regulation of body weight and energy balance, in fever, and defense against generation of reactive oxygen species. PUMP has been discovered in potato tubers and immunologically detected in fruits and corn, whereas StUCP has been cloned and sequenced froma a potato gene library. PUMP is supposed to act in the termination of synthetic processes in mature fruits and during the climacteric respiratory rise.

Peroxisome proliferator-activated receptor γ coactivator-1-dependent uncoupling protein-2 expression in pancreatic islets of rats: a novel pathway for neural control of insulin secretion

“…UCP-2 is a member of the mitochondrial uncoupling protein family [26,27]. Proteins that belong to this family are characterized by sub-cellular localization to the inner mitochondrial membrane where they uncouple biochemical respiration from oxidative phosphorylation by leaking protons into the mitochondrial matrix, which leads to a bypass of ATP synthase [28].…”

The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP

“…The identification of UCP homologues in plants [60,61] followed reports of the existence of regulated respiration un- coupling mechanisms in plants [219]. Although a true uncoupling activity of plant UCPs has not yet been demonstrated, the marked effect of StUCP on mitochondrial membrane potential strongly suggests that this protein is an uncoupler [60].…”

Adaptive thermogenesis and uncoupling proteins: a reappraisal of their roles in fat metabolism and energy balance

“…In the skeletal muscle, the increased UCP2 and UCP3 expressions are in line with the wellknown fasting-induced shift in substrate utilization in favour of lipids as the predominant metabolic fuel and hence allowing the sparing of glucose for organs/tissues with an obligatory requirement for glucose, notably the brain. Could it then be that the structural homology of UCP2 and UCP3 to UCP1 has been made with the wrong function of UCP1-since the primary function of this uncoupling protein as a mediator of adaptive thermogenesis via mitochondrial proton leak has often been linked (by mechanisms that are poorly understood) to a putative secondary function as an anion/substrate transporter across the mitochondrial membranes [70,71]. This reevaluation presented in Table 4 constituted the backbone of the proposal that the primary function of UCP1-homologues in the skeletal muscle and BAT may somehow be involved actively or passively with the regulation of lipids as fuel substrate rather than in the mediation of thermogenesis [69].…”

“…In other models, UCP2 and/or UCP3 are postulated to be involved in the translocation of the fatty acid anions from the matrix side to the cytosolic side of the mitochondrial membrane [42,71,79]. The fatty acid anions would be protonated, and the UCP1-homologues would then dflipflopT these neutral fatty acids back to the matrix side [70,71,79], resulting in a lowering of the proton gradient and hence increased heat production.…”