Mitochondrial uncoupling: Role of uncoupling protein anion carriers and relationship to thermogenesis and weight control "The benefits of losing control"

Uncoupling proteins, a subgroup of the mitochondrial anion transporter supe rfamily, have been identified in prokaryotes, plants, and mammalian cells. Evolutionary conservation of these molecules reflects their importance as r egulators of two critical mitochondrial functions, i.e., ATP synthesis and the production of reactive oxygen species (ROS). Although the amino acid se quences of the three mammalian uncoupling proteins, UCP1, UCP2 and UCP3, ar e very similar, each homolog is the product of a unique gene and important differences have been demonstrated in their tissue-specific expression and regulation. UCP1 and UCP3 appear to be key regulators of energy expenditure , and hence, nonshivering thermogenesis, either in brown adipose tissue (UC P1) or skeletal muscle (UCP3). UCP2 is expressed more ubiquitously, althoug h generally at low levels, in many tissues. There is conflicting evidence a bout its importance as a regulator of resting metabolic rate. However, evid ence SUUUPCrT that this homolog might modulate the mitochondrial generation of ROS in some cell types, including macrophages and hepatocytes. While th e induction of various uncoupling protein homologs provides adaptive advant ages, both to the organism (e.g., thermogenesis) and to individual cells (e .g., reduced ROS), increased uncoupling protein activity also increases cel lular vulnerability to necrosis by compromising the mitochondrial membrane potential. This narrow "risk-benefit" margin necessitates tight control of uncoupling protein activity in order to preserve cellular viability and muc h remains to be learned about the regulatory mechanisms involved.