Lessons from the diversity of uncoupling proteins: Understanding the evolution of brown adipose tissue and the emergence of a powerful energy dissipating mitochondrial protein

It was generally believed that uncoupling protein 1 (UCP1) is a unique trait of eutherian mammals allowing them to burn fat and to defend body temperature in the cold. In the past years, we analyzed the evolution of UCP1 and established that UCP1 orthologs are already present at early stages of vertebrate diversification, before the conception of nonshivering thermogenesis. Although tissue‐specificity and transcriptional control changed during evolution, there is evidence that uncoupling activity is a general feature of all UCP1 orthologs. Major functional adjustments of UCP1 during early mammalian radiation, however, appear as increased amino acid substitutions between marsupials and eutherians. We discuss the physiological significance of mitochondrial uncoupling and the requirements to integrate this small mitochondrial carrier protein in a powerful heat‐generating machinery. We also address other physiological functions that may require inducible proton leak by ancient UCPs. We here emphasize that nature's evolutionary diversity may be harnessed to address UCP structure‐function relationships, as protein integrity is debated during previous site‐directed mutagenesis attempts. The understanding of molecular mechanisms underlying mitochondrial energy dissipation will assist to utilize UCPs as therapeutic tools in obesity and oxidative stress‐related diseases.