Acquisition of the endosymbiotic ancestor of mitochondria was a critical event in eukaryote evolution. Mitochon- dria offered an unparalleled source of metabolic energy through oxidative phosphorylation and allowed the de- velopment of multicellular life. However, as molecular oxygen had become the terminal electron acceptor in most eukaryotic cells, the electron transport chain proved to be the largest intracellular source of superoxide, contributing to macromolecular injury, aging, and cancer. Hence, the ‘contract of endosymbiosis’ represents a compromise between the possibilities and perils of multicellular life. Uncoupling proteins (UCPs), a group of the solute carrier family of transporters, may remove some of the physiologic constraints that link mitochondrial respiration and ATP synthesis by mediating inducible proton leak and limiting oxidative cell injury. This impor- tant property makes UCPs an ancient partner in the metabolic adaptation of cancer cells. Efforts are underway to explore the therapeutic opportunities stemming from the intriguing relationship of UCPs and cancer. This article is part of a Special Issue entitled Respiratory complex I, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux
