Unveiling the Role of the Proton Gateway, Uncoupling Proteins (UCPs), in Cancer Cachexia

SIMPLE SUMMARY: Cancer cachexia is a wasting syndrome mainly driven by chronic inflammation and high energy expenditure. The hyperactivation of the catabolic pathway leads to higher energy utilization by the body. Uncoupling proteins are involved in uncoupling the electron transport chain and thereby halting the ATP production and releasing energy in the form of heat, which increases the body’s overall energy utilization. UCPs may play an important role during cancer cachexia. This review aims to highlight the role of UCPs in cancer and cancer cachexia and provide new knowledge to tackle this wasting syndrome. ABSTRACT: Uncoupling proteins (UCPs) are identified as carriers of proton ions between the mitochondrial inner membrane and the mitochondrial matrix. ATP is mainly generated through oxidative phosphorylation in mitochondria. The proton gradient is generated across the inner mitochondrial membrane and the mitochondrial matrix, which facilitates a smooth transfer of electrons across ETC complexes. Until now, it was thought that the role of UCPs was to break the electron transport chain and thereby inhibit the synthesis of ATP. UCPs allow protons to pass from the inner mitochondrial membrane to the mitochondrial matrix and decrease the proton gradient across the membrane, which results in decreased ATP synthesis and increased production of heat by mitochondria. In recent years, the role of UCPs in other physiological processes has been deciphered. In this review, we first highlighted the different types of UCPs and their precise location across the body. Second, we summarized the role of UCPs in different diseases, mainly metabolic disorders such as obesity and diabetes, cardiovascular complications, cancer, wasting syndrome, neurodegenerative diseases, and kidney complications. Based on our findings, we conclude that UCPs play a major role in maintaining energy homeostasis, mitochondrial functions, ROS production, and apoptosis. Finally, our findings reveal that mitochondrial uncoupling by UCPs may treat many diseases, and extensive clinical studies are required to meet the unmet need of certain diseases.