Grant: Discovery Grants Program - Individual

Molecular interactions and biophysical characterization of mammalian mitochondrial uncoupling proteins (UCPs) are the focuses of this research program. So far, five UCPs have been discovered in mammalian tissues, three of which (neuronal UCPs 2, 4 and 5) are widely distributed in the central nervous system. These intriguing proteins are located in the inner membrane of the mitochondria of different mammalian tissues and, acting as antioxidants, disrupt the mitochondrial respiration by uncoupling the electron transport process from the synthesis of ATP. Mitochondria are the main producers of ATP, which is the source of cellular energy for maintenance of life. Paradoxically, mitochondria are also important sources of excessive reactive oxygen species (ROS), which are deleterious to both mitochondria and cells. Damaged dysfunctional mitochondria are considered to be one of the main causes of neurodegeneration of brain tissues, posttraumatic death, and ageing. It has been widely suggested that UCPs can reduce ROS production through their uncoupling function. In addition to the antioxidant role of UCPs in response to oxidative stress, their involvement in cancer, type 2 diabetes, inflammatory processes and activation of antiobesity mechanism have been suggested. Despite these suggested significant physiological roles, apart from the established role of the prototypical UCP1 (widely found in brown adipose tissues) in regulating the body temperature in young mammals, limited information is known about the details of structures and mechanisms of the biological function of other mammalian UCPs. A comprehensive molecular study is therefore necessary to unravel some of the unanswered questions about the diverse physiological roles of UCPs in different tissues. The proposed research program will be a continuation of an existing well-established research program in my laboratory and will concentrate on: (i) the structures and molecular interactions of the neuronal uncoupling proteins in mitochondrial model membranes; (ii) the mechanisms of proton and anion transport in neuronal UCPs; and (iii) the role of neuronal UCPs in regulation of oxidative stress and neuroprotection in the central nervous system. The proposed research program is interdisciplinary, and combines different methods of structural analysis with spectroscopic, electrophysiological and molecular modeling techniques to explore the molecular basis of the structure-function relationships in the neuronal UCPs. The results of this biophysical study can have important implications for understanding the mechanisms of function/dysfunction of mitochondria and their role in health and disease.