TSPO & BRAIN · Role of the mitochondrial Translocator Protein (mTSPO) in Brain Cellular Physiology: a Neglected Pathway in Signalling and Self-conservation Mechanisms

Balanced energy homeostasis and correct functioning of regulatory processes are the basis of cellular health. The impaired interplay between these is thus responsible for the pathology of tissues especially for those undergoing stress and unable to regenerate such as the Brain. An exhaustive comprehension of the physiology of molecules intimately involved in these phenomena is therefore essential both to increase our understanding of Brain fundamental physiology and to delineate novel approaches to tackle pathologies at their origin. The mitochondrial Translocator Protein (mTSPO) is one of these molecules as critically located on the outer membrane of the mitochondrion and in close association with the multi-functional protein Voltage Dependent Anion Channel (VDAC). mTSPO is increases during brain inflammation but, in spite of this, its cell biology and the underlying events associated to changes in its expression are still obscure.The research program I propose here aims to elucidate this pathway for mitochondrial and cellular physiology and so finalize an understating on a neglected molecule upon which the homeostasis of the cell dependents.We will address the mTSPO role in mitochondrial and cell metabolism and to the processes guarding cell integrity such as Apoptosis and Autophagy; we will do so by ascertaining how mTSPO ratio of expression with that of VDAC defines the signalling of Ca2+, dynamics of the Reactive Oxygen Species (ROS), ATP rationing and Redox State. How modifications in ROS impinge on downstream kinases will be also determined. Pharmacological tools to modulate mTSPO activity will be employed as a further means of investigation and finally the relation between mTSPO/VDAC ratio of expression and pathological behaviour of tissues will be scrutinized.These results will shed light on an important molecular player and form a conceptual and experimental framework for future investigations in the Physio-Pathology of the Brain.