Uspenska K. The mechanisms of signaling and the biological role of nicotinic acetylcholine receptors in mitochondria

The thesis describes the study of the structure, mechanisms of signaling and biological role of nicotinic acetylcholine receptors (nAChRs) in mitochondria. It was found that mitochondrial nAChRs contain more carbohydrate residues than those targeted to the cell plasma membrane. The carbohydrate component composition can be that signal, which that directs nAChRs to different cellular compartments. It was found that the absence of α3, α7 or β2 nAChR subunits does not critically affect the mitochondria resistance to the effect of Ca2+ due to the compensatory expression of α9 and/or β4 nAChR subunits. The presence of a heteromeric α9β4 nAChR subtype was shown in mitochondria for the first time. It was found that conformational changes caused by the ligand binding in the transmembrane domain of the receptor (mainly, between two different subunits) are sufficient for engaging the intra-mitochondrial kinases. It has been established that α3, α7, β2 and β4 nAChR subunits are functionally linked to different intra-mitochondrial kinases. The study demonstrates the role of mitochondrial nAChRs during the initiation phase of liver regeneration, which requires support of the cell viability after partial hepatectomy. It also shows the pathogenic effect of neuroinflammation on the expression and functioning of nAChRs in the brain mitochondria, as well as a therapeutic effect of N-stearoylethanolamine to support mitochondria upon neuroinflammation.