Mitochondrial Nicotinic Acetylcholine Receptors Support Liver Cells Viability After Partial Hepatectomy.

Nicotinic acetylcholine receptors (nAChRs) expressed on the cell plasma membrane are ligand-gated ion channels mediating fast synaptic transmission, regulating neurotransmitter and cytokine release and supporting the viability of many cell types. The nAChRs expressed in mitochondria regulate the release of pro-apoptotic factors, like cytochrome , in ion channel-independent manner. Here we show that α3β2, α7β2, and α9α10 nAChR subtypes are up-regulated in rat liver mitochondria 3-6 h after partial hepatectomy resulting in increased sustainability of mitochondria to apoptogenic effects of Ca and HO. In contrast, laparotomy resulted in down-regulation of all nAChR subunits, except α9, and decreased mitochondria sustainability to apoptogenic effects of Ca and HO. Experiments performed in liver mitochondria from α3+/-, α7-/-, β4-/-, α7β2-/-, or wild-type C57Bl/6J mice demonstrated that the decrease of α3 or absence of α7 or α7/β2 subunits in mitochondria is compensated with β4 and α9 subunits, which could be found in α3β4, α4β4, α9β4, and α9α10 combinations. Mitochondria from knockout mice maintained their sustainability to Ca but were differently regulated by nAChR subtype-specific ligands: PNU-282987, methyllycaconitine, dihydro-β-erythroidine, α-conotoxin MII, and α-conotoxin PeIA. It is concluded that mitochondrial nAChRs play an important role in supporting the viability of hepatic cells and, therefore, may be a pharmacological target for pro-survival therapy. The concerted action of multiple nAChR subtypes controlling either CaKMII- or Src-dependent signaling pathways in mitochondria ensures a reliable protection against apoptogenic factors of different nature.