Mitochondrial Nicotinic Acetylcholine Receptors Support Liver Cells Viability After Partial Hepatectomy

Abstract

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 c, 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 Ca2+ and H2O2. In contrast, laparotomy resulted in down-regulation of all nAChR subunits, except α9, and decreased mitochondria sustainability to apoptogenic effects of Ca2+ and H2O2. 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 Ca2+ 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.

Proteomic Investigation of Murine Neuronal α7-Nicotinic Acetylcholine Receptor Interacting Proteins

“…Interestingly, localization to the mitochondria (GO:0005739, FDR 0.0004) was also enriched, agreeing with previous studies that identified α 7-nAChR function in the mitochondrial membrane. 36 Proteins localized in neuron projections (GO:0043005, FDR 0.008), including α 7 subunits, were also enriched, which is consistent with the observation that development of neuron projections (i.e., neurites) is mediated by α 7-nAChRs (Figure 5, Figure 7). 37…”

Retrograde signaling by a mtDNA-encoded non-coding RNA preserves mitochondrial bioenergetics

“…Several components of CSE may influence different steps in mito-ncR-805 regulation. Nicotine has pro-survival effects, with cell-type-specific responses that depend on the repertoire of nicotinic acetylcholine receptors (nAChRs) on the cell surface and on the mitochondrial membrane itself in the given cell type 59 – 61 . We do not know whether a single component of CSE is responsible for all spatial–temporal changes in mito-ncR-805, or the response is a complex reaction that culminates from the effects of several CS components, or is a result of a signaling event through nAChRs or other mechanisms.…”

Positive Allosteric Modulation of Alpha7 Nicotinic Acetylcholine Receptors Transiently Improves Memory but Aggravates Inflammation in LPS-Treated Mice

“…The ability of both PNU282 and PNU120 to influence the nAChR content in the brain of LPS-injected mice demonstrated two important things: the ''plasticity'' of the brain nAChRs and the potency of α7 nAChRs in influencing the expression of other nAChR subtypes in the brain. We have already reported up-regulation of α3β4 and α9β4 nAChRs in the mitochondria of α7−/− mice (Arias et al, 2018;Uspenska et al, 2018b) and up-regulation of α3β4 nAChRs in LPS-treated mice where α7 and α4β2 nAChRs were down-regulated (Lykhmus et al, 2015a(Lykhmus et al, , 2019a. Therefore, the deficiency of cognitively important α7 and α4β2 nAChRs was accompanied by up-regulation of α3β4 and α9β4 nAChRs that neither compensated memory decline nor supported mitochondria stability.…”

“…A separate line of evidence demonstrates that α7-containing nAChRs are expressed in the outer membrane of mitochondria and regulate the early events of mitochondria-driven apoptosis, such as cytochrome c release (reviewed in . The initial finding (Gergalova et al, 2012) was further supported by the data showing the involvement of mitochondrial nAChRs in liver regeneration (Uspenska et al, 2018b) and in neuroinflammation (Lykhmus et al, 2015a). In contrast to the nAChRs expressed in the plasma membrane, those exposed to the intracellular environment do not function as ion channels but influence intramitochondrial kinases in an ion-independent manner (Gergalova et al, 2014).…”