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Mitochondrial Nicotinic Acetylcholine Receptors Support Liver Cells Mitochondrial Nicotinic Acetylcholine Receptors Support Liver Cells Viability After Partial Hepatectomy Kateryna Uspenska, Olena Lykhmus, Maria Obolenskaya, Stéphanie Pons, Uwe Maskos, Serhiy Komisarenko, Maryna Skok To cite this version: Kateryna Uspenska, Olena Lykhmus, Maria Obolenskaya, Stéphanie Pons, Uwe Maskos, et al.. Mito- chondrial Nicotinic Acetylcholine Receptors Support Liver Cells Viability After Partial Hepatectomy. Frontiers in Pharmacology, Frontiers, 2018, 9, pp.626. 10.3389/fphar.2018.00626. hal-02888329 HAL Id: hal-02888329 https://hal.archives-ouvertes.fr/hal-02888329 Submitted on 3 Jul 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License fphar-09-00626 June 11, 2018 Time: 17:15 # 1 ORIGINAL RESEARCH published: 13 June 2018 doi: 10.3389/fphar.2018.00626 Mitochondrial Nicotinic Acetylcholine Receptors Support Liver Cells Viability After Partial Hepatectomy Kateryna Uspenska1, Olena Lykhmus1, Maria Obolenskaya2, Stephanie Pons3, Uwe Maskos3, Serhiy Komisarenko1 and Maryna Skok1* 1 Laboratory of Cell Receptors Immunology, O. V. Palladin Institute of Biochemistry, Kiev, Ukraine, 2 System Biology Group, Institute of Molecular Biology and Genetics, Kiev, Ukraine, 3 Integrative Neurobiology of Cholinergic Systems, Institut Pasteur, Paris, France 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 a3b2, a7b2, and a9a10 nAChR subtypes are up-regulated in rat liver mitochondria 3– 6 h after partial hepatectomy resulting in increased sustainability of mitochondria to 2C apoptogenic effects of Ca and H2O2. In contrast, laparotomy resulted in down- Edited by: regulation of all nAChR subunits, except a9, and decreased mitochondria sustainability Domenico Tricarico, 2C Università degli Studi di Bari Aldo to apoptogenic effects of Ca and H2O2. Experiments performed in liver mitochondria Moro, Italy from a3C/−, a7−/−, b4−/−, a7b2−/−, or wild-type C57Bl/6J mice demonstrated Reviewed by: that the decrease of a3 or absence of a7 or a7/b2 subunits in mitochondria is Antonio R. Artalejo, Complutense University of Madrid, compensated with b4 and a9 subunits, which could be found in a3b4, a4b4, a9b4, and Spain a9a10 combinations. Mitochondria from knockout mice maintained their sustainability to Madeline Nieves-Cintron, Ca2C but were differently regulated by nAChR subtype-specific ligands: PNU-282987, University of California, Davis, United States methyllycaconitine, dihydro-b-erythroidine, a-conotoxin MII, and a-conotoxin PeIA. It is *Correspondence: concluded that mitochondrial nAChRs play an important role in supporting the viability Maryna Skok of hepatic cells and, therefore, may be a pharmacological target for pro-survival therapy. [email protected] The concerted action of multiple nAChR subtypes controlling either CaKMII- or Src- Specialty section: dependent signaling pathways in mitochondria ensures a reliable protection against This article was submitted to apoptogenic factors of different nature. Pharmacology of Ion Channels and Channelopathies, Keywords: nicotinic acetylcholine receptor, mitochondria, knockout mice, partial hepatectomy, cytochrome c, a section of the journal mitochondrial kinases Frontiers in Pharmacology Received: 03 April 2018 Accepted: 24 May 2018 INTRODUCTION Published: 13 June 2018 Nicotinic acetylcholine receptors are ligand-gated ion channels initially discovered in neuro- Citation: muscular synapses and further found in neurons and in many non-excitable cells (Skok, Uspenska K, Lykhmus O, Obolenskaya M, Pons S, Maskos U, 2002; Kalamida et al., 2007; Kawashima and Fujii, 2008; Gotti et al., 2009). The classical Komisarenko S and Skok M (2018) idea on the nAChR involvement in fast synaptic transmission has evolved along with the Mitochondrial Nicotinic Acetylcholine understanding of universal and evolutionary ancient kind of acetylcholine signaling in the living Receptors Support Liver Cells Viability nature (Wessler and Kirkpatrick, 2008). Now it is clear that acetylcholine and its receptors After Partial Hepatectomy. Front. Pharmacol. 9:626. Abbreviations: CaMKII, calcium-calmodulin-dependent kinase; cyt c, cytochrome c; DhbE, dihydro-b-erythroidine; LT, doi: 10.3389/fphar.2018.00626 laparotomy; MLA, methyllycaconitine; nAChR, nicotinic acetylcholine receptor; PHE, partial hepatectomy. Frontiers in Pharmacology| www.frontiersin.org 1 June 2018| Volume 9| Article 626 fphar-09-00626 June 11, 2018 Time: 17:15 # 2 Uspenska et al. Mitochondrial Nicotinic Receptors Upon Hepatectomy (both nicotinic and muscarinic) appeared in evolution long indicated. Antibodies against a7(1–208) (Lykhmus et al., 2010), before the development of nerve and muscle systems and were a3(181–192), a4(181–192), a7(179–190) (Skok et al., 1999), initially intended to regulate the vital functions of primitive cells a9(11–23) (Koval et al., 2011), b2(190–200) or b4(190–200) like survival, proliferation and adhesion (Kawashima and Fujii, (Koval et al., 2004) nAChR fragments were obtained and 2008). The prototypes of nAChRs were found in bacteria where characterized previously in our lab. Antibody against a10(404– they respond to the changes in the environmental pH (Bocquet 417) (Lips et al., 2002) was a kind gift of Dr. W. Kummer (Justus et al., 2007). Liebig University Giessen, Giessen, Germany). The antibodies Structurally, the nAChRs are homo- or hetero-pentamers were biotinylated according to standard procedure (Harlow and composed of established combinations of ten a (a1 to a10) and Lane, 1988). Rabbit cyt c-specific antibodies were generated as four b (b1 to b4) subunits; muscular nAChRs contain 2a1, b1, previously described (Gergalova et al., 2014). Conotoxin MII, g and d or + subunits (Kalamida et al., 2007). Binding of agonist synthesized according to Surin et al.(2012) and a-conotoxin results in concerted conformational movement of the subunits PeIA, synthesized as described (Koval et al., 2011) was a within the pentamer leading to ion channel opening (gating) kind gift of Prof. V. Tsetlin (Shemyakin-Ovchinnikov Institute (Changeux, 2012). However, certain kinds of nAChR signaling, of Bioorganic Chemistry, RAS, Russia). Dexalgin (analog of especially in non-excitable cells, seem not to require gating as Dexketoprofen, (2S)-2-[3-(benzoyl)phenyl]propanoic acid) was such and are, therefore, ion-independent (Skok, 2009). Probably, purchased from the public drugstore in Kiev. this is the most ancient type of cholinergic signaling not related to significant changes in the cell membrane polarity. Animals and Procedures The important step in the understanding of the universal Animals were kept in the animal facilities of Institut Pasteur, character of cholinergic signaling was the discovery of functional Paris, France and O. V. Palladin Institute of Biochemistry, Kiev, nAChRs in mitochondria (Gergalova et al., 2012). Previously, we Ukraine. They were housed in quiet, temperature-controlled reported that several nAChR subtypes are found in the outer rooms and provided with water and food pellets ad libitum. All membrane of mouse mitochondria in a tissue-specific manner procedures conformed with the guidelines of the Center National and in close relation to voltage-dependent anion channels de la Recherche Scientifique or Palladin Institute’s IACUC. Before (VDACs) (Gergalova et al., 2012; Lykhmus et al., 2014). The starting the experiments, the protocols were approved by the function of mitochondrial nAChRs appeared to be ion channel- IACUC. independent, because they engage intramitochondrial kinases Age-matched C57BL/6J wild-type (WT) and knockout mice under the effect of agonists, antagonists and even positive lacking either a7 (Orr-Urtreger et al., 1997), a7 and b2 or b4 (Xu allosteric modulators (Gergalova et al., 2014; Uspenska et al., et al., 1999b) nAChR subunits, 20–22 g, of both genders were 2017). The main function of mitochondrial nAChRs known used. Since homozygous a3−/− mice do not survive (Xu et al., by now is to regulate the early stages of mitochondria-driven 1999a), heterozygous a3C/− mice were used instead. Before apoptosis like cyt c release (reviewed in Skok et al., 2016). removing the liver mice were sacrificed by cervical dislocation. In contrast, nicotine effects on mitochondria respiratory chain Male Wistar rats (200–250 g) were operated under ether appeared to be receptor-independent (Cormier et al., 2001). The anesthesia according to standard procedures (Higgins and nAChRs found in the brain mitochondria are modulated by Anderson, 1931; Tannuri et al., 2007). The animal’s abdomen was inflammation (Lykhmus et al., 2016) and influence accumulation opened carefully. In PHE, medial and left lateral
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