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Mitochondrial dysfunction induced by sertraline, an antidepressant agent.

ABSTRACT: Sertraline, a selective serotonin reuptake inhibitor, has been used for the treatment of depression. Although it is generally considered safe, cases of sertraline-associated liver injury have been documented; however, the possible mechanism of sertraline-associated hepatotoxicity is entirely unknown. Here, we report that mitochondrial impairment may play an important role in liver injury induced by sertraline. In mitochondria isolated from rat liver, sertraline uncoupled mitochondrial oxidative phosphorylation and inhibited the activities of oxidative phosphorylation complexes I and V. Additionally, sertraline induced Ca(2+)-mediated mitochondrial permeability transition (MPT), and the induction was prevented by bongkrekic acid (BA), a specific MPT inhibitor targeting adenine nucleotide translocator (ANT), implying that the MPT induction is mediated by ANT. In freshly isolated rat primary hepatocytes, sertraline rapidly depleted cellular adenosine triphosphate (ATP) and subsequently induced lactate dehydrogenase leakage; both were attenuated by BA. Our results, including ATP depletion, induction of MPT, inhibition of mitochondrial respiration complexes, and uncoupling oxidative phosphorylation, indicate that sertraline-associated liver toxicity is possibly via mitochondrial dysfunction.

SUBMITTER: Li Y

PROVIDER: S-EPMC5736306 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Mitochondrial dysfunction induced by sertraline, an antidepressant agent.

Li Yan Y Couch Letha L Higuchi Masahiro M Fang Jia-Long JL Guo Lei L

Toxicological sciences : an official journal of the Society of Toxicology 20120302 2

Sertraline, a selective serotonin reuptake inhibitor, has been used for the treatment of depression. Although it is generally considered safe, cases of sertraline-associated liver injury have been documented; however, the possible mechanism of sertraline-associated hepatotoxicity is entirely unknown. Here, we report that mitochondrial impairment may play an important role in liver injury induced by sertraline. In mitochondria isolated from rat liver, sertraline uncoupled mitochondrial oxidative ...[more]

PMID: 22387747

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Project description:Macroautophagy/autophagy (hereafter autophagy), the process of mass degradation of unnecessary elements within the cell, is often dysregulated in many diseases such as cancer, atherosclerosis, and neurodegenerative diseases. Hence, autophagy modulating agents have a great potential to be therapeutic agents for the autophagy-related diseases. Here we report that an anti-depressant drug sertraline (Sert) is an autophagy-inducing agent. Mechanistically, Sert potentially binds to and antagonizes the mitochondrial VDAC1 (voltage dependent anion channel 1), resulting in reduced cellular ATP (adenosine triphosphate) level, activation of AMP-activated protein kinase (AMPK) and inhibition of its downstream, MTOR (mechanistic target of rapamycin kinase)-RPS6KB1 (ribosomal protein S6 kinase B1) signaling pathway. Cells lacking VDAC1 expression completely abrogate the modulatory effect of Sert on AMPK-MTOR pathway and autophagy-inducing activity. We further show that Sert suppresses tauopathy by promoting the autophagic degradation of MAPT (microtubule associated protein tau) protein via inducing autophagy. Our study demonstrates the potential of Sert as a novel small molecule autophagy-inducing agent and provides a new drug candidate to treat autophagy related diseases by targeting VDAC1.Abbreviations: AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; Baf: bafilomycin A1; BiFC: biomolecular fluorescence complementation; CAMKK2/CAMKKB: calcium/calmodulin dependent protein kinase kinase 2; CC: compound C; DARTS: drug affinity responsive target stability; HUVECs: human umbilical vein endothelial cells; Inda: indatraline; STK11/LKB1: serine/threonine kinase 11; MAPT: microtubule associated protein tau; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; 3-MA: 3-methyladenine; MEFs: mouse embryonic fibroblasts; MTOR: mechanistic target of rapamycin kinase; PI3K: phosphoinositide 3-kinase; Rapa: rapamycin; Sert: sertraline; RPS6KB1: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; SLC6A4/SERT1: solute carrier family 6 member 4; TFEB: transcription factor EB; VDAC1: voltage dependent anion channel 1; WT: wild-type; WM: wortmannin.

Project description:Study questionDo selective serotonin reuptake inhibitor (SSRI) antidepressants affect the function of human sperm?Summary answerThe SSRI antidepressant Sertraline (e.g. Zoloft) inhibits the sperm-specific Ca2+ channel CatSper and affects human sperm function in vitro.What is known alreadyIn human sperm, CatSper translates changes of the chemical microenvironment into changes of the intracellular Ca2+ concentration ([Ca2+]i) and swimming behavior. CatSper is promiscuously activated by oviductal ligands, but also by synthetic chemicals that might disturb the fertilization process. It is well known that SSRIs have off-target actions on Ca2+, Na+ and K+ channels in somatic cells. Whether SSRIs affect the activity of CatSper is, however, unknown.Study design, size, durationWe studied the action of the seven drugs belonging to the most commonly prescribed class of antidepressants, SSRIs, on resting [Ca2+]i and Ca2+ influx via CatSper in human sperm. The SSRI Sertraline was selected for in-depth analysis of its action on steroid-, prostaglandin-, pH- and voltage-activation of human CatSper. Moreover, the action of Sertraline on sperm acrosomal exocytosis and penetration into viscous media was evaluated.Participants/materials, setting, methodsThe activity of CatSper was investigated in sperm of healthy volunteers, using kinetic Ca2+ fluorimetry and patch-clamp recordings. Acrosomal exocytosis was investigated using Pisum sativum agglutinin and image cytometry. Sperm penetration in viscous media was evaluated using the Kremer test.Main results and the role of chanceSeveral SSRIs affected [Ca2+]i and attenuated ligand-induced Ca2+ influx via CatSper. In particular, the SSRI Sertraline almost completely suppressed Ca2+ influx via CatSper. Remarkably, the drug was about four-fold more potent to suppress prostaglandin- versus steroid-induced Ca2+ influx. Sertraline also suppressed alkaline- and voltage-activation of CatSper, indicating that the drug directly inhibits the channel. Finally, Sertraline impaired ligand-induced acrosome reaction and sperm penetration into viscous media.Limitations, reasons for cautionThis is an in vitro study. Future studies have to assess the physiological relevance in vivo.Wider implications of the findingsThe off-target action of Sertraline on CatSper in human sperm might impair the fertilization process. In a research setting, Sertraline may be used to selectively inhibit prostaglandin-induced Ca2+ influx.Study funding/competing interest(s)This work was supported by the Swiss Centre for Applied Human Toxicology (SCAHT), the Département de l'Instruction Publique of the State of Geneva, the German Research Foundation (CRU326), the Interdisciplinary Center for Clinical Research, Münster (IZKF; Str/014/21), the Innovation Fund Denmark (grant numbers 14-2013-4) and the EDMaRC research grant from the Kirsten and Freddy Johansen's Foundation. The authors declare that no conflict of interest could be perceived as prejudicing the impartiality of the research reported.Trial registration numberNA.

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Mitochondrial dysfunction induced by sertraline, an antidepressant agent.

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Mitochondrial dysfunction induced by sertraline, an antidepressant agent.

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