Mitochondrial dysfunction is involved in the pathophysiology of psychiatric and neurodegenerative disorders and can be used as a modulator and/or predictor of treatment responsiveness. Understanding the mitochondrial effects of antidepressants is important to connect mitochondria with their therapeutic and/or adverse effects. Pig brain-isolated mitochondria were used to evaluate antidepressant-induced changes in the activity of electron transport chain (ETC) complexes, monoamine oxidase (MAO), mitochondrial respiratory rate, and ATP. Bupropion, escitalopram, fluvoxamine, sertraline, paroxetine, and trazodone were tested. All tested antidepressants showed significant inhibition of complex I and IV activities at high concentrations (50 and 100 µmol/L); complex II + III activity was reduced by all antidepressants except bupropion. Complex I-linked respiration was reduced by escitalopram >> trazodone >> sertraline. Complex II-linked respiration was reduced only by bupropion. Significant positive correlations were confirmed between complex I-linked respiration and the activities of individual ETC complexes. MAO activity was inhibited by all tested antidepressants, with SSRIs causing a greater effect than trazodone and bupropion. The results indicate a probable association between the adverse effects of high doses of antidepressants and drug-induced changes in the activity of ETC complexes and the respiratory rate of mitochondria. In contrast, MAO inhibition could be linked to the antidepressant, procognitive, and neuroprotective effects of the tested antidepressants.

• Klíčová slova
• ATP, antidepressants, mitochondrial respiration, monoamine oxidase, oxidative phosphorylation, reactive oxygen species,
• Publikační typ
• časopisecké články MeSH

This determination of the mitochondrial effect of pharmacologically different antidepressants (agomelatine, ketamine and vortioxetine) was evaluated and quantified in vitro in pig brain-isolated mitochondria. We measured the activity of mitochondrial complexes, citrate synthase, malate dehydrogenase and monoamine oxidase, and the mitochondrial respiratory rate. Total hydrogen peroxide production and ATP production were assayed. The most potent inhibitor of all mitochondrial complexes and complex I-linked respiration was vortioxetine. Agomelatine and ketamine inhibited only complex IV activity. None of the drugs affected complex II-linked respiration, citrate synthase or malate dehydrogenase activity. Hydrogen peroxide production was mildly increased by agomelatine, which might contribute to increased oxidative damage and adverse effects at high drug concentrations. Vortioxetine significantly reduced hydrogen peroxide concentrations, which might suggest antioxidant mechanism activation. All tested antidepressants were partial MAO-A inhibitors, which might contribute to their antidepressant effect. We observed vortioxetine-induced MAO-B inhibition, which might be linked to decreased hydrogen peroxide formation and contribute to its procognitive and neuroprotective effects. Mitochondrial dysfunction could be linked to the adverse effects of vortioxetine, as vortioxetine is the most potent inhibitor of mitochondrial complexes and complex I-linked respiration. Clarifying the molecular interaction between drugs and mitochondria is important to fully understand their mechanism of action and the connection between their mechanisms and their therapeutic and/or adverse effects.

• Klíčová slova
• ATP, agomelatine, antidepressants, ketamine, mitochondrial respiration, monoamine oxidase, oxidative phosphorylation, reactive oxygen species, vortioxetine,
• MeSH
• antidepresiva farmakologie   MeSH
• citrátsynthasa MeSH
• ketamin * farmakologie   MeSH
• malátdehydrogenasa MeSH
• monoaminoxidasa MeSH
• peroxid vodíku MeSH
• prasata MeSH
• respirační komplex I MeSH
• vortioxetin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• agomelatine MeSH Prohlížeč
• antidepresiva MeSH
• citrátsynthasa MeSH
• ketamin * MeSH
• malátdehydrogenasa MeSH
• monoaminoxidasa MeSH
• peroxid vodíku MeSH
• respirační komplex I MeSH
• vortioxetin MeSH

Mitochondria are targets of newly synthesized drugs and being tested for the treatment of various diseases caused or accompanied by disruption of cellular bioenergetics. In drug development, it is necessary to test for drug-induced changes in mitochondrial enzyme activity that may be related to therapeutic or adverse drug effects. Measurement of drug effect on mitochondrial oxygen consumption kinetics and/or protective effects of drugs against calcium-induced inhibition of the mitochondrial respiration can be used for the study mitochondrial toxicity and neuroprotective effects of drugs. Supposing that the drug-induced inhibition of the mitochondrial respiratory rate and/or individual mitochondrial complexes is associated with adverse drug effects, the effects of drugs on mitochondrial respiration in isolated mitochondria allow selection of novel molecules that are relatively safe for mitochondrial toxicity.

• Klíčová slova
• Drug development, High-resolution respirometry, Isolated mitochondria, Mitochondrial respiration, Mitochondrial toxicity, Pig brain,
• MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• mozek cytologie   MeSH
• prasata MeSH
• preklinické hodnocení léčiv přístrojové vybavení   metody   MeSH
• respirační komplex I metabolismus   MeSH
• respirační komplex III metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• respirační komplex I MeSH
• respirační komplex III MeSH

The trends of novel AD therapeutics are focused on multitarget-directed ligands (MTDLs), which combine cholinesterase inhibition with additional biological properties such as antioxidant properties to positively affect neuronal energy metabolism as well as mitochondrial function. We examined the in vitro effects of 10 novel MTDLs on the activities of mitochondrial enzymes (electron transport chain complexes and citrate synthase), mitochondrial respiration, and monoamine oxidase isoform (MAO-A and MAO-B) activity. The drug-induced effects of 7-MEOTA-adamantylamine heterodimers (K1011, K1013, K1018, K1020, and K1022) and tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers (K1046, K1053, K1056, K1060, and K1065) were measured in pig brain mitochondria. Most of the substances inhibited complex I- and complex II-linked respiration at high concentrations; K1046, K1053, K1056, and K1060 resulted in the least inhibition of mitochondrial respiration. Citrate synthase activity was not significantly inhibited by the tested substances; the least inhibition of complex I was observed for compounds K1060 and K1053, while both complex II/III and complex IV activity were markedly inhibited by K1011 and K1018. MAO-A was fully inhibited by K1018 and K1065, and MAO-B was fully inhibited by K1053 and K1065; the other tested drugs were partial inhibitors of both MAO-A and MAO-B. The tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers K1046, K1053, and K1060 seem to be the most suitable molecules for subsequent in vivo studies. These compounds had balanced inhibitory effects on mitochondrial respiration, with low complex I and complex II/III inhibition and full or partial inhibition of MAO-B activity.

• Klíčová slova
• Alzheimer’s disease, Cholinesterase inhibitors, Electron transport chain complexes, Mitochondrial respiration, Monoamine oxidase, Multitarget-directed ligands,
• MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• buněčné dýchání účinky léků   MeSH
• energetický metabolismus * účinky léků   MeSH
• inhibitory MAO farmakologie   MeSH
• mitochondrie účinky léků   enzymologie   metabolismus   MeSH
• monoaminoxidasa metabolismus   MeSH
• prasata MeSH
• respirační komplex II metabolismus   MeSH
• takrin chemie   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inhibitory MAO MeSH
• monoaminoxidasa MeSH
• respirační komplex II MeSH
• takrin MeSH

The evaluation of drug-induced mitochondrial impairment may be important in drug development as well as in the comprehension of molecular mechanisms of the therapeutic and adverse effects of drugs. The primary aim of this study was to investigate the effects of four drugs for treatment of depression (bupropion, fluoxetine, amitriptyline, and imipramine) and five drugs for bipolar disorder treatment (lithium, valproate, valpromide, lamotrigine, and carbamazepine) on cell energy metabolism. The in vitro effects of the selected psychopharmaca were measured in isolated pig brain mitochondria; the activities of citrate synthase (CS) and electron transport chain (ETC) complexes (I, II + III, and IV) and mitochondrial respiration rates linked to complex I and complex II were measured. Complex I was significantly inhibited by lithium, carbamazepine, fluoxetine, amitriptyline, and imipramine. The activity of complex IV was decreased after exposure to carbamazepine. The activities of complex II + III and CS were not affected by any tested drug. Complex I-linked respiration was significantly inhibited by bupropion, fluoxetine, amitriptyline, imipramine, valpromide, carbamazepine, and lamotrigine. Significant inhibition of complex II-linked respiration was observed after mitochondria were exposed to amitriptyline, fluoxetine, and carbamazepine. Our outcomes confirm the need to investigate the effects of drugs on both the total respiration rate and the activities of individual enzymes of the ETC to reveal the risk of adverse effects as well as to understand the molecular mechanisms leading to drug-induced changes in the respiratory rate. Our approach can be further replicated to study the mechanisms of action of newly developed drugs.

• Klíčová slova
• Antidepressant, Citrate synthase, Electron transport chain complexes, Mitochondrial respiration, Mood-stabilizing drugs,
• MeSH
• antidepresiva toxicita   MeSH
• antimanika toxicita   MeSH
• buněčné dýchání účinky léků   MeSH
• elektronový transportní řetězec metabolismus   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• mozek účinky léků   metabolismus   MeSH
• oxidativní fosforylace účinky léků   MeSH
• subcelulární frakce MeSH
• Sus scrofa MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antidepresiva MeSH
• antimanika MeSH
• elektronový transportní řetězec MeSH

Assessment of drug-induced mitochondrial dysfunctions is important in drug development as well as in the understanding of molecular mechanism of therapeutic or adverse effects of drugs. The aim of this study was to investigate the effects of three typical antipsychotics (APs) and seven atypical APs on mitochondrial bioenergetics. The effects of selected APs on citrate synthase, electron transport chain complexes (ETC), and mitochondrial complex I- or complex II-linked respiratory rate were measured using mitochondria isolated from pig brain. Complex I activity was decreased by chlorpromazine, haloperidol, zotepine, aripiprazole, quetiapine, risperidone, and clozapine. Complex II + III was significantly inhibited by zotepine, aripiprazole, quetiapine, and risperidone. Complex IV was inhibited by zotepine, chlorpromazine, and levomepromazine. Mitochondrial respiratory rate was significantly inhibited by all tested APs, except for olanzapine. Typical APs did not exhibit greater efficacy in altering mitochondrial function compared to atypical APs except for complex I inhibition by chlorpromazine and haloperidol. A comparison of the effects of APs on individual respiratory complexes and on the overall mitochondrial respiration has shown that mitochondrial functions may not fully reflect the disruption of complexes of ETC, which indicates AP-induced modulation of other mitochondrial proteins. Due to the complicated processes associated with mitochondrial activity, it is necessary to measure not only the effect of the drug on individual mitochondrial enzymes but also the respiration rate of the mitochondria or a similar complex process. The experimental approach used in the study can be applied to mitochondrial toxicity testing of newly developed drugs.

• Klíčová slova
• Antipsychotics, Citrate synthase, Electron transport chain complexes, Mitochondrial respiration,
• MeSH
• antipsychotika toxicita   MeSH
• energetický metabolismus účinky léků   MeSH
• mitochondrie účinky léků   patologie   MeSH
• mozek účinky léků   metabolismus   MeSH
• prasata MeSH
• respirační komplex I účinky léků   metabolismus   MeSH
• respirační komplex II účinky léků   metabolismus   MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• antipsychotika MeSH
• respirační komplex I MeSH
• respirační komplex II MeSH

BACKGROUND: Mitochondrial dysfunctions are implicated in the pathophysiology of mood disorders. We measured and examined the following selected mitochondrial parameters: citrate synthase (CS) activity, electron transport system (ETS) complex (complexes I, II, and IV) activities, and mitochondrial respiration in blood platelets. PATIENTS AND METHODS: The analyses were performed for 24 patients suffering from a depressive episode of bipolar affective disorder (BD), compared to 68 patients with MDD and 104 healthy controls. BD and unipolar depression were clinically evaluated using well-established diagnostic scales and questionnaires. RESULTS: The CS, complex II, and complex IV activities were decreased in the depressive episode of BD patients; complex I and complex I/CS ratio were significantly increased compared to healthy controls. We observed significantly decreased complex II and CS activities in patients suffering from MDD compared to controls. Decreased respiration after complex I inhibition and increased residual respiration were found in depressive BD patients compared to controls. Physiological respiration and capacity of the ETS were decreased, and respiration after complex I inhibition was increased in MDD patients, compared to controls. Increased complex I activity can be a compensatory mechanism for decreased CS and complex II and IV activities. CONCLUSION: We can conclude that complex I and its abnormal activity contribute to the defects in cellular energy metabolism during a depressive episode of BD. The observed parameters could be used in a panel of biomarkers that could selectively distinguish BD depression from MDD and can be easily examined from blood elements.

• Klíčová slova
• affective disorder, biomarker, mitochondrial enzyme, oxidative phosphorylation, platelet,
• Publikační typ
• časopisecké články MeSH

Impairment of mitochondrial metabolism, particularly the electron transport chain (ETC), as well as increased oxidative stress might play a significant role in pathogenesis of Alzheimer's disease (AD). Some effects of drugs used for symptomatic AD treatment may be related to their direct action on mitochondrial function. In vitro effects of pharmacologically different cognitives (galantamine, donepezil, rivastigmine, 7-MEOTA, memantine) and nootropic drugs (latrepirdine, piracetam) were investigated on selected mitochondrial parameters: activities of ETC complexes I, II + III, and IV, citrate synthase, monoamine oxidase (MAO), oxygen consumption rate, and hydrogen peroxide production of pig brain mitochondria. Complex I activity was decreased by galantamine, donepezil, and memantine; complex II + III activity was increased by galantamine. None of the tested drugs caused significant changes in the rate of mitochondrial oxygen consumption, even at high concentrations. Except galantamine, all tested drugs were selective MAO-A inhibitors. Latrepirdine, donepezil, and 7-MEOTA were found to be the most potent MAO-A inhibitors. Succinate-induced mitochondrial hydrogen peroxide production was not significantly affected by the drugs tested. The direct effect of cognitives and nootropics used in the treatment of AD on mitochondrial respiration is relatively small. The safest drugs in terms of disturbing mitochondrial function appear to be piracetam and rivastigmine. The MAO-A inhibition by cognitives and nootropics may also participate in mitochondrial neuroprotection. The results support the future research aimed at measuring the effects of currently used drugs or newly synthesized drugs on mitochondrial functioning in order to understand their mechanism of action.

• Klíčová slova
• Cognitives, Mitochondrial respiration, Monoamine oxidase, Nootropics, Reactive oxygen species,
• MeSH
• Alzheimerova nemoc metabolismus   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• donepezil MeSH
• galantamin metabolismus   MeSH
• indany farmakologie   MeSH
• kognice účinky léků   MeSH
• memantin farmakologie   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• monoaminoxidasa účinky léků   metabolismus   MeSH
• mozek účinky léků   metabolismus   MeSH
• nootropní látky farmakologie   MeSH
• piperidiny farmakologie   MeSH
• prasata MeSH
• rivastigmin farmakologie   MeSH
• spotřeba kyslíku účinky léků   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholinesterasové inhibitory MeSH
• donepezil MeSH
• galantamin MeSH
• indany MeSH
• memantin MeSH
• monoaminoxidasa MeSH
• nootropní látky MeSH
• piperidiny MeSH
• rivastigmin MeSH

Respiratory complex II (CII, succinate dehydrogenase, SDH) inhibition can induce cell death, but the mechanistic details need clarification. To elucidate the role of reactive oxygen species (ROS) formation upon the ubiquinone-binding (Qp) site blockade, we substituted CII subunit C (SDHC) residues lining the Qp site by site-directed mutagenesis. Cell lines carrying these mutations were characterized on the bases of CII activity and exposed to Qp site inhibitors MitoVES, thenoyltrifluoroacetone (TTFA) and Atpenin A5. We found that I56F and S68A SDHC variants, which support succinate-mediated respiration and maintain low intracellular succinate, were less efficiently inhibited by MitoVES than the wild-type (WT) variant. Importantly, associated ROS generation and cell death induction was also impaired, and cell death in the WT cells was malonate and catalase sensitive. In contrast, the S68A variant was much more susceptible to TTFA inhibition than the I56F variant or the WT CII, which was again reflected by enhanced ROS formation and increased malonate- and catalase-sensitive cell death induction. The R72C variant that accumulates intracellular succinate due to compromised CII activity was resistant to MitoVES and TTFA treatment and did not increase ROS, even though TTFA efficiently generated ROS at low succinate in mitochondria isolated from R72C cells. Similarly, the high-affinity Qp site inhibitor Atpenin A5 rapidly increased intracellular succinate in WT cells but did not induce ROS or cell death, unlike MitoVES and TTFA that upregulated succinate only moderately. These results demonstrate that cell death initiation upon CII inhibition depends on ROS and that the extent of cell death correlates with the potency of inhibition at the Qp site unless intracellular succinate is high. In addition, this validates the Qp site of CII as a target for cell death induction with relevance to cancer therapy.

• MeSH
• buněčná smrt fyziologie   MeSH
• konformace proteinů MeSH
• lidé MeSH
• mitochondrie metabolismus   fyziologie   MeSH
• molekulární sekvence - údaje MeSH
• mutageneze cílená MeSH
• respirační komplex II chemie   genetika   metabolismus   fyziologie   MeSH
• sekvence aminokyselin MeSH
• ubichinon chemie   genetika   metabolismus   MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• respirační komplex II MeSH
• respiratory complex II MeSH Prohlížeč
• ubichinon MeSH