Neuroreceptor Inhibition by Clozapine Triggers Mitohormesis and Metabolic Reprogramming in Human Blood Cells
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Culture
2.2. Isolation of Peripheral Blood Mononuclear Cells (PBMCs) and Granulocytes
2.3. Glucose Assay
2.4. Protein Concentration
2.5. Western Blots
2.6. Apoptosis
2.7. Oil Red Staining
2.8. RT-PCR Analysis
2.9. LC–MS/MS Measurement
2.10. High-Resolution Respirometry
2.11. Immunohistochemistry
2.12. Determination of VEGF Levels
2.13. Acridine Orange Staining
2.14. Statistical Analysis
3. Results
3.1. Glucose Uptake
3.2. Apoptosis
3.3. ER Stress
3.4. Gene-Expression Analysis
3.5. Metabolic Changes under Clozapine Treatment
3.6. Lipid Droplets (LD)
3.7. Oxygen Consumption
4. Discussion
Study Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Kolar, D.; Krajcovic, B.; Kleteckova, L.; Kuncicka, D.; Vales, K.; Brozka, H. Review: Genes Involved in Mitochondrial Physiology Within 22q11.2 Deleted Region and Their Relevance to Schizophrenia. Schizophr. Bull. 2023, 49, 1637–1653. [Google Scholar] [CrossRef] [PubMed]
- Umare, M.D.; Wankhede, N.L.; Bajaj, K.K.; Trivedi, R.V.; Taksande, B.G.; Umekar, M.J.; Mahore, J.G.; Kale, M.B. Interweaving of reactive oxygen species and major neurological and psychiatric disorders. Ann. Pharm. Fr. 2022, 80, 409–425. [Google Scholar] [CrossRef]
- Bergman, O.; Ben-Shachar, D. Mitochondrial Oxidative Phosphorylation System (OXPHOS) Deficits in Schizophrenia: Possible Interactions with Cellular Processes. Can. J. Psychiatry 2016, 61, 457–469. [Google Scholar] [CrossRef] [PubMed]
- Ben-Shachar, D. Mitochondrial multifaceted dysfunction in schizophrenia; complex I as a possible pathological target. Schizophr. Res. 2017, 187, 3–10. [Google Scholar] [CrossRef] [PubMed]
- McDermott, E.; de Silva, P. Impaired neuronal glucose uptake in pathogenesis of schizophrenia—Can GLUT 1 and GLUT 3 deficits explain imaging, post mortem and pharmacological findings? Med. Hypotheses. 2005, 65, 1076–1081. [Google Scholar] [CrossRef] [PubMed]
- Emamian, E.S. AKT/GSK3 signaling pathway and schizophrenia. Front. Mol. Neurosci. 2012, 5, 33. [Google Scholar] [CrossRef] [PubMed]
- Fehsel, K.; Christl, J. Comorbidity of osteoporosis and Alzheimer’s disease: Is ‘AKT’-ing on cellular glucose uptake the missing link? Ageing Res. Rev. 2022, 76, 101592. [Google Scholar] [CrossRef] [PubMed]
- Shroitman, K.N.; Yitzhaky, A.; Ben Shachar, D.; Gurwitz, D.; Hertzberg, L. Meta-analysis of brain samples of individuals with schizophrenia detects down-regulation of multiple ATP synthase encoding genes in both females and males. J. Psychiatr. Res. 2023, 158, 350–359. [Google Scholar] [CrossRef] [PubMed]
- Dror, N.; Klein, E.; Karry, R.; Sheinkman, A.; Kirsh, Z.; Mazor, M.; Tzukerman, M.; Ben-Shachar, D. State-dependent alterations in mitochondrial complex I activity in platelets: A potential peripheral marker for schizophrenia. Mol. Psychiatry 2002, 7, 995–1001. [Google Scholar] [CrossRef]
- Hardy, R.E.; Chung, I.; Yu, Y.; Loh, S.H.Y.; Morone, N.; Soleilhavoup, C.; Travaglio, M.; Serreli, R.; Panman, L.; Cain, K.; et al. The antipsychotic medications aripiprazole, brexpiprazole and cariprazine are off-target respiratory chain complex I inhibitors. Biol. Direct. 2023, 18, 43. [Google Scholar] [CrossRef]
- Tulipano, G.; Rizzetti, C.; Bianchi, I.; Fanzani, A.; Spano, P.; Cocchi, D. Clozapine-induced alteration of glucose homeostasis in the rat: The contribution of hypothalamic-pituitary-adrenal axis activation. Neuroendocrinology 2007, 85, 61–70. [Google Scholar] [CrossRef] [PubMed]
- Dwyer, D.S.; Pinkofsky, H.B.; Liu, Y.; Bradley, R.J. Antipsychotic drugs affect glucose uptake and the expression of glucose transporters in PC12 cells. Prog. Neuropsychopharmacol. Biol. Psychiatry 1999, 23, 69–80. [Google Scholar] [CrossRef] [PubMed]
- Miyakoshi, T.; Ishikawa, S.; Okubo, R.; Hashimoto, N.; Sato, N.; Kusumi, I.; Ito, Y.M. Risk factors for abnormal glucose metabolism during antipsychotic treatment: A prospective cohort study. J. Psychiatr. Res. 2023, 168, 149–156. [Google Scholar] [CrossRef] [PubMed]
- De Silva, P.N. Does the association with diabetes say more about schizophrenia and its treatment?—The GLUT hypothesis. Med. Hypotheses. 2011, 77, 529–531. [Google Scholar] [CrossRef] [PubMed]
- Porras-Segovia, A.; Krivoy, A.; Horowitz, M.; Thomas, G.; Bolstridge, M.; Ion, D.; Shergill, S.S. Rapid-onset clozapine-induced loss of glycaemic control: Case report. BJPsych Open. 2017, 3, 138–140. [Google Scholar] [CrossRef] [PubMed]
- Patergnani, S.; Bonora, M.; Ingusci, S.; Previati, M.; Marchi, S.; Zucchini, S.; Perrone, M.; Wieckowski, M.R.; Castellazzi, M.; Pugliatti, M.; et al. Antipsychotic drugs counteract autophagy and mitophagy in multiple sclerosis. Proc. Natl. Acad. Sci. USA 2021, 118, e2020078118. [Google Scholar] [CrossRef] [PubMed]
- Lindsley, C.W.; Hopkins, C.R. Return of D4 Dopamine Receptor Antagonists in Drug Discovery. J. Med. Chem. 2017, 60, 7233–7243. [Google Scholar] [CrossRef] [PubMed]
- Choi, Y.; Jeong, H.J.; Liu, Q.F.; Oh, S.T.; Koo, B.S.; Kim, Y.; Chung, I.W.; Kim, Y.S.; Jeon, S. Clozapine Improves Memory Impairment and Reduces Aβ Level in the Tg-APPswe/PS1dE9 Mouse Model of Alzheimer’s Disease. Mol. Neurobiol. 2017, 54, 450–460. [Google Scholar] [CrossRef] [PubMed]
- Kaar, S.J.; Natesan, S.; McCutcheon, R.; Howes, O.D. Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology 2020, 172, 107704. [Google Scholar] [CrossRef]
- Kim, Y.; Kim, S. Target Discovery Using Deep Learning-Based Molecular Docking and Predicted Protein Structures With AlphaFold for Novel Antipsychotics. Psychiatry Investig. 2023, 20, 504–514. [Google Scholar] [CrossRef]
- Liu, X.; Wu, Z.; Lian, J.; Hu, C.H.; Huang, X.F.; Deng, C. Time-dependent changes and potential mechanisms of glucose-lipid metabolic disorders associated with chronic clozapine or olanzapine treatment in rats. Sci. Rep. 2017, 7, 2762. [Google Scholar] [CrossRef] [PubMed]
- Rocha, A.; Bellaver, B.; Souza, D.G.; Schu, G.; Fontana, I.C.; Venturin, G.T.; Greggio, S.; Fontella, F.U.; Schiavenin, M.L.; Machado, L.S.; et al. Clozapine induces astrocyte-dependent FDG-PET hypometabolism. Eur. J. Nucl. Med. Mol. Imaging 2022, 49, 2251–2264. [Google Scholar] [CrossRef] [PubMed]
- de la Cadena, S.G.; Hernández-Fonseca, K.; Camacho-Arroyo, I.; Massieu, L. Glucose deprivation induces reticulum stress by the PERK pathway and caspase-7- and calpain-mediated caspase-12 activation. Apoptosis 2014, 19, 414–427. [Google Scholar] [CrossRef] [PubMed]
- Lauressergues, E.; Bert, E.; Duriez, P.; Hum, D.; Majd, Z.; Staels, B.; Cussac, D. Does endoplasmic reticulum stress participate in APD-induced hepatic metabolic dysregulation? Neuropharmacology 2012, 62, 784–796. [Google Scholar] [CrossRef]
- Fu, J.; Zhang, X.; Chen, P.; Zhang, Y. Endoplasmic reticulum stress is involved in 2, 4-dichlorophenol-induced hepatotoxicity. J. Toxicol. Sci. 2016, 41, 745–756. [Google Scholar] [CrossRef]
- Löffler, S.; Löffler-Ensgraber, M.; Fehsel, K.; Klimke, A. Clozapine therapy raises serum concentrations of high sensitive C-reactive protein in schizophrenic patients. Int. Clin. Psychopharmacol. 2010, 25, 101–106. [Google Scholar] [CrossRef]
- Zhang, K.; Shen, X.; Wu, J.; Sakaki, K.; Saunders, T.; Rutkowski, D.T.; Back, S.H.; Kaufman, R.J. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 2006, 124, 587–599. [Google Scholar] [CrossRef] [PubMed]
- Sharpe, J.K.; Stedman, T.J.; Byrne, N.M.; Wishart, C.; Hills, A.P. Energy expenditure and physical activity in clozapine use: Implications for weight management. Aust. N. Z. J. Psychiatry 2006, 40, 810–814. [Google Scholar] [CrossRef] [PubMed]
- Oyewumi, L.K.; Cernovsky, Z.Z.; Freeman, D.J. Autonomic signs and dosing during the initial stages of clozapine therapy. Med. Sci. Monit. 2004, 10, PI19–PI23. [Google Scholar]
- Allison, D.B.; Mentore, J.L.; Heo, M.; Chandler, L.P.; Cappelleri, J.C.; Infante, M.C.; Weiden, P.J. Antipsychotic-induced weight gain: A comprehensive research synthesis. Am. J. Psychiatry 1999, 156, 1686–1696. [Google Scholar] [CrossRef]
- Groenewald, F.C.E.; Kok, R.M. Side effects of clozapine in older adults with treatment-resistant schizophrenia compared to younger adults. Int. J. Geriatr. Psychiatry 2024, 39, e6051. [Google Scholar] [CrossRef] [PubMed]
- Skurikhin, E.G.; Andreeva, T.V.; Khmelevskaya, E.S.; Ermolaeva, L.A.; Pershina, O.V.; Krupin, V.A.; Ermakova, N.N.; Reztsova, A.M.; Stepanova, I.E.; Gol’dberg, V.E.; et al. Effect of antiserotonin drug on the development of lung fibrosis and blood system reactions after intratracheal administration of bleomycin. Bull. Exp. Biol. Med. 2012, 152, 519–523. [Google Scholar] [CrossRef] [PubMed]
- Bennet, H.; Mollet, I.G.; Balhuizen, A.; Medina, A.; Nagorny, C.; Bagge, A.; Fadista, J.; Ottosson-Laakso, E.; Vikman, P.; Dekker-Nitert, M.; et al. Serotonin (5-HT) receptor 2b activation augments glucose-stimulated insulin secretion in human and mouse islets of Langerhans. Diabetologia 2016, 59, 744–754. [Google Scholar] [CrossRef] [PubMed]
- Ustione, A.; Piston, D.W. Dopamine synthesis and D3 receptor activation in pancreatic β-cells regulates insulin secretion and intracellular [Ca(2+)] oscillations. Mol. Endocrinol. 2012, 26, 1928–1940. [Google Scholar] [CrossRef] [PubMed]
- Yang, S.; Li, T.; Zhang, A.; Gao, R.; Peng, C.; Liu, L.; Cheng, Q.; Mei, M.; Song, Y.; Xiang, X.; et al. Dysregulated autophagy in hepatocytes promotes bisphenol A (BPA)-induced hepatic lipid accumulation in male mice. Endocrinology 2017, 158, 2799–2812. [Google Scholar] [CrossRef] [PubMed]
- Gespach, C.; Marrec, N.; Abita, J.P. Pharmacological characterization of the histamine uptake system in HL-60 human promyelocytic leukemia cells. Biosci. Rep. 1986, 6, 403–407. [Google Scholar] [CrossRef] [PubMed]
- Yen, A. HL-60 cells as a model of growth control and differentiation: The significance of variant cells. Hematol. Rev. 1990, 4, 5–46. [Google Scholar]
- Steidl, U.; Bork, S.; Schaub, S.; Selbach, O.; Seres, J.; Aivado, M.; Schroeder, T.; Rohr, U.P.; Fenk, R.; Kliszewski, S.; et al. Primary human CD34+ hematopoietic stem and progenitor cells express functionally active receptors of neuromediators. Blood 2004, 104, 81–88. [Google Scholar] [CrossRef] [PubMed]
- Suganuma, K.; Miwa, H.; Imai, N.; Shikami, M.; Gotou, M.; Goto, M.; Mizuno, S.; Takahashi, M.; Yamamoto, H.; Hiramatsu, A.; et al. Energy metabolism of leukemia cells: Glycolysis versus oxidative phosphorylation. Leuk. Lymphoma 2010, 51, 2112–2119. [Google Scholar] [CrossRef]
- Chen, B.; Zhang, W.; Lin, C.; Zhang, L.A. Comprehensive Review on Beneficial Effects of Catechins on Secondary Mitochondrial Diseases. Int. J. Mol. Sci. 2022, 23, 11569. [Google Scholar] [CrossRef]
- Castellano-González, G.; Pichaud, N.; Ballard, J.W.; Bessede, A.; Marcal, H.; Guillemin, G.J. Epigallocatechin-3-gallate induces oxidative phosphorylation by activating cytochrome c oxidase in human cultured neurons and astrocytes. Oncotarget 2016, 7, 7426–7440. [Google Scholar] [CrossRef]
- Fehsel, K.; Loeffler, S.; Krieger, K.; Henning, U.; Agelink, M.; Kolb-Bachofen, V.; Klimke, A. Clozapine induces oxidative stress and proapoptotic gene expression in neutrophils of schizophrenic patients. J. Clin. Psychopharmacol. 2005, 25, 419–426. [Google Scholar] [CrossRef]
- Madeo, M.; Carrisi, C.; Iacopetta, D.; Capobianco, L.; Cappello, A.R.; Bucci, C.; Palmieri, F.; Mazzeo, G.; Montalto, A.; Dolce, V. Abundant expression and purification of biologically active mitochondrial citrate carrier in baculovirus-infected insect cells. J. Bioenerg. Biomembr. 2009, 41, 289–297. [Google Scholar] [CrossRef] [PubMed]
- Frolova, A.; Flessner, L.; Chi, M.; Kim, S.T.; Foyouzi-Yousefi, N.; Moley, K.H. Facilitative Glucose Transporter Type 1 Is Differentially Regulated by Progesterone and Estrogen in Murine and Human Endometrial Stromal Cells. Endocrinology 2009, 150, 1512–1520. [Google Scholar] [CrossRef] [PubMed]
- Luo, B.; Groenke, K.; Takors, R.; Wandrey, C.; Oldiges, M. Simultaneous determination of multiple intracellular metabolites in glycolysis, pentose phosphate pathway and tricarboxylic acid cycle by liquid chromatography-mass spectrometry. J. Chromatogr. A 2007, 1147, 153–164. [Google Scholar] [CrossRef]
- Liu, K.; Tang, Q.; Fu, C.; Peng, J.; Yang, H.; Li, Y.; Hong, H. Influence of glucose starvation on the pathway of death in insect cell line Sl: Apoptosis follows autophagy. Cytotechnology 2007, 54, 97–105. [Google Scholar] [CrossRef] [PubMed]
- Hermida, M.A.; Dinesh Kumar, J.; Leslie, N.R. GSK3 and its interactions with the PI3K/AKT/mTOR signalling network. Adv. Biol. Regul. 2017, 65, 5–15. [Google Scholar] [CrossRef]
- Pereira, E.R.; Frudd, K.; Awad, W.; Hendershot, L.M. Endoplasmic reticulum (ER) stress and hypoxia response pathways interact to potentiate hypoxia-inducible factor 1 (HIF-1) transcriptional activity on targets like vascular endothelial growth factor (VEGF). J. Biol. Chem. 2014, 289, 3352–3364. [Google Scholar] [CrossRef]
- Harding, H.P.; Novoa, I.; Zhang, Y.; Zeng, H.; Wek, R.; Schapira, M.; Ron, D. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell. 2000, 6, 1099–1108. [Google Scholar] [CrossRef]
- Motta, J.M.; Sperandio, A.; Castelo-Branco, M.T.; Rumjanek, V.M. Induction of suppressive phenotype in monocyte-derived dendritic cells by leukemic cell products and IL-1β. Hum. Immunol. 2014, 75, 641–649. [Google Scholar] [CrossRef]
- Sciarretta, S.; Zhai, P.; Shao, D.; Zablocki, D.; Nagarajan, N.; Terada, L.S. Activation of NADPH oxidase 4 in the endoplasmic reticulum promotes cardiomyocyte autophagy and survival during energy stress through the protein kinase RNA-activated-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/activating transcription factor 4 pathway. Circ. Res. 2013, 113, 1253–1264. [Google Scholar] [CrossRef] [PubMed]
- Lee, S.J.; Park, B.N.; Roh, J.H.; An, Y.S.; Hur, H.; Yoon, J.K. Enhancing the Therapeutic efficacy of 2-Deoxyglucose in Breast Cancer Cells Using Cell-cycle Synchronization. Anticancer. Res. 2016, 36, 5975–5980. [Google Scholar] [CrossRef] [PubMed]
- Cochran, S.M.; McKerchar, C.E.; Morris, B.J.; Pratt, J.A. Induction of differential patterns of local cerebral glucose metabolism and immediate-early genes by acute clozapine and haloperidol. Neuropharmacology 2002, 43, 394–407. [Google Scholar] [CrossRef] [PubMed]
- Moreira, L.; Araújo, I.; Costa, T.; Correia-Branco, A.; Faria, A.; Martel, F.; Keating, E. Quercetin and epigallocatechin gallate inhibit glucose uptake and metabolism by breast cancer cells by an estrogen receptor-independent mechanism. Exp. Cell Res. 2013, 319, 1784–1795. [Google Scholar] [CrossRef]
- Kodandaraman, G.; Bankoglu, E.E.; Stopper, H. Overlapping mechanism of the induction of genomic damage by insulin and adrenaline in human promyelocytic HL-60 cells. Toxicol. In Vitro 2020, 66, 104867. [Google Scholar] [CrossRef]
- Kowalchuk, C.; Castellani, L.N.; Chintoh, A.; Remington, G.; Giacca, A.; Hahn, M.K. Antipsychotics and glucose metabolism: How brain and body collide. Am. J. Physiol. Endocrinol. Metab. 2019, 316, E1–E15. [Google Scholar] [CrossRef]
- Vargas, F.; Rivas, C.; Perdomo, H.; Rivas, A.; Ojeda, L.E.; Velásquez, M.; Correia, H.; Hernández, A.; Fraile, G. Clozapine prevents apoptosis and enhances receptor-dependent respiratory burst in human neutrophils. Pharmazie 2005, 60, 364–368. [Google Scholar] [PubMed]
- Niemann, B.; Li, L.; Simm, A.; Molenda, N.; Kockskämper, J.; Boening, A.; Rohrbach, S. Caloric restriction reduces sympathetic activity similar to beta-blockers but conveys additional mitochondrio-protective effects in aged myocardium. Sci. Rep. 2021, 11, 1931. [Google Scholar] [CrossRef]
- Contreras-Shannon, V.; Heart, D.L.; Paredes, R.M.; Navaira, E.; Catano, G.; Maffi, S.K.; Walss-Bass, C. Clozapine-induced mitochondria alterations and inflammation in brain and insulin-responsive cells. PLoS ONE. 2013, 8, e59012. [Google Scholar] [CrossRef]
- Ho, K.H.; Chen, P.H.; Chou, C.M.; Shih, C.M.; Lee, Y.T.; Cheng, C.H.; Chen, K.C. A Key Role of DNA Damage-Inducible Transcript 4 (DDIT4) Connects Autophagy and GLUT3-Mediated Stemness To Desensitize Temozolomide Efficacy in Glioblastomas. Neurotherapeutics 2020, 17, 1212–1227. [Google Scholar] [CrossRef]
- Chen, C.; Zhang, Z.; Liu, C.; Wang, B.; Liu, P.; Fang, S.; Yang, F.; You, Y.; Li, X. ATF4-dependent fructolysis fuels growth of glioblastoma multiforme. Nat. Commun. 2022, 13, 6108. [Google Scholar] [CrossRef] [PubMed]
- Palavicino-Maggio, C.B.; Kuzhikandathil, E.V. Dietary Fructose and GLUT5 Transporter Activity Contribute to Antipsychotic-Induced Weight Gain. Schizophr. Bull. 2016, 42, 1270–1279. [Google Scholar] [CrossRef] [PubMed]
- Chee, N.T.; Carriere, C.H.; Miller, Z.; Welford, S.; Brothers, S.P. Activating transcription factor 4 regulates hypoxia inducible factor 1α in chronic hypoxia in pancreatic cancer cells. Oncol. Rep. 2023, 49, 14. [Google Scholar] [CrossRef] [PubMed]
- Nishimoto, A.; Kugimiya, N.; Hosoyama, T.; Enoki, T.; Li, T.S.; Hamano, K. HIF-1α activation under glucose deprivation plays a central role in the acquisition of anti-apoptosis in human colon cancer cells. Int. J. Oncol. 2014, 44, 2077–2084. [Google Scholar] [CrossRef] [PubMed]
- Whitlock, N.A.; Agarwal, N.; Ma, J.X.; Crosson, C.E. Hsp27 upregulation by HIF-1 signaling offers protection against retinal ischemia in rats. Invest. Ophthalmol. Vis. Sci. 2005, 46, 1092–1098. [Google Scholar] [CrossRef] [PubMed]
- Lu, C.W.; Lin, S.C.; Chen, K.F.; Lai, Y.Y.; Tsai, S.J. Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J. Biol. Chem. 2008, 283, 28106–28114. [Google Scholar] [CrossRef] [PubMed]
- Huang, L.J.; Chuang, I.C.; Dong, H.P.; Yang, R.C. Hypoxia-inducible factor 1α regulates the expression of the mitochondrial ATPase inhibitor protein (IF1) in rat liver. Shock 2011, 36, 90–96. [Google Scholar] [CrossRef] [PubMed]
- Bateman, R.M.; Tokunaga, C.; Kareco, T.; Dorscheid, D.R.; Walley, K.R. Myocardial hypoxia-inducible HIF-1alpha, VEGF, and GLUT1 gene expression is associated with microvascular and ICAM-1 heterogeneity during endotoxemia. Am. J. Physiol. Heart Circ. Physiol. 2007, 293, H448–H456. [Google Scholar] [CrossRef] [PubMed]
- Arrigo, A.P. Mammalian HspB1 (Hsp27) is a molecular sensor linked to the physiology and environment of the cell. Cell Stress. Chaperones. 2017, 22, 517–529. [Google Scholar] [CrossRef]
- Cheng, J.; Lv, Z.; Weng, X.; Ye, S.; Shen, K.; Li, M.; Qin, Y.; Hu, C.; Zhang, C.; Wu, J.; et al. Hsp27 Acts as a Master Molecular Chaperone and Plays an Essential Role in Hepatocellular Carcinoma Progression. Digestion 2015, 92, 192–202. [Google Scholar] [CrossRef]
- Guo, K.; Kang, N.X.; Li, Y.; Sun, L.; Gan, L.; Cui, F.J.; Gao, M.D.; Liu, K.Y. Regulation of HSP27 on NF-kappaB pathway activation may be involved in metastatic hepatocellular carcinoma cells apoptosis. BMC Cancer. 2009, 9, 100. [Google Scholar] [CrossRef] [PubMed]
- Li, C.; Liu, C.; Zhang, J.; Lu, Y.; Jiang, B.; Xiong, H.; Li, C. Pyruvate dehydrogenase kinase regulates macrophage polarization in metabolic and inflammatory diseases. Front. Immunol. 2023, 14, 1296687. [Google Scholar] [CrossRef] [PubMed]
- Palmieri, E.M.; Spera, I.; Menga, A.; Infantino, V.; Porcelli, V.; Iacobazzi, V.; Pierri, C.L.; Hooper, D.C.; Palmieri, F.; Castegna, A. Acetylation of human mitochondrial citrate carrier modulates mitochondrial citrate/malate exchange activity to sustain NADPH production during macrophage activation. Biochim. Biophys. Acta. 2015, 1847, 729–738. [Google Scholar] [CrossRef] [PubMed]
- Formentini, L.; Pereira, M.P.; Sánchez-Cenizo, L.; Santacatterina, F.; Lucas, J.J.; Navarro, C.; Martínez-Serrano, A.; Cuezva, J.M. In vivo inhibition of the mitochondrial H+-ATP synthase in neurons promotes metabolic preconditioning. EMBO J. 2014, 33, 762–778. [Google Scholar] [CrossRef] [PubMed]
- Cosi, C.; Waget, A.; Rollet, K.; Tesori, V.; Newman-Tancredi, A. Clozapine, ziprasidone and aripiprazole but not haloperidol protect against kainic acid-induced lesion of the striatum in mice, in vivo: Role of 5-HT1A receptor activation. Brain Res. 2005, 1043, 32–41. [Google Scholar] [CrossRef] [PubMed]
- Steiner, J.; Sarnyai, Z.; Westphal, S.; Gos, T.; Bernstein, H.G.; Bogerts, B.; Keilhoff, G. Protective effects of haloperidol and clozapine on energy-deprived OLN-93 oligodendrocytes. Eur. Arch. Psychiatry Clin. Neurosci. 2011, 261, 477–482. [Google Scholar] [CrossRef] [PubMed]
- Tan, M.; Mosaoa, R.; Graham, G.T.; Kasprzyk-Pawelec, A.; Gadre, S.; Parasido, E.; Catalina-Rodriguez, O.; Foley, P.; Giaccone, G.; Cheema, A.; et al. Inhibition of the mitochondrial citrate carrier, Slc25a1, reverts steatosis, glucose intolerance, and inflammation in preclinical models of NAFLD/NASH. Cell Death Differ. 2020, 27, 2143–2157. [Google Scholar] [CrossRef]
- Damiano, F.; Tocci, R.; Gnoni, G.V.; Siculella, L. Expression of citrate carrier gene is activated by ER stress effectors XBP1 and ATF6α, binding to an UPRE in its promoter. Biochim. Biophys. Acta. 2015, 1849, 23–31. [Google Scholar] [CrossRef]
- Menga, A.; Infantino, V.; Iacobazzi, F.; Convertini, P.; Palmieri, F.; Iacobazzi, V. Insight into mechanism of in vitro insulin secretion increase induced by antipsychotic clozapine: Role of FOXA1 and mitochondrial citrate carrier. Eur. Neuropsychopharmacol. 2013, 23, 978–987. [Google Scholar] [CrossRef]
- Ruderman, N.B.; Saha, A.K.; Vavvas, D.; Witters, L.A. Malonyl-CoA, fuel sensing, and insulin resistance. Am. J. Physiol. 1999, 276, E1–E18. [Google Scholar] [CrossRef]
- Koizume, S.; Miyagi, Y. Lipid Droplets: A Key Cellular Organelle Associated with Cancer Cell Survival under Normoxia and Hypoxia. Int. J. Mol. Sci. 2016, 17, 1430. [Google Scholar] [CrossRef]
- von Wilmsdorff, M.; Bouvier, M.L.; Henning, U.; Schmitt, A.; Schneider-Axmann, T.; Gaebel, W. Sex-dependent metabolic alterations of rat liver after 12-week exposition to haloperidol or clozapine. Horm. Metab. Res. 2014, 46, 782–788. [Google Scholar] [CrossRef]
- Yang, M.; Li, K.; Ng, P.C.; Chuen, C.K.; Lau, T.K.; Cheng, Y.S.; Liu, Y.S.; Li, C.K.; Yuen, P.M.; James, A.E.; et al. Promoting effects of serotonin on hematopoiesis: Ex vivo expansion of cord blood CD34+ stem/progenitor cells, proliferation of bone marrow stromal cells, and antiapoptosis. Stem Cells. 2007, 25, 1800–1806. [Google Scholar] [CrossRef]
- Sánchez-Cenizo, L.; Formentini, L.; Aldea, M.; Ortega, A.D.; García-Huerta, P.; Sánchez-Aragó, M.; Cuezva, J.M. Up-regulation of the ATPase inhibitory factor 1 (IF1) of the mitochondrial H+-ATP synthase in human tumors mediates the metabolic shift of cancer cells to a Warburg phenotype. J. Biol. Chem. 2010, 285, 25308–25313. [Google Scholar] [CrossRef]
- Nury, C.; Merg, C.; Eb-Levadoux, Y.; Bovard, D.; Porchet, M.; Maranzano, F.; Loncarevic, I.; Tavalaei, S.; Lize, E.; Demenescu, R.L.; et al. Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol. Mech. Methods 2023, 33, 401–410. [Google Scholar] [CrossRef]
- Bailey, A.P.; Koster, G.; Guillermier, C.; Hirst, E.M.; MacRae, J.I.; Lechene, C.P.; Postle, A.D.; Gould, A.P. Antioxidant Role for Lipid Droplets in a Stem Cell Niche of Drosophila. Cell 2015, 163, 340–353. [Google Scholar] [CrossRef]
- Tian, X.; Zhao, L.; Song, X.; Yan, Y.; Liu, N.; Li, T.; Yan, B.; Liu, B. HSP27 Inhibits Homocysteine-Induced Endothelial Apoptosis by Modulation of ROS Production and Mitochondrial Caspase-Dependent Apoptotic Pathway. Biomed. Res. Int. 2016, 2016, 4847874. [Google Scholar] [CrossRef]
- Forristal, C.E.; Nowlan, B.; Jacobsen, R.N.; Barbier, V.; Walkinshaw, G.; Walkley, C.R.; Winkler, I.G.; Levesque, J.P. HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α. Leukemia 2015, 29, 1366–1378. [Google Scholar] [CrossRef]
- Löffler, S.; Klimke, A.; Kronenwett, R.; Kobbe, G.; Haas, R.; Fehsel, K. Clozapine mobilizes CD34+ hematopoietic stem and progenitor cells and increases plasma concentration of interleukin 6 in patients with schizophrenia. J. Clin. Psychopharmacol. 2010, 30, 591–595. [Google Scholar] [CrossRef]
- Lindholm, M.E.; Fischer, H.; Poellinger, L.; Johnson, R.S.; Gustafsson, T.; Sundberg, C.J.; Rundqvist, H. Negative regulation of HIF in skeletal muscle of elite endurance athletes: A tentative mechanism promoting oxidative metabolism. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014, 307, R248–R255. [Google Scholar] [CrossRef]
- Zhang, N.; Yang, X.; Yuan, F.; Zhang, L.; Wang, Y.; Wang, L.; Mao, Z.; Luo, J.; Zhang, H.; Zhu, W.G.; et al. Increased Amino Acid Uptake Supports Autophagy-Deficient Cell Survival upon Glutamine Deprivation. Cell Rep. 2018, 23, 3006–3020. [Google Scholar] [CrossRef] [PubMed]
- Newman, J.C.; He, W.; Verdin, E. Mitochondrial protein acylation and intermediary metabolism: Regulation by sirtuins and implications for metabolic disease. J. Biol. Chem. 2012, 287, 42436–42443. [Google Scholar] [CrossRef] [PubMed]
- Finley, L.W.; Haas, W.; Desquiret-Dumas, V.; Wallace, D.C.; Procaccio, V.; Gygi, S.P.; Haigis, M.C. Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. PLoS ONE. 2011, 6, e23295. [Google Scholar] [CrossRef]
- Traba, J.; Geiger, S.S.; Kwarteng-Siaw, M.; Han, K.; Ra, O.H.; Siegel, R.M.; Gius, D.; Sack, M.N. Prolonged fasting suppresses mitochondrial NLRP3 inflammasome assembly and activation via SIRT3-mediated activation of superoxide dismutase 2. J. Biol. Chem. 2017, 292, 12153–12164. [Google Scholar] [CrossRef] [PubMed]
- Mills, E.L.; Kelly, B.; O’Neill, L.A.J. Mitochondria are the powerhouses of immunity. Nat. Immunol. 2017, 18, 488–498. [Google Scholar] [CrossRef] [PubMed]
- Tannahill, G.M.; Curtis, A.M.; Adamik, J.; Palsson-McDermott, E.M.; McGettrick, A.F.; Goel, G.; Frezza, C.; Bernard, N.J.; Kelly, B.; Foley, N.H.; et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 2013, 496, 238–242. [Google Scholar] [CrossRef] [PubMed]
- Androsova, L.V.; Kaleda, V.G.; Barkhatova, A.N.; Tsutsul’kovskaia, M.; Koliaskina, G. The effect of treatment on interleukin-1beta production in patients with first episode of juvenile psychosis. Zhurnal Nevrologii i Psikhiatrii Imeni SS Korsakova 2007, 107, 50–54. [Google Scholar]
- Trushina, E.; Nguyen, T.K.O.; Trushin, S. Modulation of Mitochondrial Function as a Therapeutic Strategy for Neurodegenerative Diseases. J. Prev. Alzheimers Dis. 2023, 10, 675–685. [Google Scholar] [CrossRef]
- Howes, O.D.; Bukala, B.R.; Beck, K. Schizophrenia: From neurochemistry to circuits, symptoms and treatments. Nat. Rev. Neurol. 2024, 20, 22–35. [Google Scholar] [CrossRef]
- Carboni, L.; Domenici, E. Proteome effects of antipsychotic drugs: Learning from preclinical models. Proteomics Clin. Appl. 2016, 10, 430–441. [Google Scholar] [CrossRef]
- Li, J.; Huang, Q.; Long, X.; Guo, X.; Sun, X.; Jin, X.; Li, Z.; Ren, T.; Yuan, P.; Huang, X.; et al. Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress. Oncogene 2017, 36, 4901–4912. [Google Scholar] [CrossRef] [PubMed]
- Uranova, N.A. Ultrastructure of the frontal cortex in response to leponex. Zhurnal Nevrologii i Psikhiatrii Imeni SS Korsakova 1986, 86, 1016–1021. [Google Scholar]
- Tagaya, M.; Arasaki, K. Regulation of Mitochondrial Dynamics and Autophagy by the Mitochondria-Associated Membrane. Adv. Exp. Med. Biol. 2017, 997, 33–47. [Google Scholar] [CrossRef]
- Rice, C.M.; Davies, L.C.; Subleski, J.J.; Maio, N.; Gonzalez-Cotto, M.; Andrews, C.; Patel, N.L.; Palmieri, E.M.; Weiss, J.M.; Lee, J.M.; et al. Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression. Nat. Commun. 2018, 9, 5099. [Google Scholar] [CrossRef]
- Delieu, J.M.; Badawoud, M.; Williams, M.A.; Horobin, R.W.; Duguid, J.K. Antipsychotic drugs result in the formation of immature neutrophil leucocytes in schizophrenic patients. J. Psychopharmacol. 2001, 15, 191–194. [Google Scholar] [CrossRef]
- Fujikawa, M.; Imamura, H.; Nakamura, J.; Yoshida, M. Assessing actual contribution of IF1, inhibitor of mitochondrial FoF1, to ATP homeostasis, cell growth, mitochondrial morphology, and cell viability. J. Biol. Chem. 2012, 287, 18781–18787. [Google Scholar] [CrossRef]
- Elmorsy, E.; Alelwani, W.; Kattan, S.; Babteen, N.; Alnajeebi, A.; Ghulam, J.; Mosad, S. Antipsychotics inhibit the mitochondrial bioenergetics of pancreatic beta cells isolated from CD1 mice. Basic. Clin. Pharmacol. Toxicol. 2021, 128, 154–168. [Google Scholar] [CrossRef] [PubMed]
- Panizzutti, B.; Bortolasci, C.C.; Spolding, B.; Kidnapillai, S.; Connor, T.; Martin, S.D.; Truong, T.T.T.; Liu, Z.S.J.; Gray, L.; Kowalski, G.M.; et al. Effects of antipsychotic drugs on energy metabolism. Eur. Arch. Psychiatry Clin. Neurosci, 2023; Epub ahead of print. [Google Scholar] [CrossRef]
- Amiri, S.; Dizaji, R.; Momeny, M.; Gauvin, E.; Hosseini, M.J. Clozapine attenuates mitochondrial dysfunction, inflammatory gene expression, and behavioral abnormalities in an animal model of schizophrenia. Neuropharmacology 2021, 187, 108503. [Google Scholar] [CrossRef] [PubMed]
- Ji, Y.; Chen, S.; Li, K.; Xiao, X.; Xu, T.; Zheng, S. Upregulated autocrine vascular endothelial growth factor (VEGF)/VEGF receptor-2 loop prevents apoptosis in haemangioma-derived endothelial cells. Br. J. Dermatol. 2014, 170, 78–86. [Google Scholar] [CrossRef]
- Jais, A.; Solas, M.; Backes, H.; Chaurasia, B.; Kleinridders, A.; Theurich, S.; Mauer, J.; Steculorum, S.M.; Hampel, B.; Goldau, J.; et al. Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity. Cell 2016, 166, 1338–1340. [Google Scholar] [CrossRef]
- Henning, U.; Löffler, S.; Krieger, K.; Klimke, A. Uptake of clozapine into HL-60 promyelocytic leukaemia cells. PharmacoPsychiatry 2002, 35, 90–95. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Fehsel, K.; Bouvier, M.-L.; Capobianco, L.; Lunetti, P.; Klein, B.; Oldiges, M.; Majora, M.; Löffler, S. Neuroreceptor Inhibition by Clozapine Triggers Mitohormesis and Metabolic Reprogramming in Human Blood Cells. Cells 2024, 13, 762. https://doi.org/10.3390/cells13090762
Fehsel K, Bouvier M-L, Capobianco L, Lunetti P, Klein B, Oldiges M, Majora M, Löffler S. Neuroreceptor Inhibition by Clozapine Triggers Mitohormesis and Metabolic Reprogramming in Human Blood Cells. Cells. 2024; 13(9):762. https://doi.org/10.3390/cells13090762
Chicago/Turabian StyleFehsel, Karin, Marie-Luise Bouvier, Loredana Capobianco, Paola Lunetti, Bianca Klein, Marko Oldiges, Marc Majora, and Stefan Löffler. 2024. "Neuroreceptor Inhibition by Clozapine Triggers Mitohormesis and Metabolic Reprogramming in Human Blood Cells" Cells 13, no. 9: 762. https://doi.org/10.3390/cells13090762