Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models.

Autor: Costa-Machado LF; Metabolic Syndrome Group - BIOPROMET. Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM + CSIC, E28049, Madrid, Spain.; Kaertor Foundation, EMPRENDIA Building, Floor 2, Office 4, Campus Vida, E-15706, Santiago de Compostela, Spain, E-15706, Santiago de Compostela, Spain.; BioFarma Research Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain., Garcia-Dominguez E; Freshage Research Group, Department of Physiology, Faculty of Medicine, CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, University of Valencia, Valencia, Spain., McIntyre RL; Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands., Lopez-Aceituno JL; Metabolic Syndrome Group - BIOPROMET. Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM + CSIC, E28049, Madrid, Spain., Ballesteros-Gonzalez Á; Developmental Biology and Disease Models Group, Centro de Investigación Príncipe Felipe, 46012, Valencia, Spain., Tapia-Gonzalez A; Neural Plasticity Group, Centro de Investigación Príncipe Felipe, 46012, Valencia, Spain., Fabregat-Safont D; Applied Metabolomics Research Group, Hospital del Mar Medical Research Institute - (IMIM), Barcelona, Spain.; Environmental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water, University Jaume I, 12006, Castelló de la Plana, Castellón, Spain., Eisenberg T; Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, 8010, Graz, Austria.; BioTechMed Graz, 8010, Graz, Austria.; Field of Excellence BioHealth - University of Graz, Graz, Austria., Gomez J; Confocal Microscopy Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain., Plaza A; Metabolic Syndrome Group - BIOPROMET. Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM + CSIC, E28049, Madrid, Spain., Sierra-Ramirez A; Metabolic Syndrome Group - BIOPROMET. Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM + CSIC, E28049, Madrid, Spain., Perez M; Confocal Microscopy Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain., Villanueva-Bermejo D; Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL UAM-CSIC), C/ Nicolás Cabrera, 9, P.O. Box. 28049, Madrid, Spain., Fornari T; Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL UAM-CSIC), C/ Nicolás Cabrera, 9, P.O. Box. 28049, Madrid, Spain., Loza MI; Kaertor Foundation, EMPRENDIA Building, Floor 2, Office 4, Campus Vida, E-15706, Santiago de Compostela, Spain, E-15706, Santiago de Compostela, Spain.; BioFarma Research Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain., Herradon G; Lab. Pharmacology, Faculty of Pharmacy, Universidad CEU San Pablo, Urb. Montepríncipe, 28668, Boadilla del Monte, Madrid, Spain., Hofer SJ; Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, 8010, Graz, Austria.; BioTechMed Graz, 8010, Graz, Austria.; Field of Excellence BioHealth - University of Graz, Graz, Austria., Magnes C; HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, 8010, Graz, Austria., Madeo F; Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, 8010, Graz, Austria.; BioTechMed Graz, 8010, Graz, Austria.; Field of Excellence BioHealth - University of Graz, Graz, Austria., Duerr JS; Department of Biological Sciences, Ohio University, Athens, OH, 45701, USA., Pozo OJ; Applied Metabolomics Research Group, Hospital del Mar Medical Research Institute - (IMIM), Barcelona, Spain., Galindo MI; Developmental Biology and Disease Models Group, Centro de Investigación Príncipe Felipe, 46012, Valencia, Spain.; Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Universitat de València, 46022, Valencia, Spain.; UPV-CIPF Joint Research Unit 'Disease Mechanisms and Nanomedicine'. Centro de Investigación Príncipe Felipe, 46012, Valencia, Spain., Del Pino I; Neural Plasticity Group, Centro de Investigación Príncipe Felipe, 46012, Valencia, Spain.; Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, Campus de Sant Joan, 03550, Alicante, Spain., Houtkooper RH; Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands., Megias D; Confocal Microscopy Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain., Viña J; Freshage Research Group, Department of Physiology, Faculty of Medicine, CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, University of Valencia, Valencia, Spain., Gomez-Cabrera MC; Freshage Research Group, Department of Physiology, Faculty of Medicine, CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, University of Valencia, Valencia, Spain., Fernandez-Marcos PJ; Metabolic Syndrome Group - BIOPROMET. Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM + CSIC, E28049, Madrid, Spain. pablojose.fernandez@imdea.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 May 15; Vol. 14 (1), pp. 2779. Date of Electronic Publication: 2023 May 15.
DOI: 10.1038/s41467-023-38410-y
Abstrakt: Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood-brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis.
(© 2023. The Author(s).)
Databáze: MEDLINE
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