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

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  • dc.contributor.author Costa-Machado, Luis Filipe
  • dc.contributor.author Fabregat-Safont, David
  • dc.contributor.author Pozo Mendoza, Óscar J., 1975-
  • dc.contributor.author Fernandez-Marcos, Pablo J.
  • dc.date.accessioned 2024-04-04T06:26:08Z
  • dc.date.available 2024-04-04T06:26:08Z
  • dc.date.issued 2023
  • dc.description.abstract 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.
  • dc.description.sponsorship Work in the laboratory of P.J.F.-M. was funded by the IMDEA Food Institute, the Ramón Areces Foundation (CIVP18A3891), the AECC (SIRTBIO, LABAE18008FERN), the MICINN (SAF2017-85766-R and PRPPID2020-114077RB-I00) co-funded by the European Regional Development Fund, and a Ramon y Cajal Fellowship (MICINN, RYC-2017-22335). J.L.L.-A. was funded by the Spanish Ministry of Science and Innovation (MICINN) (PTA2017‐14689‐I). Work in FreshAge laboratory was funded by: Instituto de Salud Carlos III CB16/10/00435 (CIBERFES), (PID2019-110906RB-I00/AEI/10.13039/501100011033) from the Spanish Ministry of Innovation and Science; FGCSIC/PSLINTERREG/FEDER; PROMETEO/2019/097 de “Consellería de Sanitat de la Generalitat Valenciana” and EU Funded H2020- DIABFRAIL-LATAM (Ref: 825546). Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with ERDF funds (OP ERDF of Comunitat Valenciana). Support from Ramón Areces Fundation and Soria Melguizo Foundation is also acknowledged. E.G.-D. was a recipient of a predoctoral grant financed by the Spanish Ministry (FPU18/05350). Work in the laboratory of IdP was funded by the MICINN (RTI2018-100872-J-I00) and PlaGenT excellence research program of the Valencian regional government (CIDENGENT/2019/044). Work in the laboratory of M.-I.G. was funded by PROMETEU/2018/135 from “Consellería, de Sanitat de la Generalitat Valenciana” and part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with ERDF funds (OP ERDF of Comunitat Valenciana 2014–2020). F.M. is grateful to the Austrian Science Fund FWF (SFB-LIPOTOX F3007 & F3012, W1226, P29203, P29262, P27893, and P31727); the Austrian Federal Ministry of Education, Science and Research and the University of Graz for grants Unkonventionelle Forschung-InterFast and ysleep (BMWFW-80.109/0001-WF/V/3b/2015) and the field of excellence program BioHealth. We acknowledge support from NAWI Graz, the BioTechMed-Graz agship project EPIAge. T.E. acknowledges support from Austrian Science Fund FWF (P 33957 and TAI 602 1000). Work in the laboratory of R.H.H. was financially supported by a VIDI grant from ZonMw (no. 91715305). J.S.D. was supported by Ohio University. D.F.-S. acknowledges Ministerio de Universidades in Spain for his Margarita Salas postdoctoral grant (Ref. MGS/2021/15). The CGC group is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Costa-Machado LF, Garcia-Dominguez E, McIntyre RL, Lopez-Aceituno JL, Ballesteros-Gonzalez Á, Tapia-Gonzalez A et al. Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models. Nat Commun. 2023 May 15;14(1):2779. DOI: 10.1038/s41467-023-38410-y
  • dc.identifier.doi http://dx.doi.org/10.1038/s41467-023-38410-y
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/59646
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nat Commun. 2023 May 15;14(1):2779
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/825546
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-85766-R
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-114077RB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RYC-2017-22335
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-110906RB-I00
  • dc.rights © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Mechanisms of disease
  • dc.subject.keyword Mitochondria
  • dc.title Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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