biostudies-literatureCosta-Machado LFAustrian Science Fund FWFZonMwMinisterio de Educación, Cultura y DeporteFundación Científica Asociación Española Contra el CáncerGeneralitat ValencianaNIH HHS2779https://www.ebi.ac.uk/biostudies/studies/S-EPMC10185515biostudies-literatureUnknown14(1)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 mitNature communicationsPeripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models.PMC10185515W 1226MGS/2021/15CIDENGENT/2019/044P40 OD01044091715305LABAE18008FERNP 27893P 29203P 31727OP ERDFTAI 602P 33957P 29262Plaza AEisenberg TGomez-Cabrera MCDuerr JSVina JCosta-Machado LFHofer SJLoza MIVillanueva-Bermejo DMagnes CPerez MDel Pino IPozo OJGarcia-Dominguez EFornari THerradon GLopez-Aceituno JLMcIntyre RLGomez JTapia-Gonzalez ASierra-Ramirez AFernandez-Marcos PJFabregat-Safont DMadeo FBallesteros-Gonzalez AGalindo MIMegias DHoutkooper RHfalsePeripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models.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 mit2023-01-01T00:00:00Z2023 May2026-05-29T13:00:53.485Z2025-02-19T04:44:15.232ZS-EPMC101855153718870510.1038/s41467-023-38410-y