Cicuéndez, BeatrizMora, AlfonsoLópez, Juan AntonioCurtabbi, AndreaPérez-García, JavierPorteiro, BegoñaJimenez-Blasco, DanielLatorre-Muro, PedroVo, PaulaJerome, MadisonGómez-Santos, BeatrizRomero-Becerra, RafaelLeiva, MagdalenaRodríguez, ElenaLeón, MartaLeiva-Vega, LuisGómez-Lado, NoemiTorres, Jorge LHernández-Cosido, LourdesAguiar, PabloMarcos, MiguelJastroch, MartinDaiber, AndreasAspichueta, PatriciaBolaños, Juan PedroSpinelli, Jessica BPuigserver, PereEnriquez, José AntonioVázquez, JesúsFolgueira, CintiaSabio, Guadalupe2025-06-172025-06-172025-01-13Nat Commun. 2025 Jan 13;16(1):229.https://hdl.handle.net/20.500.12105/26759Obesity poses a global health challenge, demanding a deeper understanding of adipose tissue (AT) and its mitochondria. This study describes the role of the mitochondrial protein Methylation-controlled J protein (MCJ/DnaJC15) in orchestrating brown adipose tissue (BAT) thermogenesis. Here we show how MCJ expression decreases during obesity, as evident in human and mouse adipose tissue samples. MCJ mice, even without UCP1, a fundamental thermogenic protein, exhibit elevated BAT thermogenesis. Electron microscopy unveils changes in mitochondrial morphology resembling BAT activation. Proteomic analysis confirms these findings and suggests involvement of the eIF2α mediated stress response. The pivotal role of eIF2α is scrutinized by in vivo CRISPR deletion of eIF2α in MCJ mice, abrogating thermogenesis. These findings uncover the importance of MCJ as a regulator of BAT thermogenesis, presenting it as a promising target for obesity therapy.We thank Electron Microscopy Facility (Centro Nacional de Biotecnología, CSIC) for preparing samples (Epon embedding), obtaining the ultrathin sections and TEM visualization. The project that gave rise to these results received the support of a fellowship from” la Caixa” Foundation (ID 100010434). The fellowship code is LCF/BQ/DR21/11880010 to B.C. C.F was funded with Sara Borrell (CD19/ 00078), NNF23SA0083952-EASO/Novo Nordisk New Investigator Award in Basic Sciences 2023, EFSD/Lilly Young Investigator Award 2022, Society for Endocrinology/Early Career Grant 2022, FSEEN/ Jóvenes endocrinólogos 2022, EFSD/Novo Nordisk Rising Star 2024, IBSA Foundation Fellowship Endocrinology 2023. This work has been supported by the following projects: PMP21/00057 funded by the Instituto de Salud Carlos III (ISCIII) - European Union (FEDER/FSE) “Una manera de hacer Europa”/ “El FSE invierte en tu futuro”/ Next Generation EU and cofunded by the European Union / Plan de Recuperación, Transformación y Resiliencia (PRTR); PID2022-138525OB-I00 de la Agencia Estatal de Investigación 10.13039/501100011033, financiado por MICIU/AEI/10.13039/501100011033 fondos FEDER and EU, PDC2021-121147-I00 and PID2019-104399RB-I00 funded by MCIN/AEI/10.13039/501100011033 and the European Union “NextGenerationEU”/Plan de Recuperación Transformación y Resiliencia -PRTR; Grant RED2022-134397-T funded by MCIN/AEI/10.13039/501100011033 and, as appropriate, by “ERDF A way of making Europe”, by the “European Union” or by the “European Union NextGenerationEU/PRTR”; Fundación Jesús Serra; EFSD/Lilly Dr Sabio; 2017 Leonardo Grant BBVA Foundation (Investigadores-BBVA-2017); Comunidad de Madrid IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/BMD-373; Fundación AECC PROYE19047SABI. PreMed-Exp: PMP21/00057, PMP21/00113 Infraestructura de Medicina de Precisión asociada a la Ciencia y Tecnología IMPACT-2021, Instituto de Salud Carlos III (GS, JLT). The project leading to these results has received funding from the” la Caixa” Foundation under the project code “HR24-00581” (G.S). G.S is a Miembro Numerario of the RACVE. J.P-G was supported by the fellowship from” la Caixa” Foundation (ID 100010434), the fellowship code is LCF/BQ/DR24/12080018. A.C was supported by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement n. 713,673 and by Becas de doctorado INPhINIT “la Caixa” 2018. PLM acknowledges NIH NIDDK grant K99DK133502. M.M is supported by Instituto de Salud Carlos III (ISCIII) and the European Union project PI20/00743. P.A is supported by MCIU/AEI/FEDER, UE (PID2021-124425OB-I00) and Basque Government, Department of Education (IT1476-22) and PMP21/00080 de Medicina de Precisión asociada a la Ciencia y Tecnología IMPACT2021, Instituto de Salud Carlos III. J.P.B is funded by MICIU/AEI (PID2022-138813OB-I00), la Caixa Foundation (grant agreement LCF/PR/HR23/ 52430016), Instituto de Salud Carlos III (CB16/10/00282) and the European Union’s Horizon Europe research and innovation program under the MSCA Doctoral Networks 2021 (101072759; FuEl ThEbRaiN In healtThY aging and age-related diseases, ETERNITY), AEI grants PID2019-105699RB-I00, PID2022-138813OB-I00 and PDC2021-121013-I00; HORIZON-MSCA-2021-DN-01grant 101072759; and La Caixa Research Health grant HR23-00793. PP acknowledges NIH grant R01DK136640. JAE was supported by competitive grants: PID2021-127988OB-I00 funded by MCIN/AEI/10.13039/501100011033/ FEDER, UE; Human Frontier Science Program (grant RGP0016/2018), Leducq Transatlantic Networks (17CVD04) and CIBERFES [CB16/10/00282], Centro de Investigación Biomédica. Instituto de Salud Carlos III.The CNIO and CNIC are supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation) and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033).engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 International39805849Nature Communicationsopen access