Absence of MCJ/DnaJC15 promotes brown adipose tissue thermogenesis

• Published in: Nature communications 2025-01, Vol.16 (1), p.229, Article 229
• Main Authors: Cicuéndez, Beatriz, Mora, Alfonso, López, Juan Antonio, Curtabbi, Andrea, Pérez-García, Javier, Porteiro, Begoña, Jimenez-Blasco, Daniel, Latorre-Muro, Pedro, Vo, Paula, Jerome, Madison, Gómez-Santos, Beatriz, Romero-Becerra, Rafael, Leiva, Magdalena, Rodríguez, Elena, León, Marta, Leiva-Vega, Luis, Gómez-Lado, Noemi, Torres, Jorge L., Hernández-Cosido, Lourdes, Aguiar, Pablo, Marcos, Miguel, Jastroch, Martin, Daiber, Andreas, Aspichueta, Patricia, Bolaños, Juan Pedro, Spinelli, Jessica B., Puigserver, Pere, Enriquez, José Antonio, Vázquez, Jesús, Folgueira, Cintia, Sabio, Guadalupe
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/31; 13/89; 14; 14/28; 38; 38/77; 38/89; 38/90; 38/91; 59; 631/80/304; 64; 64/60; 692/163/2743/393; 82/1; 82/80; 82/81; Adipose tissue; Adipose tissue (brown); Adipose Tissue, Brown - metabolism; Animal tissues; Animals; Body fat; Comorbidity; CRISPR; Electron microscopy; Eukaryotic Initiation Factor-2 - genetics; Eukaryotic Initiation Factor-2 - metabolism; Female; Gene deletion; Global health; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; Humanities and Social Sciences; Humans; In vivo methods and tests; J protein; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; multidisciplinary; Obesity; Obesity - genetics; Obesity - metabolism; Proteins; Proteomics; Public health; Science; Science (multidisciplinary); Thermogenesis; Thermogenesis - genetics; Uncoupling Protein 1 - genetics; Uncoupling Protein 1 - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54353-4

Obesity 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 KO 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 KO 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. How adipose mitochondria activity is fine-tuned in response to obesity is an active area of study. Here, the authors show that mitochondrial protein MCJ can block thermogenesis and that silencing this gene can correct obesity-related comorbidities.