MCJ/DnaJC15缺失促进棕色脂肪组织产热。

Absence of MCJ/DnaJC15 promotes brown adipose tissue thermogenesis.

作者信息

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

机构信息

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

Organ Crosstalk in Metabolic Diseases Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.

出版信息

Nat Commun. 2025 Jan 13;16(1):229. doi: 10.1038/s41467-024-54353-4.

DOI:10.1038/s41467-024-54353-4

PMID:39805849

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11730624/

Abstract

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 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.

摘要

肥胖构成了一项全球性的健康挑战，需要对脂肪组织（AT）及其线粒体有更深入的了解。本研究描述了线粒体蛋白甲基化控制的J蛋白（MCJ/DnaJC15）在协调棕色脂肪组织（BAT）产热中的作用。在此我们展示了在肥胖过程中MCJ表达如何降低，这在人类和小鼠脂肪组织样本中很明显。MCJ小鼠即使没有UCP1（一种基本的产热蛋白），也表现出BAT产热增加。电子显微镜揭示了线粒体形态的变化，类似于BAT的激活。蛋白质组学分析证实了这些发现，并表明eIF2α介导的应激反应参与其中。通过在MCJ小鼠体内对eIF2α进行CRISPR缺失来仔细研究eIF2α的关键作用，结果消除了产热。这些发现揭示了MCJ作为BAT产热调节因子的重要性，使其成为肥胖治疗的一个有前景的靶点。