Latorre-Muro Pedro, Vitale Tevis, Ravichandran Matthew, Zhang Katherine, Palozzi Jonathan M, Bennett Christopher F, Lamas-Paz Arantza, Sohn Jee Hyung, Jackson Thomas D, Jedrychowski Mark, Gygi Steven P, Kajimura Shingo, Schmoker Anna, Jeon Hyesung, Eck Michael J, Puigserver Pere
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Nat Cell Biol. 2025 Jan;27(1):130-140. doi: 10.1038/s41556-024-01555-z. Epub 2025 Jan 3.
Outer mitochondrial membrane (OMM) proteins communicate with the cytosol and other organelles, including the endoplasmic reticulum. This communication is important in thermogenic adipocytes to increase the energy expenditure that controls body temperature and weight. However, the regulatory mechanisms of OMM protein insertion are poorly understood. Here the stress-induced cytosolic chaperone PPID (peptidyl-prolyl isomerase D/cyclophilin 40/Cyp40) drives OMM insertion of the mitochondrial import receptor TOM70 that regulates body temperature and weight in obese mice, and respiratory/thermogenic function in brown adipocytes. PPID PPIase activity and C-terminal tetratricopeptide repeats, which show specificity towards TOM70 core and C-tail domains, facilitate OMM insertion. Our results provide an unprecedented role for endoplasmic-reticulum-stress-activated chaperones in controlling energy metabolism through a selective OMM protein insertion mechanism with implications in adaptation to cold temperatures and high-calorie diets.
线粒体外膜（OMM）蛋白与细胞质及包括内质网在内的其他细胞器进行通讯。这种通讯在产热脂肪细胞中对于增加控制体温和体重的能量消耗很重要。然而，人们对OMM蛋白插入的调控机制了解甚少。在这里，应激诱导的细胞质伴侣蛋白PPID（肽基脯氨酰异构酶D/亲环蛋白40/Cyp40）驱动线粒体导入受体TOM70插入OMM，该受体调节肥胖小鼠的体温和体重以及棕色脂肪细胞的呼吸/产热功能。PPID的肽基脯氨酰异构酶活性和C末端四肽重复序列，对TOM70的核心和C末端结构域具有特异性，促进了OMM插入。我们的研究结果揭示了内质网应激激活的伴侣蛋白通过选择性OMM蛋白插入机制在控制能量代谢中前所未有的作用，这对适应低温和高热量饮食具有重要意义。
