Chaperone-mediated insertion of mitochondrial import receptor TOM70 protects against diet-induced obesity

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. Latorre-Muro et al. show that the cytosolic chaperone PPID drives insertion of the mitochondrial import receptor TOM70 into the mitochondrial outer membrane, thereby regulating body temperature, glucose homeostasis and body weight in obese mice.