A chaperone-assisted mechanism of outer mitochondrial membrane TOM70 insertion protective against diet-induced obesity

Outer mitochondrial membrane (OMM) proteins communicate with the cytosol and other organelles including the endoplasmic reticulum (ER) ^1,2 . This communication is important in thermogenic adipocytes to increase energy expenditure that controls body temperature and weight ^3,4 . However, the regulatory mechanisms of OMM protein insertion are poorly understood. Herein, stress-induced cytosolic chaperone PPID (peptidyl-prolyl isomerase D/cyclophilin 40/Cyp40) drives OMM insertion of the mitochondrial import receptor TOM70 regulating body temperature and weight in obese mice, and respiratory/thermogenic function in brown adipocytes. PPID PPIase activity and C-terminal tetratricopeptide repeats (TPR), which show specificity towards TOM70 core and C-tail domains, facilitate OMM insertion. Our results provide an unprecedented role for ER-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.