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

Abstract 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 weight3,4. 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.