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

Summary

This mechanistic study shows that the stress-induced chaperone PPID inserts TOM70 into the outer mitochondrial membrane, enhancing brown adipocyte respiration and thermogenesis. In obese mice, this mechanism protects body temperature regulation and mitigates weight gain, revealing an ER-stress–activated chaperone route for tuning energy metabolism.

Key Findings

• PPID drives outer mitochondrial membrane insertion of TOM70 via its PPIase activity and C-terminal TPR domains.
• Enhancing TOM70 insertion improves brown adipocyte respiratory/thermogenic function.
• In obese mice, the PPID–TOM70 pathway modulates body temperature and weight under cold and high-calorie conditions.

Clinical Implications

Although preclinical, targeting PPID–TOM70 insertion or its regulatory domains may offer novel strategies to boost adaptive thermogenesis in obesity and metabolic syndrome.

Limitations

• Preclinical model without human validation
• Safety and on-target specificity of manipulating PPID activity remain untested clinically

Future Directions

Validate PPID–TOM70 modulation in human adipocytes and delineate druggable nodes; assess cardio-metabolic safety and efficacy in higher organisms.