Uncoupling of ER/Mitochondrial Oxidative Stress in mTORC1 Hyperactivation-Associated Skin Hypopigmentation

Area of Science:

• Cell Biology
• Dermatology
• Molecular Biology

Background:

• mTORC1 signaling is implicated in pigmentation regulation, but its precise role remains unclear.
• TSC2 is a known suppressor of mTORC1 signaling.

Purpose of the Study:

• To investigate the role of mTORC1 signaling, specifically the suppressor TSC2, in regulating skin pigmentation in vivo.
• To elucidate the molecular mechanisms underlying mTORC1-mediated pigmentation changes.

Main Methods:

• Generated mice with conditional deletion of Tsc2 in melanocytes to induce mTORC1 hyperactivation.
• Assessed skin pigmentation, melanocyte number, melanogenesis-related enzyme expression, and cellular stress markers (ER and mitochondrial).
• Utilized pharmacological interventions (rapamycin, SMER28, PBA, ATP) to modulate mTORC1 and stress pathways.
• Examined human melanocytes and patient skin lesions with TSC2 mutations.

Main Results:

• Conditional deletion of Tsc2 in melanocytes led to mTORC1 hyperactivation and reduced skin pigmentation.
• Reduced pigmentation was associated with endoplasmic reticulum and mitochondrial oxidative stress and decreased melanosome melanization, not altered melanocyte count or enzyme expression.
• Rapamycin treatment completely reversed the pigmentation reduction.
• Alleviation of ER stress or mitochondrial oxidative stress partially reversed the reduced pigmentation.
• Similar mechanisms were observed in cultured human melanocytes and patient skin lesions.

Conclusions:

• mTORC1 hyperactivation in melanocytes impairs skin pigmentation through cellular stress pathways, particularly ER and mitochondrial oxidative stress, and affects melanosome maturation.
• Targeting mTORC1 or alleviating cellular stress represents potential therapeutic strategies for pigmentation disorders associated with TSC2 mutations.