Repression of oxidative phosphorylation by NR2F2, MTERF3 and GDF15 in human skin under high-glucose stress

Le résumé fourni par la source

Lifestyle factors such as a Western diet or metabolic diseases like diabetes disrupt glucose homeostasis and induce stress responses, yet their impact on skin metabolism and structural integrity remains poorly understood. Here, we performed multiomic and bioenergetic analyses of human dermal fibroblasts (HDFs), human equivalent dermis (HED), human reconstructed skin (HRS), and skin explants from diabetic patients. We found that 12 mM glucose stress represses oxidative phosphorylation (OXPHOS) through a dual mechanism: the glucose-dependent nuclear receptor NR2F2 activates mitochondrial transcription termination factor 3 (MTERF3) while inhibiting growth-differentiation factor 15 (GDF15). Promoter assays revealed that MTERF3 is regulated by NR2F2 and MYCN, whereas GDF15 is modulated by NR2F2 and FOS. Consequently, OXPHOS proteins and mitochondrial respiration were suppressed, and MTERF3 overexpression additionally interfered with collagen biosynthesis. In contrast, GDF15 supplementation fully rescued hyperglycemia-induced bioenergetic and metabolomic alterations, suggesting a pharmacological strategy to mitigate hyperglycemic damage in the skin. Finally, silencing GDF15 or TFAM impaired fibroblast haptotaxis and skin reconstruction, underscoring the crucial role of mitochondrial energetics in dermal structure and function. Collectively, these findings identify the NR2F2–MTERF3–GDF15 axis as a key mediator of OXPHOS suppression and highlight a potential therapeutic target to preserve skin integrity under hyperglycemic stress. We identify the NR2F2-GDF15-MTERF3 axis as a key regulatory mechanism that represses oxidative phosphorylation in human skin under high-glucose stress. This repression profoundly impacts collagen organization and overall skin physiology. By integrating both bioenergetic and structural responses, the NR2F2-GDF15-MTERF3 axis supports skin resilience, enabling tissues to adapt to hyperglycemia. These findings reveal new insights into how skin homeostasis is maintained under metabolic stress and highlight potential therapeutic targets for improving skin integrity in hyperglycemic conditions. • 12 mM glucose stress represses oxidative phosphorylation in human dermis and reconstructed skin. • NR2F2 activates MTERF3 and inhibits GDF15 upon hyperglycemia. • NR2F2, FOS, MYCN, ATF3 and ATF4 combine to repress OXPHOS in human skin. • Nanomolar GDF15 supplementation activates mitochondrial respiration in the dermis. • GDF15 silencing abolishes human skin reconstruction and alter mitochondrial network.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.