MFN2-CD36 interaction regulates mitochondrial lipid digestion in cancer-associated fibroblasts and promotes esophageal squamous cell carcinoma progression

Le résumé fourni par la source

Stromal cells in the tumor microenvironment actively drive tumor progression, with cancer-associated fibroblasts (CAFs) representing its most abundant and functionally critical component. CAFs hijack the mitochondrial fusion pathway in esophageal squamous cell carcinoma (ESCC), promoting tumor progression by optimizing lipid metabolism and preserving mitochondrial integrity against damage from metabolic waste. Further investigation is needed to understand how tumor tissues avoid damage from substances, such as reactive oxygen species, while accumulating and absorbing lipids. This study investigates the hypothesis that mitochondria achieve lipophilic localization on the inner side of the cell membrane through the fatty acid transferase CD36 and promote mitochondrial fusion by interacting with mitofusin-2 (MFN2), thereby integrating smaller-volume mitochondria into larger ones that better withstand external stress and maintain mitochondrial bioactivity. We evaluated the interaction between MFN2 and CD36 using molecular simulations and amino acid mutations and screened compounds such as rosmarinic acid (RA) that inhibits this protein interaction. RA hinders CAF survival by disrupting the protective mitochondrial mechanisms. Our findings show that the MFN2-CD36 interaction enhances CAF energy metabolism and preserves mitochondrial activity. Thus, this study established that CD36 mediates the localization of CAF mitochondria to the cytoplasm and promotes lipid metabolism. CD36 enhances mitochondrial fusion by interacting with MFN2, thereby enabling CAFs to tolerate harmful damage during metabolic processes. Understanding how CD36 and MFN2 interact in CAFs can provide valuable references for clinical diagnosis and treatment of ESCC.

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