NET‐DNA Activates the ANXA2/TMEM215/BiP Axis to Promote Mitophagy‐Mediated Anoikis Resistance in Endometriosis
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
ABSTRACT Endometriosis (EMs) features ectopic implantation of endometrial stromal cells (EESCs) and strong anoikis resistance, yet how inflammatory signals reprogram mitochondrial function remains unclear. Here, neutrophil extracellular traps (NETs), particularly their DNA scaffold (NET‐DNA), are identified as enriched in early lesions and associated with enhanced mitophagy and EESCs survival. In primary human EESCs, NET‐DNA suppresses anoikis, increases mitochondrial membrane potential, decreases reactive oxygen species, and enhances ER–mitochondria contacts. NET‐DNA directly binds Annexin A2 (ANXA2), promotes its redistribution from the plasma membrane to the cytoplasm, and independently upregulates the ER‐resident transmembrane protein TMEM215. TMEM215 facilitates formation of a Ca2+‐dependent ANXA2–TMEM215 complex, enhancing ER–mitochondria contacts and PINK1/Parkin‐mediated mitophagy. Silencing ANXA2 or TMEM215 disrupts mitophagy, impairs mitochondrial Ca2+ handling, reduces ER–mitochondria contacts, and restores anoikis sensitivity. Proteomic analysis identifies Binding Immunoglobulin Protein (BiP/GRP78) as a TMEM215‐interacting partner, and NET‐DNA promotes assembly of a TMEM215–ANXA2–BiP complex that reinforces mitochondrial quality control. In mouse EMs models, knockdown of TMEM215 or ANXA2 reduces lesion growth and partially reverses LPS‐associated progression. These findings reveal a mechanism linking inflammation to mitochondrial reprogramming in EMs and suggest a
Abstract
ABSTRACT Endometriosis (EMs) features ectopic implantation of endometrial stromal cells (EESCs) and strong anoikis resistance, yet how inflammatory signals reprogram mitochondrial function remains unclear. Here, neutrophil extracellular traps (NETs), particularly their DNA scaffold (NET‐DNA), are identified as enriched in early lesions and associated with enhanced mitophagy and EESCs survival. In primary human EESCs, NET‐DNA suppresses anoikis, increases mitochondrial membrane potential, decreases reactive oxygen species, and enhances ER–mitochondria contacts. NET‐DNA directly binds Annexin A2 (ANXA2), promotes its redistribution from the plasma membrane to the cytoplasm, and independently upregulates the ER‐resident transmembrane protein TMEM215. TMEM215 facilitates formation of a Ca2+‐dependent ANXA2–TMEM215 complex, enhancing ER–mitochondria contacts and PINK1/Parkin‐mediated mitophagy. Silencing ANXA2 or TMEM215 disrupts mitophagy, impairs mitochondrial Ca2+ handling, reduces ER–mitochondria contacts, and restores anoikis sensitivity. Proteomic analysis identifies Binding Immunoglobulin Protein (BiP/GRP78) as a TMEM215‐interacting partner, and NET‐DNA promotes assembly of a TMEM215–ANXA2–BiP complex that reinforces mitochondrial quality control. In mouse EMs models, knockdown of TMEM215 or ANXA2 reduces lesion growth and partially reverses LPS‐associated progression. These findings reveal a mechanism linking inflammation to mitochondrial reprogramming in EMs and suggest a potential therapeutic target. NET‐DNA is enriched during early endometriotic lesion establishment and drives anoikis resistance by promoting an ANXA2–TMEM215–BiP axis. This pathway strengthens ER–mitochondria contacts, enhances PINK1/Parkin‐associated mitophagy, preserves mitochondrial homeostasis, and supports ectopic stromal cell survival, thereby facilitating lesion persistence and progression. advs75442-abs-0001 graphical