MAM‐Localized MANF Counteracts Microinflammatory Stress to Attenuate Mitochondrial Dysfunction and Cataractogenesis in High Myopia

Chronic microinflammation drives tissue degeneration, particularly in age‐related and metabolic diseases, yet how it disrupts inter‐organelle communication that leads to cellular failure remains largely unexplored. Utilizing highly myopic cataract (HMC) as a paradigm, we uncover a non‐canonical defense mechanism centered on mitochondria‐associated endoplasmic reticulum membranes (MAMs). Under microinflammatory stress, mesencephalic astrocyte‐derived neurotrophic factor (MANF), conventionally recognized as an ER‐resident protein, specifically localizes to MAMs in lens epithelial cells (LECs). At this critical interface, MANF acts as a metabolic sensor that safeguards calcium homeostasis by directly promoting the ubiquitin‐mediated degradation of the sarco/endoplasmic reticulum Ca 2 + ‐ATPase 2 (SERCA2). Microinflammation‐induced MANF deficiency triggers pathological SERCA2 accumulation, MAM hyperassembly, disrupted ER‐to‐mitochondria calcium coupling, profound oxidative stress, and mitochondrial bioenergetic collapse, culminating in LEC apoptosis. We validate this pathogenic cascade using human HMC specimens, a unilateral defocus‐induced high myopia model, and a novel lens‐specific Manf conditional knockdown mouse. Strikingly, in vivo AAV2‐mediated MANF gene delivery successfully normalizes MAM architecture, rescues mitochondrial function, and prevents cataractogenesis, demonstrating therapeutic reversibility. In summary, this study establishes the MANF‐SERCA2 axis at the MAM interface as a critical pathway linking microinflammation to organelle dysfunction and proposes this interaction as a promising therapeutic target for cataractogenesis and other microinflammation‐driven degenerations.