Adv Sci (Weinh). 2026 Jul 8:e76342. doi: 10.1002/advs.76342. Online ahead of print.
ABSTRACT
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 Ca2 +-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.
PMID:42419372 | DOI:10.1002/advs.76342