POI-associated LMD-3 mutation impairs B12-regulated lysosomal function and reproductive capacity in C. elegans

Abstract

Reproductive longevity decline is a key feature of aging and premature ovarian insufficiency (POI). While proteostasis collapse is implicated in reproductive aging, the molecular link remains elusive. Here, we engineered the clinically relevant W690C mutation into C. elegans lmd-3 gene, the human NCOA7 ortholog, to establish a valuable in vivo POI model. The mutation severely compromises LMD-3 protein stability and expression, leading to a profound collapse in reproductive capacity driven by germline apoptosis. We demonstrate that this defect drives catastrophic autophagic-lysosomal dysfunction, blocking degradation and causing proteotoxic accumulation of misfolded proteins. Crucially, we define this pathology as a functional B12 deficiency and show that mecobalamin (meCbl) supplementation successfully restores proteostasis. Together, these findings delineate a conserved genetic pathway from LMD-3 destabilization to reproductive failure and propose vitamin B12 as a readily translatable therapeutic intervention for age-related reproductive decline.