Researchers model premature ovarian insufficiency mutation in C. elegans, identifying lysosomal dysfunction and rescue by vitamin B12

A study in C. elegans demonstrates that modeling a human premature ovarian insufficiency-associated mutation causes systemic autophagic-lysosomal dysfunction and reproductive decline, which can be mitigated via vitamin B12 supplementation.

Researchers modeled the premature ovarian insufficiency (POI)-associated human NCOA7 W804C mutation by engineering the orthologous W690C substitution into the C. elegans lmd-3 locus.

The single-nucleotide substitution severely compromised LMD-3 protein stability and reduced transcript levels, driving systemic autophagic-lysosomal dysfunction and proteotoxic accumulation of misfolded proteins.

Mutant animals exhibited an early-onset collapse in reproductive capacity driven by elevated germline apoptosis.

Mecobalamin (vitamin B12) supplementation mitigated the lysosomal block, restoring autophagic flux, proteostasis, and fecundity in the mutant organisms.

The findings establish a direct mechanistic link between clinical POI mutations, systemic lysosomal failure, and reproductive decline.

By showing that vitamin B12 supplementation can bypass the lysosomal block and restore germline viability, the study highlights a promising, readily accessible metabolic intervention for translational exploration in ovarian aging.

This discovery highlights reproductive aging as a systemic metabolic and proteostatic challenge, expanding potential therapeutic angles beyond localized ovarian signaling.

The success of a simple metabolic cofactor in rescuing genetically driven lysosomal failure may encourage broader screening of dietary and metabolic interventions within the reproductive longevity field.

In vivo validation studies in mammalian models to confirm whether the NCOA7 mutation causes identical autophagic failure in mammalian oocytes, and whether mecobalamin can preserve ovarian reserves in mice.