Authors
Yile Zhai, Tiantian Wang, Meixi Gong, Yuhan Liang, Wenfei Li, Xin Wang, Zhe Zhang
Published in
PloS one. Volume 21. Issue 10. Pages e0361215. Epub Oct 27, 2026.
Abstract
Reproductive longevity decline characterizes both natural aging and premature ovarian insufficiency (POI). While our previous work established C. elegans LMD-3 as a critical regulator of reproductive capacity, the in vivo consequences of specific clinical mutations remain unclear. Here, we modeled the POI-associated human NCOA7 W804C mutation by engineering the orthologous W690C substitution into the C. elegans lmd-3 locus. We demonstrate that this single-nucleotide substitution severely compromises LMD-3 protein stability and reduces transcript levels. This mutational destabilization is associated with profound systemic autophagic-lysosomal dysfunction, which impairs macromolecular degradation and leads to widespread proteotoxic accumulation of misfolded proteins. Coincident with these organismal defects, mutant animals exhibit an early-onset collapse in reproductive capacity driven by elevated germline apoptosis. Crucially, this pathology is consistent with reduced vitamin B12 availability; mecobalamin supplementation can mitigate the lysosomal block, restoring autophagic flux, proteostasis, and fecundity. These findings elucidate how a clinical mutation drives systemic lysosomal failure and reproductive decline, suggesting vitamin B12 supplementation as a promising metabolic intervention worth further translational exploration.
PMID:
42945204
Bibliographic data and abstract were imported from PubMed on 28 Oct 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 7
- Comments 0