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Peer-reviewedCC BY 4.0PLOS One

A premature ovarian insufficiency-associated LMD-3 point mutation impairs protein stability and causes autophagic-lysosomal dysfunction in Caenorhabditis elegans

  • Yile Zhai1
  • Tiantian Wang2
  • Meixi Gong2
  • Yuhan Liang2
  • Wenfei Li2
  • Xin Wang3
  • Zhe Zhang1,2
  1. 1Institute of Medical Sciences, The Second Qilu Hospital of Shandong University, Jinan, Shandong, China
  2. 2Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
  3. 3State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, Yunnan, China
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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.

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Cite

BibTeXRIS
BibTeX
@article{zhai2026premature,
  title = {{A premature ovarian insufficiency-associated LMD-3 point mutation impairs protein stability and causes autophagic-lysosomal dysfunction in Caenorhabditis elegans}},
  author = {Yile Zhai and Tiantian Wang and Meixi Gong and Yuhan Liang and Wenfei Li and Xin Wang and Zhe Zhang},
  journal = {PLOS One},
  year = {2026},
  month = oct,
  doi = {10.1371/journal.pone.0361215},
  url = {https://doi.org/10.1371/journal.pone.0361215},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A premature ovarian insufficiency-associated LMD-3 point mutation impairs protein stability and causes autophagic-lysosomal dysfunction in Caenorhabditis elegans
AU  - Yile Zhai
AU  - Tiantian Wang
AU  - Meixi Gong
AU  - Yuhan Liang
AU  - Wenfei Li
AU  - Xin Wang
AU  - Zhe Zhang
PY  - 2026
DA  - 2026/10/27
JO  - PLOS One
DO  - 10.1371/journal.pone.0361215
UR  - https://doi.org/10.1371/journal.pone.0361215
AB  - 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.
SN  - 1932-6203
ER  -