POI-associated LMD-3 mutation impairs B12-regulated lysosomal function and reproductive capacity in C. elegans
Zhai, Y.; Wang, T.; Gong, M.; Li, W.; Wang, X.; Zhang, Z.
Show 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.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- eIF2B extends lifespan through inhibition of the integrated stress response 97%
- The 18S rRNA Methyltransferase DIMT-1 Regulates Lifespan in the Germline Later in Life 97%
- The ubiquitin ligase Hecw controls oogenesis and neuronal homeostasis by promoting the liquid state of ribonucleoprotein particles 97%
Similar papers in this journal
Similar papers in this journal
- fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans 96%
- Mechanical force of uterine occupation enables large vesicle extrusion from proteostressed maternal neurons 96%
- The Neuron-specific IIS/FOXO Transcriptome in Aged Animals Reveals Regulatory Mechanisms of Neuronal and Cognitive Aging 96%
Similar papers in this journal
- Lysosomal control of proteostasis and reproductive capacity by conserved LMD-3 protein in C. elegans 99%
- Persistent DNA damage rewires lipid metabolism and promotes histone hyperacetylation via MYS-1/Tip60. 96%
- Gut epithelium modifies enteric behaviors during nutritional adversity via distinct peptidergic signaling axes 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.