Zhai, Y.; Wang, T.; Han, J.; Wu, M.; Gong, M.; Li, W.; Zhang, Z.

The reproductive capacity declines markedly with female age in humans. Similarly, C. elegans exhibit a rapid age-dependent decline in fecundity shortly after reaching adulthood. Emerging evidence suggests a significant link between proteostasis disruption and reduced fertility in both worms and humans, but the regulatory mechanisms governing this connection are not fully understood. Here, we report that LMD-3, a LysM domain protein, regulates proteostasis and reproductive capacity in C. elegans. The deficiency of lmd-3 leads to striking defects in oxidation resistance and constitutively high cellular stress responses, such as ER stress response and cytosolic stress response. We demonstrate that lysosome-localized LMD-3 protein interacts with vitellogenin and V-type ATPase, which drives proton-transporting and lysosomal lumen acidification. LMD-3 regulation of lysosomal function is essential for maintaining yolk protein homeostasis and reproductive health. We also identify that vitamin B12 (meCbl) supplementation revert the fecundity decline of lmd-3 mutants by reducing oxidative stress and improving lysosomal function. Together, these findings emphasize the role of LMD-3 in sustaining protein homeostasis and oocyte quality control, and establish a model system to find potent therapeutic strategies to increase reproductive health.