The role of Atp6v0d2 deficiency in Mcoln1-deficient mice

Lysosomes play a crucial role in degrading macromolecules and maintaining cellular homeostasis. Disruptions in lysosomal function can lead to lysosomal storage disorders, such as mucolipidosis type IV (MLIV), which is characterized by neurodegeneration, vision loss, and infertility. Previous research demonstrated that female mice lacking the gene Mcoln1, which encodes lysosomal protein TRPML1, become infertile by five months of age due to degeneration of the corpus luteum (CL).

Based on these previous findings, researchers at the University of Georgia proposed that a deficiency in another gene, Atp6v0d2, could partially compensate for the loss of Mcoln1 and might help restore fertility. This gene encodes a subunit of the vacuolar-type H⁺-ATPase (V-ATPase), an enzyme that pumps hydrogen ions into lysosomes. The study was published in Reproductive and Developmental Medicine recently.

To test this hypothesis, the research team developed a double-knockout mouse model by simultaneously deleting both the Atp6v0d2 and Mcoln1 genes in female mice (Atp6v0d2^-/-Mcoln1^-/-). They then observed the fertility of these mice from the age of two to seven months and compared their findings to control mice with normal gene expression.

The results were both intriguing and promising. The double-knockout mice exhibited normal mating behavior but had reduced fertility compared to the controls. However, about 25% of the double-knockout mice remained fertile at five to seven months of age, and some of these mice also showed normal levels of progesterone (P4).

For MLIV patients and Mcoln1^-/- mice, TRPML1 deficiency in cells results in lysosomal acidification due to the accumulation of H⁺ ions in the lysosomal lumen. Prof. Xiaoqin Ye, the corresponding author, explained, "If the V-ATPase is impaired in pumping H⁺ into the lysosomal lumen, there will be less H⁺ accumulation. This reduction could enhance lysosomal functions by restoring lysosomal ionic homeostasis and membrane potential."

Through examining the morphology of CL, they found that while cell survival was restored in most double-knockout mice, only those with normal P4 levels exhibited fully restored luteal cell differentiation.

Although the mechanisms underlying the various effects remain to be investigated, this study provides in vivo genetic evidence for the coordination between different lysosomal channels in CL function.