deficiency partially restores defects in -deficient mouse corpus luteum.

Objective: ATP6V0d2 is a subunit of the vacuolar-type H-ATPase (V-ATPase) that pumps H ions into lysosomes. TRPML1 (/) transports cations out of lysosomes. mice recapitulate the lysosomal storage disorder mucolipidosis type IV (MLIV) phenotype. We previously demonstrated that female mice quickly became infertile at 5 months old (5M) with degenerating corpora lutea (CL) and progesterone (P4) deficiency. We tested our hypothesis that deficiency could partially compensate for deficiency to restore CL functions in mice.

Methods: Control and female mice underwent fertility test from 2M to 7M. A subset of them was dissected at 5M on day 3.5 post-coitum (D3.5). The D3.5 ovaries from 5M control, , and mice were evaluated for CL morphology, lipid droplet staining, and markers of mitochondria and P4 steroidogenesis in the luteal cells.

Results: The fertility test of female mice (2M-7M) revealed normal mating activity but reduced fertility compared with the control; yet ~25% of them remained fertile at 5M to 7M but with dystocia. We analyzed a subset of 11 mice (5M) in the fertility test on D3.5: three (27.3%) had normal P4 levels and all examined CL parameters, indicating full restoration of CL function compared with , whereas eight had P4 deficiency, with two (18.2%) infertile and six (54.5%) once fertile. In contrast to CLs, which had extensive amorphous cellular debris, indicating cell degeneration, CLs had reduced amorphous cellular debris regardless of P4 levels. However, similar to CLs, P4-deficient CLs showed impaired differentiation, enlarged lipid droplets, disorganized expression of endothelial basal lamina marker collagen IV, and reduced expression of mitochondrial marker heat shock protein 60 (HSP60) and steroidogenesis rate-limiting protein StAR, indicating that additional deficiency compensates for deficiency-induced cell degeneration, but is insufficient to restore luteal cell differentiation and P4 steroidogenesis in P4-deficient CLs.

Conclusion: This study shows that CLs had varied improvements compared with CLs, and it provides genetic evidence of the coordination between different lysosomal channels in CL function.