UCH-L1 inhibitor LDN-57444 hampers mouse oocyte maturation by regulating oxidative stress and mitochondrial function and reducing ERK1/2 expression

Abstract

Oocyte maturation is a prerequisite for successful fertilization and embryo development. Incomplete oocyte maturation can result in infertility. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) has been found to be implicated in oocyte maturation and embryo development. However, the cellular and molecular mechanisms of UCH-L1 underlying oocyte maturation have not been fully elucidated. In the present study, we observed that the introduction of UCH-L1 inhibitor LDN-57444 suppressed first polar body extrusion during mouse oocyte maturation. The inhibition of UCH-L1 by LDN-57444 led to the notable increase of reactive oxygen species (ROS) level, conspicuous reduction of glutathione (GSH) content and mitochondrial membrane potential (MMP), and blockade of spindle body formation. As a conclusion, UCH-L1 inhibitor LDN-57444 suppressed mouse oocyte maturation by improving oxidative stress, attenuating mitochondrial function, curbing spindle body formation and down-regulating ERK1/2 expression, providing a deep insight into the cellular and molecular basis of UCH-L1 during mouse oocyte maturation.

The Requirement of Ubiquitin C-Terminal Hydrolase L1 (UCHL1) in Mouse Ovarian Development and Fertility

“…The authors posit that this lack of developmental potential may result from impaired mitochondrial metabolism of UCHL1-deficient SSCs, and directly result from altered mitochondrial protein turnover. These findings are consistent with recent work utilizing chemical inhibition of UCHL1 in in vitro matured mouse oocytes, demonstrating aberrant maturation resulting from altered mitochondrial metabolism [68].…”

“…These findings are consistent with recent work utilizing chemical inhibition of UCHL1 in in vitro matured mouse oocytes, demonstrating aberrant maturation resulting from altered mitochondrial metabolism [64].…”

The requirement of ubiquitin C-terminal hydrolase L1 in mouse ovarian development and fertility

“…The authors posit that this lack of developmental potential may result from impaired mitochondrial metabolism of UCHL1-deficient SSCs, and directly result from altered mitochondrial protein turnover. These findings are consistent with recent work utilizing chemical inhibition of UCHL1 in in vitro matured mouse oocytes, demonstrating aberrant maturation resulting from altered mitochondrial metabolism [ 64 ].…”

Quantitative proteomic analysis after neuroprotective MyD88 inhibition in the retinal degeneration 10 mouse

“… 47 Adenomatous polyposis coli protein 2 (APC2), which regulates the response to ER stress, 48 and Uchl1, a neuroprotective ubiquitin carboxyl‐terminal hydrolase, 49 also regulates oxidative stress. 50 Chaperone proteins chaperonin 10 and Tcp1 51 were also upregulated in the MyD88‐inhibited mice. These data suggest the possibility that the MyD88 inhibitor stimulates chaperone and crystallin expression, potentially as a tissue‐protective response.…”