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Increased ROS levels in mitochondrial outer membrane protein Mul1-deficient oocytes result in abnormal
Ann Nakai1, Yuki Fukushima1, Ayaka Yamamoto1
1Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women's University, Japan.
Abstract:
Reactive oxygen species (ROS) are associated with oocyte maturation inhibition, and N-acetyl-l-cysteine (NAC) partially reduces their harmful effects. Mitochondrial E3 ubiquitin ligase 1 (Mul1) localizes to the mitochondrial outer membrane. We found that female Mul1-deficient mice are infertile, and their oocytes contain high ROS concentrations. After fertilization, Mul1-deficient embryos showed a DNA damage response (DDR) and abnormal preimplantation embryogenesis, which was rescued by NAC addition and ROS depletion. These observations clearly demonstrate that loss of Mul1 in oocytes increases ROS concentrations and triggers DDR, resulting in abnormal preimplantation embryogenesis. We conclude that manipulating the mitochondrial ROS levels in oocytes may be a potential therapeutic approach to target infertility.
Insights
Mitochondrial E3 ubiquitin ligase 1 (Mul1) deficiency in mice causes infertility due to increased reactive oxygen species (ROS) in oocytes. Restoring ROS levels improved embryo development, suggesting a therapeutic target for infertility.
Area of Science:
- Reproductive biology
- Mitochondrial biology
- Cellular stress response
Background:
- Reactive oxygen species (ROS) negatively impact oocyte maturation and fertility.
- N-acetyl-l-cysteine (NAC) can mitigate some harmful effects of ROS.
- Mitochondrial E3 ubiquitin ligase 1 (Mul1) is a key mitochondrial protein.
Purpose of the Study:
- To investigate the role of Mul1 in oocyte quality and early embryogenesis.
- To determine if Mul1 deficiency-induced infertility is linked to ROS accumulation.
- To explore NAC and ROS depletion as potential rescue strategies.
Main Methods:
- Generation and analysis of Mul1-deficient mice and their oocytes.
- Assessment of ROS levels, DNA damage response (DDR), and preimplantation embryogenesis.
- In vitro rescue experiments using NAC and ROS depletion.
Main Results:
- Mul1-deficient female mice exhibit infertility with elevated oocyte ROS levels.
- Mul1 deficiency triggers DDR and impairs preimplantation embryo development.
- NAC treatment and ROS reduction rescue these developmental defects.
Conclusions:
- Loss of Mul1 in oocytes leads to increased ROS, DDR, and impaired embryogenesis, causing infertility.
- Targeting mitochondrial ROS in oocytes presents a potential therapeutic strategy for infertility.
