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Evaluation of mitochondria in mouse oocytes following cisplatin exposure
1Ovarian Biology Laboratory, Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia.
Background:
Cisplatin is a platinum-based chemotherapeutic that damages genomic DNA leading to cell death. It also damages mitochondrial DNA and induces high levels of mitochondrial reactive oxygen species (mtROS), further sensitising cells to apoptosis. Notably, immature oocytes are particularly vulnerable to cisplatin treatment, a common side effect of which is depletion of the primordial follicle reserve, leading to infertility and early menopause. Cisplatin is known to damage the DNA of oocytes, but the possibility that cisplatin also compromises oocyte survival and quality by damaging mitochondria, has not been investigated. To begin to address this question, neonatal mice were treated with saline or cisplatin (2 mg/kg or 4 mg/kg) and the short and long-term impacts on mitochondria in oocytes were characterised.
Results:
At 6 and 24 h after treatment, mitochondrial localisation, mass and ATP content in immature oocytes were similar between groups. However, TMRM staining intensity, a marker of mitochondrial membrane potential, was decreased in immature oocytes from cisplatin treated mice compared to saline treated controls, consistent with the induction of apoptosis. When mice were super ovulated 5 weeks after exposure, the number of mature oocytes harvested from cisplatin treated mice was significantly lower than controls. Mitochondrial localisation, mass, membrane potential and ATP levels showed no differences between groups.
Conclusions:
These findings suggest that mitochondrial dysfunction may contribute to the depletion of the ovarian reserve caused by cisplatin, but long-term impacts on mitochondria may be minimal as those immature oocytes that survive cisplatin treatment develop into mature oocytes with normal mitochondrial parameters.
Insights
Cisplatin chemotherapy damages immature oocytes, reducing mitochondrial membrane potential and leading to infertility. However, surviving oocytes develop normally, suggesting minimal long-term mitochondrial impact.
Area of Science:
- Reproductive biology
- Mitochondrial medicine
- Chemotherapy research
Background:
- Cisplatin, a chemotherapy drug, induces cell death by damaging DNA and mitochondria, leading to increased reactive oxygen species (ROS).
- Immature oocytes are particularly susceptible to cisplatin, resulting in infertility and early menopause due to primordial follicle depletion.
- The impact of cisplatin on oocyte mitochondria, beyond DNA damage, remains largely unexplored.
Purpose of the Study:
- To investigate the short-term and long-term effects of cisplatin on mitochondria in immature oocytes.
- To determine if cisplatin-induced mitochondrial damage contributes to oocyte loss and subsequent infertility.
Main Methods:
- Neonatal mice were treated with saline or varying doses of cisplatin (2 mg/kg or 4 mg/kg).
- Mitochondrial parameters including localization, mass, ATP content, and membrane potential (TMRM staining) were assessed in immature oocytes at 6 and 24 hours post-treatment.
- Oocyte quality and mitochondrial function were evaluated in mature oocytes 5 weeks after cisplatin exposure.
Main Results:
- Short-term cisplatin exposure (6-24h) decreased mitochondrial membrane potential in immature oocytes, indicating apoptosis induction.
- Five weeks post-treatment, cisplatin-exposed mice yielded significantly fewer mature oocytes compared to controls.
- No significant differences in mitochondrial localization, mass, membrane potential, or ATP levels were observed in mature oocytes from cisplatin-treated mice.
Conclusions:
- Mitochondrial dysfunction likely contributes to cisplatin-induced depletion of the ovarian reserve.
- While short-term mitochondrial damage occurs, surviving oocytes develop into mature oocytes with normal mitochondrial function, suggesting limited long-term effects.
