Gas6 is a reciprocal regulator of mitophagy during mammalian oocyte maturation

Area of Science:

• Reproductive Biology
• Cellular Biology
• Mitochondrial Dynamics

Background:

• Growth arrest-specific gene 6 (Gas6) deficiency in oocytes previously linked to impaired cytoplasmic maturation and mitochondrial dysfunction.
• Oocyte competency is critical for successful fertilization and embryonic development.

Purpose of the Study:

• To investigate the role of Gas6 in regulating mitophagy and mitochondrial activity in oocytes.
• To elucidate the molecular mechanisms by which Gas6 influences oocyte maturation and competency.

Main Methods:

• RNA-sequencing (RNA-Seq) and reverse transcription-polymerase chain reaction (RT-PCR) analysis of Gas6-silenced oocytes.
• Assessment of mitochondrial proteins, mitophagy-related gene expression, and mitochondrial DNA (mtDNA) copy number.
• Pharmacological interventions including Rapamycin and Mdivi-1.

Main Results:

• Gas6 silencing decreased mitophagy-related gene expression and mtDNA copy number, while increasing mitochondrial proteins and Ptpn11.
• Gas6 depletion led to MTOR activation, mitochondrial accumulation, and mitophagy inhibition.
• Rapamycin treatment rescued mitophagy and normalized MTOR signaling in Gas6-depleted oocytes.
• Mdivi-1 treatment resulted in oocyte maturation but with mitochondrial accumulation and fertilization failure, mimicking Gas6 RNAi effects.

Conclusions:

• Gas6 signaling is crucial for controlling oocyte cytoplasmic maturation by modulating mitochondrial dynamics and activity.
• Gas6 regulates mitophagy, safeguarding mitochondrial function essential for oocyte competency.
• Dysregulation of Gas6-mediated mitophagy contributes to oocyte maturation defects and potential infertility.