Immp2l Deficiency Induced Granulosa Cell Senescence Through STAT1/ATF4 Mediated UPR^mt and STAT1/(ATF4)/HIF1α/BNIP3...

Area of Science:

• Cellular and Molecular Biology
• Reproductive Biology
• Mitochondrial Biology

Background:

• Mitochondrial dysfunction and excessive reactive oxygen species (ROS) production are key drivers of ovarian aging.
• Immp2l deficiency leads to mitochondrial dysfunction, increased ROS, and granulosa cell senescence, contributing to ovarian aging.
• Mitochondrial proteostasis, including the unfolded protein response (UPRmt) and mitophagy, is critical for maintaining mitochondrial homeostasis and preventing ROS accumulation and senescence.

Purpose of the Study:

• To investigate the role of Immp2l in ovarian aging and the potential of enocyanin as a therapeutic agent.
• To elucidate the molecular mechanisms underlying Immp2l deficiency-induced granulosa cell senescence.
• To explore the impact of enocyanin on mitochondrial function, ROS levels, and related signaling pathways.

Main Methods:

• Generation and analysis of Immp2l-knockout mouse models.
• Assessment of granulosa cell senescence, mitochondrial function, and ROS production.
• Investigation of redox-related protein modifications (S-glutathionylation, S-nitrosylation) and STAT1 expression.
• Co-immunoprecipitation (Co-IP) assays to determine protein interactions and regulation.
• Analysis of unfolded protein response (UPRmt) and mitophagy pathways, including protein aggregation and mitophagosome-lysosome fusion.

Main Results:

• Immp2l knockout induced granulosa cell senescence, characterized by impaired mitochondrial function and elevated ROS.
• Enocyanin treatment ameliorated Immp2l deficiency-induced senescence, improving mitochondrial function and reducing ROS.
• Enocyanin modulated redox-related protein modifications and decreased STAT1 expression in Immp2l-knockout cells.
• STAT1 expression was regulated by S-glutathionylation and S-nitrosylation, not phosphorylation.
• UPRmt was impaired in Immp2l-deficient cells, leading to protein aggregation and ROS accumulation.
• Mitophagy was activated but impaired due to reduced mitophagosome-lysosome fusion, exacerbating mitochondrial dysfunction and senescence.

Conclusions:

• Enocyanin alleviates granulosa cell senescence in Immp2l-deficient mice by restoring mitochondrial function and reducing oxidative stress.
• Enocyanin acts through the STAT1/ATF4-mediated UPRmt and STAT1/(ATF4)/HIF1α/BNIP3-mediated mitophagy pathways.
• Targeting mitochondrial proteostasis pathways, particularly UPRmt and mitophagy, offers a promising therapeutic strategy for ovarian aging.