Immp2l Deficiency Induced Granulosa Cell Senescence Through STAT1/ATF4 Mediated UPR[sup.mt] and STAT1//HIF1α/BNIP3 Mediated Mitophagy: Prevented by Enocyanin

• Published in: International journal of molecular sciences 2024-10, Vol.25 (20)
• Main Authors: Qu, Xiaoya, Pan, Pengge, Cao, Sinan, Ma, Yan, Yang, Jinyi, Gao, Hui, Pei, Xiuying, Yang, Yanzhou
• Format: Article
• Language: English
• Subjects: Ethylenediaminetetraacetic acid; Proteins
• ISSN: 1422-0067
• DOI: 10.3390/ijms252011122

Dysfunctional mitochondria producing excessive ROS are the main factors that cause ovarian aging. Immp2l deficiency causes mitochondrial dysfunction and excessive ROS production, leading to ovarian aging, which is attributed to granulosa cell senescence. The pathway controlling mitochondrial proteostasis and mitochondrial homeostasis of the UPR[sup.mt] and mitophagy are closely related with the ROS and cell senescence. Our results suggest that Immp2l knockout led to granulosa cell senescence, and enocyanin treatment alleviated Immp2l deficiency-induced granulosa cell senescence, which was accompanied by improvements in mitochondrial function and reduced ROS levels. Interestingly, redox-related protein modifications, including S-glutathionylation and S-nitrosylation, were markedly increased in Immp2l-knockout granulosa cells, and were markedly reduced by enocyanin treatment. Furthermore, STAT1 was significantly increased in Immp2l-knockout granulosa cells and reduced by enocyanin treatment. The co-IP results suggest that the expression of STAT1 was controlled by S-glutathionylation and S-nitrosylation, but not phosphorylation. The UPR[sup.mt] was impaired in Immp2l-deficient granulosa cells, and unfolded and misfolded proteins aggregated in mitochondria. Then, the HIF1α/BNIP3-mediated mitophagy pathway was activated, but mitophagy was impaired due to the reduced fusion of mitophagosomes and lysosomes. The excessive aggregation of mitochondria increased ROS production, leading to senescence. Hence, Enocyanin treatment alleviated granulosa cell senescence through STAT1/ATF4-mediated UPR[sup.mt] and STAT1/(ATF4)/HIF1α/BNIP3-mediated mitophagy.